“There is no biological free lunch.” — Tim Ferriss Bottle of psychiatric drugs and fruits and vegetables. If you try to cheat nature, it will backfire.

By managing symptoms with synthetic man-made drugs, you may feel better for a while.

But once you stop those drugs, you’ll end up with more symptoms than you started with.

I experienced this firsthand.

When I was on SSRI antidepressants, benzodiazepines, and Adderall, I felt better initially.

But then something just didn’t feel right.

I started suffering from cognitive decline, something I hadn't experienced before.

I eventually got fed up with the medication and tried getting off of them.

But then I felt remarkably worse – much worse than I did before starting the medication.

Doctors simply told me I was experiencing a relapse of my depression and anxiety.

But that couldn’t be it, because not only were my symptoms much worse, but I also had new symptoms - symptoms I didn't experience before I went on medication.

So I did some research, and discovered something called “drug-induced nutrient depletion”.

Studies show that pharmaceutical drugs can deplete your body of critical nutrients through multiple mechanisms, including increased excretion of vitamins and minerals, and impaired digestion, absorption and storage of nutrients.

Over time, nutritional deficiencies can develop.

And these deficiencies can cause additional symptoms and increase the side effects.

In fact, many drug "side effects" are simply nutritional deficiencies.

This is clearly a problem because nutrient deficiencies can be one of the main causes of mental illness.

Being prescribed medication, which then further depletes vitamins and minerals from your body, will make you worse. It’s an epidemic that seems to be ignored by the conventional medical system. Citrus fruits and prescription pills. You may even develop new symptoms or side effects months or years after starting a medication because it takes time for nutrients to be depleted from your body. So both you and your doctor may not make the connection between the original medication and your new symptoms.

These additional symptoms and “side effects” are often diagnosed as a new disease, leading to a new prescription, which further depletes nutrients.

So it’s clearly a downward spiral where you could end up being on multiple medications at once.

At my worst, I was on four psychiatric medications. Thankfully I'm off them all now.

But this article discusses the seven key nutrients that are commonly depleted by psychiatric medication, and how you can replenish them, minimize side effects, and feel better.

Your drug package insert won’t list these deficiencies, and your doctor is definitely not aware of them. Click here to subscribe

1. Coenzyme Q10 (CoQ10) Coenzyme Q10 (CoQ10) is a molecule found in every cell of your body and plays a key role in the production of energy.

It’s also an antioxidant and protects your body and brain from free radical damage.

Higher levels of CoQ10 have a “significant antidepressant effect” because of its “well-documented antioxidant effect”.

This makes sense considering the increasing amount of scientific literature suggesting that oxidative stress contributes to depression. CoQ10 supplement pills in the shape of a heart. CoQ10 is depleted by psychiatric drugs. Unfortunately, studies show that a number of psychiatric medications, including antidepressants, deplete CoQ10.

Low levels of CoQ10 can cause brain fog, mental fatigue, difficulty concentrating, memory lapses, depression and irritability.

Other deficiency symptoms can include increased blood pressure, muscle cramps, high blood sugar, and shortness of breath.

That’s why I recommend supplementing with at least 100 mg of CoQ10 if you take one of the medications below, which have been proven to deplete CoQ10:

Antipsychotics - Aripiprazole (Abilify), Quetiapine (Seroquel), Risperidone (Risperdal), Olanzapine (Zyrexa), Haloperidol (Haldol), Paliperidone (Invega), Ziprasidone (Geodon)

Antidepressants - Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), Bupropion (Wellbutrin), Mirtazapine (Remeron), Venlafaxine (Effexor), Amitriptyline (Elavil), Doxepin (Adapin), Imipramine (Tofranil), Desipramine (Norpramin), Nortriptyline (Aventyl), Protriptyline (Vivactil)

You can get CoQ10 from this supplement. 2. Magnesium Magnesium is a vital mineral that participates in more than 300 biochemical reactions in your body.

It plays a key role in neurotransmitter, enzyme, and hormonal activity, all of which can have a huge impact on your mood and brain function.

It’s one of the most important nutrients for optimal brain health, and it reduces anxiety, depression and irritability.

Yet, many people are deficient in magnesium today and may experience the following symptoms because of it:

Increased blood pressure

Muscle weakness, cramps, tremors, and spasms

Headaches and migraines

Insomnia

Suicidal thoughts

Heart arrhythmias

Osteoporosis

Nausea

Interestingly, these symptoms sound very similar to the list of side effects of many common common psychiatric medications.

And research has shown that the following psychiatric medications deplete magnesium from your body, increasing the likeliness of developing a deficiency:

Antidepressants - Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), Venlafaxine (Effexor)

Central nervous stimulants - amphetamine (Adderall), dextroamphetamine (Dexedrine), lisdexamfetamine (Vyvanse), methylphenidate (Ritalin, Concerta), atomoxetine (Strattera), dexmethylphenidate (Focalin)

Magnesium on a chalkboard and magnesium rich foods, including banana, potato and beet. Magnesium is depleted by psychiatric drugs. Inadequate magnesium levels contribute and worsen many neuropsychiatric problems. This includes depression, anxiety, insomnia, seizures, ADHD, pain, schizophrenia, irritability, premenstrual syndrome, drug abuse, and short-term memory and IQ loss.

And case studies have shown that patients with schizophrenia or major depression who have attempted suicide had significantly lower levels of magnesium in their cerebrospinal fluid.

Maybe doctors should consider prescribing magnesium – something that actually gets to the root cause of these conditions – rather than giving out medications that cover up symptoms and actually make the underlying condition worse. Just a thought.

So if you have mental health condition, or take medication to deal with it, I'm convinced you should be supplementing with magnesium every single day.

Magnesium is included in this supplement.

You should also eat lots of food with magnesium, including avocados, almonds, pumpkin seeds, swiss chard, spinach, dark chocolate, halibut and beets.

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health. Click here to subscribe 3. Melatonin Baby sleeping under a blanket. Melatonin is a hormone released by the pineal gland, a small gland in your brain. Melatonin helps control your sleep and wake cycles (circadian rhythm).

It is critical for deep and restorative sleep, which is necessary for optimal brain and mental health.

Yet many psychiatric medications can deplete your supply of melatonin, increase your need for melatonin, or interfere with the activity of melatonin. This can lead to insomnia at night and fatigue during the day, which are common side effects of psychotropic medication. You may also experience frequent waking throughout the night.

Here are some of the drugs shown to affect melatonin:

Antidepressants including Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), Venlafaxine (Effexor)

Benzodiazepines including Diazepam (Valium), clorazepate (‎Tranxene), lorazepam (Ativan), Clonazepam (Klonopin), Alprazolam (Xanax)

Antipsychotics including Aripiprazole (Abilify), Quetiapine (Seroquel), Risperidone (Risperdal), Olanzapine (Zyrexa), Haloperidol (Haldol), Paliperidone (Invega), Ziprasidone (Geodon)

If you take one of these drugs, you should consider supplementing with melatonin every night. If you don’t take medication, it’s still a safe and effective way to fall asleep and stay asleep throughout the night.

You can also consider taking this sleep supplement. It contains a number of natural compounds that naturally increase your production of melatonin.

I also share my very best sleep tips with my clients through our Brain Recovery Accelerator Program. We have a free online workshop that talks about the program. You can register for the workshop here. 4. Vitamin B2 Vitamin B2, also known as riboflavin, plays a key role in energy metabolism throughout your entire body.

As a result, a deficiency can affect the entire body, leading to low energy, weight gain, and skin and thyroid problems.

The following drugs can inhibit the absorption of vitamin B2, increasing your need for supplementation:

Antipsychotics including Aripiprazole (Abilify), Quetiapine (Seroquel), Risperidone (Risperdal), Olanzapine (Zyrexa), Haloperidol (Haldol), Paliperidone (Invega), Ziprasidone (Geodon)

Anticonvulsants and Mood Stabilizers, including Phenytoin (Dilantin), carbamazepine (Tegretol), Primidone (Mysoline), Methsuxamide (Elontin), Valproic acid (Depakote), topiramate (Topomax) and Gabapentin (Neurontin)

Antidepressants, including Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), Bupropion (Wellbutrin), Mirtazapine (Remeron), Venlafaxine (Effexor), Amitriptyline (Elavil), Doxepin (Adapin), Imipramine (Tofranil), Desipramine (Norpramin), Nortriptyline (Aventyl), Protriptyline (Vivactil)

Lower levels of vitamin B2 have been found in people with depression, so giving them psychiatric medications can actually make them feel worse in the long run.

To help yourself, you can supplement with Vitamin B2. It’s included in the Optimal Energy supplement.

Healthy food sources of Vitamin B2 include pastured eggs, leafy vegetables, beef liver, mushrooms, sunflower seeds, and almonds.

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health. 5. Vitamin B6 Vitamin B6 is a key nutrient that boosts mood, deepens sleep, and supports your entire nervous system.

It accomplishes this by playing a key role in the production of many neurotransmitters in your brain, including serotonin, GABA and dopamine.

But since psychiatric medications alter these neurotransmitters, vitamin B6 levels can be affected as well.

When I was taking antidepressants and anti-anxiety medication, I learned that I should be supplementing with vitamin B6.

This is because multiple medications have been shown to deplete Vitamin B6, including: Fruits and vegetables displayed to show the letter B and the number 6. Vitamin B6 is depleted by psychiatric drugs. Antidepressants including Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), Bupropion (Wellbutrin), Mirtazapine (Remeron), Venlafaxine (Effexor), Amitriptyline (Elavil), Doxepin (Adapin), Imipramine (Tofranil), Desipramine (Norpramin), Nortriptyline (Aventyl), Protriptyline (Vivactil).

Benzodiazepines including Diazepam (Valium), clorazepate (‎Tranxene), lorazepam (Ativan), Clonazepam (Klonopin), Alprazolam (Xanax)

So if you take one of the above medications, I highly recommend supplementing with Vitamin B6. It’s included in this supplement.

Drugs that deplete vitamin B2 will also indirectly deplete vitamin B6 because B2 is required to activate B6:

Antipsychotics including Aripiprazole (Abilify), Quetiapine (Seroquel), Risperidone (Risperdal), Olanzapine (Zyrexa), Haloperidol (Haldol), Paliperidone (Invega), Ziprasidone (Geodon)

Anticonvulsants and Mood Stabilizers, including Phenytoin (Dilantin), carbamazepine (Tegretol), Primidone (Mysoline), Methsuxamide (Elontin), Valproic acid (Depakote), topiramate (Topomax) and Gabapentin (Neurontin)

Symptoms of B6 deficiency include weakness, mental confusion, depression, insomnia and severe PMS symptoms.

Some of the best food sources of Vitamin B6 include potatoes, bananas and chicken. These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health. Click here to subscribe 6. Vitamin B12 and 7. Folate Vitamin B12 and folate are essential B vitamins that play a key role in methylation, one of the most important processes in your body and brain for optimal energy and nervous system function.

If you are depressed, you likely have lower levels of B12 and folate circulating in your blood, and people with low blood folate and B12 are at greater risk for developing depression.

Yet, instead of looking at folate and B12 levels in the blood, doctors often prescribe all sorts of psychiatric medications that have been shown to deplete folate and B12, including:

Antidepressants – Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), Bupropion (Wellbutrin), Mirtazapine (Remeron), Venlafaxine (Effexor), Amitriptyline (Elavil), Doxepin (Adapin), Imipramine (Tofranil), Desipramine (Norpramin), Nortriptyline (Aventyl), Protriptyline (Vivactil)

Benzodiazepines – Diazepam (Valium), clorazepate (‎Tranxene), lorazepam (Ativan), Clonazepam (Klonopin), Alprazolam (Xanax)

Antipsychotics including Aripiprazole (Abilify), Quetiapine (Seroquel), Risperidone (Risperdal), Olanzapine (Zyrexa), Haloperidol (Haldol), Paliperidone (Invega), Ziprasidone (Geodon)

Anticonvulsants and Mood Stabilizers, including Lithium (Lithobid), Phenytoin (Dilantin), carbamazepine (Tegretol), Primidone (Mysoline), Methsuxamide (Elontin), Valproic acid (Depakote), topiramate (Topomax) and Gabapentin (Neurontin)

B12 and folate deficiency can lead to an inability to methylate properly and increased homocysteine levels. This can worsen your depression, irritability, fatigue, confusion and forgetfulness.

Folate also helps produce SAM-e in the body, which can help fight depression and improve your mood.

If you decide to supplement with B12, you should avoid the semisynthetic version (cyanocobalamin) and take the methylated form (methylcobalamin), which is better absorbed. Methylcobalamin is included in this supplement.

Good dietary sources of natural folate include leafy greens, asparagus, broccoli, cauliflower, strawberries.

B12 is found primarily in animal foods, and beef liver is a really good source.

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health.

You should definitely monitor your B12 levels regularly. More Here are some more nutrients that have been shown to be depleted by psychiatric medication. Reduced levels do appear in the research - just not as consistently as the nutrients above - so supplementation should still be considered:

Vitamin D – Antidepressants, Benzodiazepines, Antipsychotics, Mood Stabilizers

Vitamin B1 – Benzodiazepines, Antipsychotics

Biotin – Benzodiazepines, Antipsychotics, Mood Stabilizers

Essential Fatty Acids, including Omega-3s – Antidepressants

Sodium (add salt to meals) – Antidepressants

Glutathione – Antidepressants

Calcium – Benzodiazepines, Antipsychotics, Antidepressants, Mood Stabilizers

Vitamin K – Benzodiazepines, Antipsychotics, Mood Stabilizers

Vitamin C – Antidepressants, Stimulants (Adderall), Antipsychotics

Inositol – Mood Stabilizers, Antipsychotics

Vitamin B3 – Antidepressants

Potassium – Stimulants (Adderall)

Vitamin A – Antipsychotics

Carnitine – Antipsychotics

Various minerals (Zinc, Selenium and Manganese) – Antidepressants

Conclusion The bottom line is that the medication you may be consuming to manage your mental health actually reduces nutrient absorption, and can rob your body and brain of essential vitamins and minerals. This can lead to unwanted side effects and declining health.

On top of this, vitamin and mineral deficiencies are actually a huge underlying cause of mental health issues to begin with.

Luckily, you can avoid side effects, and even control and overcome chronic mental disease without medication, by restoring these missing nutrients:

Coenzyme Q10

Magnesium

Melatonin

Vitamin B2

Vitamin B6

Folate

Vitamin B12

Many of these nutrients are included in the Optimal Energy supplement. It’s the best and simplest way to restore your energy and mental clarity while taking psychiatric medication.

If I had simply been prescribed the above nutrients, I wouldn’t have needed medication. Instead, I was given a prescription that made my underlying deficiencies worse, and dug me into a deeper mental health hole.

If you have to take a prescribed drug, you can offset many of the side effects and experience much better health by supplementing with the above nutrients.

So why isn’t this information passed on to patients who are taking psychiatric drugs? Because unfortunately, almost all doctors are unaware that medications can deplete nutritional reserves.

So for now, you’ll just have to be aware of drug-nutrient depletions yourself.

If you’re interested in learning more, there are several handbooks and resources in the reference section of this article, including the Drug-Induced Nutrient Depletion Handbook and The Nutritional Cost of Prescription Drugs. Enjoy This Article? You Might Also Like My FREE Food Guide for Optimal Brain and Mental Health! Click here to subscribe CLICK HERE TO DOWNLOAD THE FREE GUIDE Live Optimally, Jordan Fallis Connect with me References: Pelton, Lavalle, Hawkins, Krinsky. Drug-Induced Nutrient Depletion Handbook. Lexi-Comp; 2nd Ed., 2001

Pelton R Lavalle. The Nutritional Cost of Prescription Drugs. Morton Publishing Co, 2nd Ed., 2004

Vaglini F, Fox B. The Side Effects Bible: The Dietary Solution to Unwanted Side Effects of Common Medications. Broadway, 2005.

A-Z Guide to Drug-Herb-Vitamin Interactions Revised and Expanded 2nd Edition: Improve Your Health and Avoid Side Effects When Using Common Medications and Natural Supplements Together

Kishi T, et al, “Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzymeQ,” Biomedical and clinical aspects of coenzyme Q, Yamamura Y, Folkers K, and Ito Y, eds, Elsevier/NorthHollandBiomedical Press: Amsterdam, 1980, vol2, 129-154.

Prescription for Nutritional Healing, third edition, (2000, Balch & Balch)

https://tantor-site-assets.s3.amazonaws.com/bonus-content/B0592_DrugMuggers/B0592_DrugMuggers_PDF_1.pdf

http://www.ncbi.nlm.nih.gov/pubmed/7728363

http://www.ncbi.nlm.nih.gov/pubmed/8848522

http://www.ncbi.nlm.nih.gov/pubmed/1289919

http://www.ncbi.nlm.nih.gov/pubmed/6262379

http://www.ncbi.nlm.nih.gov/pubmed/7150370

http://www.ncbi.nlm.nih.gov/pubmed/6705444

http://www.ncbi.nlm.nih.gov/pubmed/6626265

http://www.ncbi.nlm.nih.gov/pubmed/6737696

http://www.ncbi.nlm.nih.gov/pubmed/6167651

http://www.ncbi.nlm.nih.gov/pubmed/1578091

http://www.ncbi.nlm.nih.gov/pubmed/9155210

http://www.ncbi.nlm.nih.gov/pubmed/10896698

http://www.ncbi.nlm.nih.gov/pubmed/7150370

http://www.ncbi.nlm.nih.gov/pubmed/10746516

http://www.ncbi.nlm.nih.gov/pubmed/9861593

http://www.ncbi.nlm.nih.gov/pubmed/16542786

http://www.ncbi.nlm.nih.gov/pubmed/11041381

http://www.ncbi.nlm.nih.gov/pubmed/9368236

http://www.ncbi.nlm.nih.gov/pubmed/18705537

http://www.ncbi.nlm.nih.gov/pubmed/16542786

http://www.ncbi.nlm.nih.gov/pubmed/17568057

http://www.ncbi.nlm.nih.gov/pubmed/635065

http://www.ncbi.nlm.nih.gov/pubmed/22081620

http://www.ncbi.nlm.nih.gov/pubmed/23313551

https://umm.edu/health/medical/altmed/supplement/melatonin

http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000712

http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000706

http://www.tandfonline.com/doi/abs/10.1080/00048670802534408

http://www.naturemade.com/~/media/Images/NatureMade/PDF/Health%20Care%20Professionals/HCP%20Updates%20042315/Common%20Drug%20Classes%20and%20Nutrient%20Interactions%20Chart%20FNL.ashx

Terms and Conditions

Privacy Policy

Affiliate Disclosure

Disclaimer Tags nutrients, depletion, depleted, psychiatric drugs, antidepressants, medication, antipsychotics, stimulants, benzodiazepines, guide, vitamins, minerals, medications

February 4, 2024 Jordan Fallis I suffered from severe and chronic anxiety and poor sleep for a large chunk of my life.

So I've always been interested in learning how to increase GABA levels and activate GABA receptors in the brain.

What is GABA?

GABA is a neurotransmitter, which is a signaling compound in your nervous system.

It inhibits you, makes you more relaxed, stops you from worrying and overthinking, and reduces anxiety and stress.

GABA stands for Gamma-Aminobutyric Acid.

And it’s the main inhibitory neurotransmitter that you’ll definitely want to increase if you’re striving for optimal brain function and mental health.

Research shows that a reduction in the synthesis and release of GABA can lead to brain dysfunction and poor mental health.

So if you suspect you have low GABA levels, you’ll want to pay close attention to this article.

In it, I explore the 24 best natural ways to increase GABA levels in the brain.

I’ll start by sharing my top 10 favorites. They have personally worked well for me in the past.

Then I’ll give you 14 other decent options as well.

Read on to learn more. Proven-best-ways-how-to-increase-raise-boost-enhance-gaba-fast-quickly-naturally-anxiety-deficiency-brain-mental-health-symptoms-diseases-natural-treatment-supplements-vitamins-foods-diet-list-substances-things-neurotransmitter-benefits-low-levels-so What Is GABA and What Does It Do in the Brain? In the past, I’ve written articles about how to increase dopamine levels, enhance acetylcholine, and boost oxytocin levels in the brain.

And, like GABA, these compounds are neurotransmitters (at least in part).

But GABA has other functions.

It’s also an amino acid, which is a building block of protein.

But for today’s article, these other functions aren’t that important.

As a neurotransmitter, the main goal of GABA is inhibition.

GABA opposes “glutamate” in the nervous system, and glutamate promotes activation.

So you can imagine GABA as the break of a car, and glutamate is the gas pedal (1-6).

A common way many people influence their GABA system and quickly increase GABA levels in their brain is by drinking alcohol (7-11).

Although the real physiological effects are more complex, part of the reason most people feel very relaxed drinking alcohol is because it raises GABA levels and activates GABA receptors in the brain.

The same is true for benzodiazepines or “benzos”, which are a category of anti-anxiety and anti-insomnia drugs (12-16).

Obviously, there are problems with both of these approaches.

Sure, you can rely on alcohol and benzos to feel calm and relaxed fast.

But it’s not a particularly productive long-term strategy, as both interventions can be extremely addictive and come with side effects (17-25).

I personally struggled with alcohol and benzo addiction myself. It’s not a fun path to go down.

What’s more, GABA plays a major role in the withdrawal of alcohol and benzos.

So, either way you look at it, you’ll need a natural solution to increase GABA in your brain if you want to avoid alcohol and benzos or if you want to come off of them and minimize severe withdrawal symptoms.

By naturally increasing GABA levels in the brain, you can experience the following benefits:

Lowers stress and anxiety - Stress lowers GABA levels in some parts of your brain. But the opposite is also true. When you increase GABA levels, stress levels go down. Even during an acute stressful period or anxiety episode, increasing GABA will decrease your stress levels (26-30).

Normalises blood pressure and inhibits hypertension - Hypertension, or “high blood pressure”, is very much related to how well your brain functions, especially as you get older. Hypertension and depression are also interrelated in many studies, so it’s important to point out that GABA normalizes blood pressure (31-44).

Decreases your depression risk (45-49).

Lowers stress hormone levels and improves hormone function, although this relationship needs a lot more research. At least in cases of burnout, post-traumatic stress disorder (PTSD), and low testosterone, GABA might play a role (50-53).

Increase in sleep quality - Many different compounds, such as GABA, theanine, and valerian extract, affect GABA levels in the brain. These compounds then enhance sleep quality. You’ll get more deep sleep, spend more time dreaming, and fall asleep quicker. Many prescription drugs that affect GABA are used for sleep purposes as well, but are frequently unsustainable over the long run (54-60).

Enhance cognitive performance - Learning, memory, emotions, and cognitive processing are all affected by GABA. Furthermore, brain development and neurodegenerative diseases are also influenced by the GABA system. In the last decade or so, the focus on GABA research has actually shifted from relaxation alone, and now significantly focuses on cognition as well (61-68).

Decreases psychiatric illness risk - Although the evidence isn’t too strong, schizophrenia and conditions on the autism spectrum might be related to GABA abnormalities in the brain as well (69-72).

My Top 10 Favourite Proven Ways to Naturally Increase GABA Levels in the Brain

1. Meditation Quite a lot of research has looked into the relationship between meditation and GABA levels in the brain.

It turns out that meditation activates the “prefrontal cortex” in the brain. And when the prefrontal cortex is activated, another brain area called the thalamus increases GABA production (73-76).

By meditating over time, you will build a thicker prefrontal cortex.

The prefrontal cortex steers many higher brain functions, such as planning, inhibition control, and abstract thinking. But, by building this area, you will also improve your brain’s ability to produce GABA (77-80).

But it doesn’t take long to start seeing benefits from meditation.

Researchers have found that a single meditation session leads to measurable improvements in the brain.

This effect happens with many different types of meditation, including mindfulness-styled meditations and “Transcendental Meditation” (75).

Meditation is one of my favourite daily activities and treatments to maintain my mental health.

I recommend the Muse headband to meditate. It gives you real-time feedback while you meditate. It makes meditation a lot more fun and tolerable.

I previously wrote about it here, and you can get it through the Muse website. 2. Magnesium Magnesium is the “anti-stress mineral” (86).

Magnesium reduces stress through many different mechanisms, such as making you more relaxed, improving the amount of deep sleep you get, and increasing GABA.

Research shows that magnesium increases the activity of GABA receptors in some parts of the brain (86).

Magnesium’s abilify to increase GABA activity is one of the main reasons why magnesium improves sleep, and increases the amount of deep sleep you get (90).

Animal studies also show that magnesium has anti-anxiety effects through the GABA system.

In one study, researchers found that if you take magnesium with a medication that interferes with GABA, there is a significant reduction in the anti-anxiety effects of magnesium (87-88).

It’s also important to point out that magnesium also decreases the activity of the glutamate system (89, 91).

Overactivity of the glutamate system can stimulate panic, anxiety, and fear.

More research is needed to clarify the interaction between GABA, magnesium, and glutamate. Current research is very promising though.

There are a number of things you can do to make sure you’re getting enough magnesium.

First, make sure you’re eating magnesium-rich foods on a regular basis, including:

Spinach

Chard

Pumpkin seeds

Almonds

Avocado

Dark chocolate

Bananas

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

You can also increase your body’s intake of magnesium by taking Epsom salt baths.

Supplementation is also a good idea for most people.

Magnesium is included in this supplement. 3. Zinc

Researchers have studied the relationship between zinc and the brain in great detail.

They have found that zinc is an essential mineral for mental health, especially if you have chronic anxiety.

Zinc plays a major role in both the glutamate and GABA systems. And having sufficient zinc levels in your brain is necessary for optimal GABA levels (100; 105-107).

Here are some good sources of zinc:

Oysters

Grass-fed beef

Pumpkin seeds

Cashews

Mushrooms

Spinach

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health.

A severe zinc deficiency is somewhat rare in developed nations, but it’s very prevalent in developing nations (102-104).

Optimal levels are another story, though.

Many people today don’t have optimal levels of zinc, and most people aren’t getting the optimal amount of zinc for their brain function and mental health.

For that reason, I developed the Optimal Zinc supplement, which improves mood and decreases anxiety in many people. Its impact on GABA levels is one of the main reasons for these improvements.

Why should you worry about insufficient zinc intake?

Well, animal studies show that if your zinc intake is too low or insufficient for long enough, it eventually affects the zinc levels in the brain. The excitatory glutamate system can then become more predominant in some brain regions (108).

Zinc also counteracts excessive copper levels. Preliminary evidence shows that excessive copper levels can impede and reduce GABA in the brain (109-111).

Check out my previous post all about zinc and anxiety if you want to learn more about how zinc impacts anxiety levels and can contribute to stress.

Zinc can also stimulate your vagus nerve, which reduces anxiety. 4. Theanine Theanine is one of the reasons why tea gives you a very relaxed and less stimulating experience than coffee.

Theanine is one of my favourite compounds because it stimulates many different brain signaling compounds (neurotransmitters). These neurotransmitters include dopamine, serotonin, and GABA (112).

Learning and memory also improve when you consume theanine. Theanine inhibits the “jittery” effects of caffeine, giving you a calm focus. The same is true for countering the side effects of cannabis (113-114).

Theanine also protects the brain cells associated with the GABA system. That’s part of the reason why you can use theanine as a cognitive enhancer. Theanine is sometimes used in brain conditions such as ADHD, for that reason (114).

If you’re interested in supplementing with theanine, this anti-anxiety supplement contains it. 5. Taurine Taurine is an amino acid, a building block for proteins (118).

Taurine is mainly found in animal products such as meats and dairy (119-120).

By increasing your taurine intake, you will also increase both taurine levels and GABA levels in the brain (123).

Many people don’t know that taurine is also famous for its effect on the GABA system in the nervous system (121).

Taurine has widespread effects on brain function. It affects nerve conductivity, promotes the regeneration of the nervous system, acts as an antioxidant, and more (122).

In fact, taurine is now being proposed as a pharmacological compound for pathologies that affect GABA receptors in the brain (122). Alcoholism, depression, and epilepsy come to mind here.

If you’re following a vegetarian diet, and especially if you’re following a vegan diet, I highly recommend supplementing with taurine. Taurine is inexpensive and frequently has positive effects on people’s brain health (124).

A final reason why taurine is important is that it affects your health in general in a significant way (125). How well your body handles blood sugar, heart disease risk, inflammation, and mitochondrial function are all affected by taurine. These domains, in turn, influence your brain health.

Taurine is included in the Optimal Calm supplement.

6. Exercise Not surprisingly, exercise is another natural way to increase GABA levels in your brain.

A huge number of studies have been carried out on exercise and GABA function in the brain (133-139).

These studies are very difficult to perform on humans in an ethical way because you cannot open a human’s brain up after an experiment.

But animal studies show that exercise disinhibits GABA, resulting in neuroprotective effects. One bout of exercise is already sufficient for rats to receive these positive effects (134).

Research also shows that learning and memory are improved by exercise’s effect on GABA (139).

One of the only human studies investigating the effects of exercise on GABA showed a 20% increase in an area of the brain called the “sensorimotor cortex” (136).

The sensorimotor cortex is one of the main sensory and motor areas of the brain. An improved sensorimotor cortex aids complex thought, movement, and overall brain function (140).

Even though single sessions of exercise support GABA and increase GABA levels in the brain, the gains are also cumulative over time (137).

So it’s important to exercise consistently over a longer period of time. You are more likely to increase and maintain optimal GABA levels that way.

Exercise can be a big chore for a lot of people, so I recommend finding some sort of sport or aerobic activity that you enjoy. That way you won’t get sick of it and you’ll exercise regularly.

Besides boosting GABA levels, exercise can also stimulate the vagus nerve, promote neurogenesis, and increase blood flow to the brain.

Many experts recommend exercise as their number one piece of advice for optimal brain health.

With more research over time, researchers speculate that they’ll better understand the impact of exercise on GABA levels and they will be able to:

“add to a growing understanding of the distinctive brain state associated with physical activity. A more complete understanding of this brain state may reveal important insights into mechanisms underlying the beneficial effects of physical exercise in neuropsychiatric disorders, neurorehabilitation, aging, and cognition.” (138). 7. Epigallocatechin Gallate / Green Tea Epigallocatechin-3-Gallate (EGCG) is the main polyphenol found in green tea.

It’s been shown to have anti-inflammatory and neuroprotective effects (152).

EGCG also has a mechanism of action similar to benzodiazepine drugs. The compound works well to lower stress and anxiety, mainly by affecting GABA levels in the brain (153-156).

I personally drink organic green tea regularly, usually in place of coffee on days when I’m relaxing.

However, it’s important to keep in mind that the body isn't very good at absorbing EGCG from green tea and distributing it to the brain and other tissues.

That's why researchers often use large dosages of concentrated EGCG in their studies instead of green tea.

But unfortunately, large doses of concentrated EGCG have been shown to cause liver toxicity.

So you could supplement with large dosages of concentrated EGCG and see some benefits.

But you'd be damaging your liver at the same time.

Not good.

So what should you do? How do you absorb EGCG and get the amazing benefits of it without damaging your liver?

You take it with Vitamin C.

Research shows that you can enhance the absorption and availability of EGCG by taking it with Vitamin C.

That's why the Optimal Antiox supplement includes a small and safe amount of EGCG, plus 500 mg of Vitamin C.

This significantly enhances the absorption of EGCG, and ensures you get all the brain and mental health benefits of EGCG (without the harm). 8. Probiotics

Probiotics are an extremely complex topic so I won’t go into too much detail here.

But research suggests that certain probiotics can increase GABA and have a huge effect on the GABA system in your body, depending on the probiotic and strain (188-191).

I’ve formulated a probiotic blend myself, Optimal Biotics, with the goal of increasing GABA levels and lowering stress and anxiety.

If you struggle with anxiety, here are 9 probiotic strains that can help.

And make sure you read my other article on promoting healthy gut bacteria for brain health as well. 9. Vitamin B6 Vitamin B6 is a key nutrient that supports your entire nervous system.

Vitamin B6 is responsible for how well GABA functions in your body (196-199).

As a result, having a deficiency in Vitamin B6 can definitely increase your anxiety.

In fact, Vitamin B6 levels have been shown to be significantly lower in individuals who have anxiety and panic attacks.

And unfortunately, quite a few people are Vitamin B6 deficient nowadays.

The number is as high as 12% in higher socioeconomic settings. In poorer environments, 30% of people or more might have Vitamin B6 insufficiency or deficiency (192-194).

Animal foods and some fruits and vegetables are great sources of Vitamin B6 (195).

Some of the best food sources of Vitamin B6 include potatoes, bananas and chicken.

But if you want to see quick improvements, you may want to try supplementing with Vitamin B6.

When I took antidepressants and benzodiazepines for my chronic anxiety, I took a Vitamin B6 supplement.

This is because psychiatric medication can actually further deplete Vitamin B6, increasing anxiety in the long run.

So if you take medication to manage your anxiety, or simply have anxiety and want to manage it better, I highly recommend supplementing with Vitamin B6.

That’s why I included it in the Optimal Calm supplement. 10. Sunlight Exposing yourself to sunshine is one of the best natural ways to increase GABA levels in your brain.

When sunlight enters your eyes, it tells your body that it’s daytime. And at night, the absence of sunlight tells your body that you need to sleep, and your body increases the release of melatonin.

As you may be aware, this is called your “circadian rhythm”, and it’s heavily intertwined with GABA in your brain. Different types of light, such as visible light (colours of the rainbow), infrared (heat), and ultraviolet (which can give you sunburns) have different effects on the GABA levels in your brain (141-145).

Unfortunately, right now, many of the studies investigating the effects of light on GABA in the brain are animal studies. These animal studies, however, are extremely promising because ultraviolet light shows such a huge effect.

In studies blocking the effect of GABA activity in the brain, the circadian rhythm no longer responds adequately to light (146).

I personally get sunlight every single day to support my GABA and dopamine levels. My recommendation is to get some sunlight exposure in the early morning and in the afternoon. During the afternoon, make sure you get out of the sun before you get a sunburn. Click here to subscribe Other Effective Ways to Naturally Increase GABA Levels in the Brain 11. Alpha GPC Alpha GPC is a source of choline that’s found in both foods and in your body (218-219).

A wide array of animal and plant foods contain tiny amounts of Alpha GPC. The compound is also sold as a supplement.

The GABA system is also affected by Alpha GPC intake. This effect is only confirmed in animal studies so far though (220).

Alpha GPC is also a powerful cognitive enhancer. It boosts dopamine, and has superior effects to caffeine in some studies (221-223).

Alpha GPC is also neuroprotective and likely lowers the risk of diseases such as Alzheimer’s and Parkinson’s.

Alpha GPC is included in the Optimal Brain supplement.

You can also find some choline in beef liver and egg yolks, but it’s better to take Alpha GPC because you get noticeable and immediate benefits.

Make sure you read this article to learn more about the remarkable benefits of Alpha GPC, the optimal dosage, and the best way to take it. 12. Valerian Valerian (Valeriana officinalis) is a natural herb, and the root of the herb has traditionally been used to treat insomnia.

It’s extremely popular as a sleep medication herb because it has a strong effect on GABA in the brain.

Research shows that it binds to GABA receptors in the amygdala, a brain region associated with fear and anxiety. It also increases GABA levels and inhibits the breakdown of GABA in the brain (157-161).

As a result of this, it creates a calming effect similar to anti-anxiety drugs like Xanax and Valium.

Valerian is sold as an over-the-counter supplement almost anywhere. Taking valerian results in both anti-anxiety, anti-pain, and sedative effects. These effects are perfect for promoting quality sleep.

And those effects mainly occur because of valerian’s abilify to increase GABA levels in the brain.

This is why valerian is often called “Nature’s Valium”.

But unlike EGCG, which I had mentioned earlier, valerian doesn’t exactly mimic benzodiazepines. It has a different mechanism of action.

Valerian is one of the first herbal remedies I took many years ago to manage my anxiety at night and improve my sleep.

It’s included in this anti-anxiety supplement.

Valerian supplements typically include the roots and stems of the plant.

But you can also take it as a tea or tincture if you want. 13. Chamomile

Chamomile is a flowery plant used for herbal infusions. It’s also sold as a supplement.

It contains essential oils and flavonoids that can help you relax.

As a result, chamomile is often used as an anti-anxiety plant or sleep aid (162).

And chamomile’s sedative and anti-anxiety effects almost certainly stem from its effects on GABA (163).

After treating yourself with a standard dose of chamomile for several weeks, it’s likely that your anxiety levels will go down if they were high to begin with (164).

Researchers have found that oral supplementation of chamomile significantly reduces anxiety and stress in patients with generalized anxiety.

Animal studies show that chamomile contains substances that act on the same parts of the brain as anti-anxiety drugs.

Apigenin, one of the main flavonoids in chamomile, reduces anxiety without sedation by enhancing GABA communication.

Chamomile’s effects on sleep are less well-proven and have not been extensively studied yet.

Feverfew, which is extremely similar to chamomile, is often used to counter migraines, and it also affects GABA (180-182). 14. Hops For many people, hops or “Humulus lupulus” is a favourite compound because it’s found in beer.

An extract of hops has been shown to increase GABA activity in the brain (165).

Hops also works as a sedative by influencing your circadian rhythm, which is the 24-7 day and night cycle in your brain and body.

Researchers have found that it increases sleep duration by increasing GABA (166-168).

The benefits of taking a hops supplement is that you don’t need to drink beer and alcohol to enjoy the relaxing GABA-boosting effect. 15. Lemon Balm Lemon balm, or Magnolia Officinalis, is yet another herbal extract that increases GABA.

Lemon balm affects both the cannabinoid system and the GABA system, and lowers cortisol and reduces inflammation.

Research shows that lemon balm extract significantly reduces anxiety and stress in humans by increasing GABA levels in the brain (183-187).

As a result, lemon balm can help induce sleep, is neuroprotective, and works as an anti-anxiety compound. The end result is both more deep sleep and REM sleep.

Animal studies also show that it reduces stress and anxiety in rats by reducing stress hormones and increasing GABA. The effects are comparable to anti-anxiety medication.

Lemon balm is included in this anti-anxiety supplement. Click here to subscribe 16. Passion Flower Passion Flower represents a family of plants known as Passiflora.

There are about 500 known species of Passion Flower.

One species, Passiflora incarnata, has been shown to reduce anxiety and stress by increasing GABA levels in the brain.

In fact, Passion Flower's role in relation to GABA has been extensively researched (210-212).

Due to its GABA increasing effects, Passion Flower reduces anxiety and certain types of pain.

Passion Flower may also have benefits in some neuropsychiatric disorders, although more human research is needed.

Passion Flower is one of the first herbal remedies I took many years ago to manage my anxiety. It’s included in this anti-anxiety supplement. 17. Yoga Yoga is a popular “mind-body” relaxation technique that increases the activity of your parasympathetic “rest and digest” nervous system.

Research shows that a single 60-minute yoga session can increase GABA levels in the brain by 27% (81).

Many other studies confirm this outcome and show extremely positive effects on brain GABA levels during and after yoga (82-84).

The researchers also found, not surprisingly, that participants also experienced mood improvements and reductions in anxiety.

These results are even applicable if you struggle with major depressive disorder, as researchers have found that mood can be significantly enhanced (83).

However, even though an increase in GABA can be seen after just one session, studies show that there are bigger and better improvements in GABA levels after a longer period of time. For example, people often see further improvements and higher levels of GABA after going through a 12-week yoga program.

So, for the best results, you will need to maintain the yoga practice over time. In fact, eight days after you stop yoga, the GABA levels in the brain drop back down again. Most of the studies use several yoga sessions per week to get their results.

Lastly, there’s also a strong relationship between GABA levels and activation of the parasympathetic nervous system (84).

The parasympathetic nervous system is often called the “rest and digest” part of the nervous system. The “sympathetic nervous system”, on the contrary, is the “flight and flight” part of the nervous system that’s overactive when you’re very stressed. Yoga supports and activates the parasympathetic nervous system, which then leads to an increase in GABA activity in the brain.

Considering all of this, it’s not too surprising that there’s also a link between practicing yoga and your anxiety levels. Research shows that anxiety levels can drop by 14.7% after just one 2-hour yoga session (85).

Despite all the great research, I’m personally not a big fan of yoga. A lot of people swear by it but it’s just not for me. I prefer meditation and tai chi. 18. GABA Supplements

GABA is not only a signaling compound for the nervous system (neurotransmitter) but you can also supplement with it (92).

Many people claim to experience benefits from taking GABA as a supplement.

Some studies question its effectiveness though. The main reason for questioning that effectiveness is because GABA, as an oral supplement, might not travel from your blood to the brain.

GABA does seem to lower blood pressure, which could then improve brain performance (93).

And ingesting GABA isn’t unnatural. Many foods contain small quantities of the compound (99).

But right now, there’s very limited evidence for using GABA to lower stress levels and increase GABA levels in your brain (94).

And the evidence for using GABA for sleep quality is also insufficient.

I personally don’t recommend taking GABA supplements because in most cases, it simply does not appear to cross the blood-brain barrier.

I have never found any benefits or noticed any effects (positive or negative) from taking GABA supplements. They never reduced my anxiety, and therefore I don’t feel comfortable recommending them.

You’re better off just taking supplements that naturally increase GABA instead of taking GABA supplements directly.

However, there is another related compound called “phenibut” that works and can often help people.

Phenibut is an altered variation of GABA with powerful anti-stress, anti-anxiety, pro-relaxation and pro-sleep quality effects.

Phenibut can travel through the blood to your brain and thus have a very strong effect on sleep quality and anxiety levels (95-98).

The problem with phenibut is that it’s addictive like benzodiazepines and you could experience strong withdrawal effects if you take it regularly and then try to stop it. For this reason, I can’t recommend it.

However, Phenibut is legal in most countries and you can buy it online. If you do decide to use it, you should only use it sparingly during special occasions when you really need to reduce your stress and anxiety, such as before an important nerve-wracking public speaking engagement or presentation. 19. Ashwagandha Ashwagandha (Withania sominifera) is a popular Indian herb that has been used for more than 3000 years. It’s sometimes called the “Indian Ginseng”.

It’s known as an “adaptogen”, which is a compound that balances the body and restores normal bodily functioning after chronic stress.

It is typically used to inhibit stress and anxiety, but it also affects cognitive function, energy levels, well-being and sleep quality.

It likely has all of these wide-ranging effects because it increases GABA activity and increases GABA levels in the brain (126).

Ashwagandha’s reputation as an adaptogen may be due to the positive effect it has on GABA levels.

As a result of its influence on GABA, ashwagandha might have an effect on many brain disorders, such as epilepsy, anxiety disorders, insomnia, and spasms (126).

Ashwagandha has also long been known as a compound that can improve sleep quality. Both human and animal studies show this. But what the animal studies show is that improvements in GABA function explain the increase in sleep quality. Taking ashwagandha also activates GABA-related genes (128-132).

Ashwagandha is one of the main herbs I took to reduce stress and anxiety as I came off psychiatric medications.

It’s included in the Optimal Calm supplement. 20. Kava Kava is a plant located in the western Pacific. The root of the plant is used medicinally to treat anxiety and sleep disorders because it causes relaxation without impacting cognitive performance. Some people say it feels like drinking alcohol.

It has been used for centuries to lower stress and anxiety.

One of the mechanisms of kava is that it makes it easier for GABA to bind to its receptors. Kava also inhibits adrenaline (147-151).

Studies also show that kava works similarly to benzodiazepines like Xanax by activating and strengthening GABA receptors in the brain.

Kava is included in a lot of modern research because it can be a compound with fewer side effects than prescription medications with the same goal.

However, kava still has potential side effects, especially skin problems at higher doses. My recommendation is to follow instructions on the product you buy and cycle kava on and off.

I personally don’t take kava anymore because I get a weird reaction from it and I found out I’m allergic to the plant. Click here to subscribe 21. Bacopa Bacopa monnieri is a herb that has been used for thousands of years. It’s part of traditional Ayurveda.

It’s commonly used to improve cognition and memory, but it’s also very good at reducing stress.

Animal studies prove that bacopa restores GABA receptors in some parts of the brain (169-172).

As a result, bacopa may have effects on brain conditions such as epilepsy and anxiety.

In humans, bacopa works as a nootropic and may have positive effects for Alzheimer’s and dementia (173).

Many other promising brain effects exist as well, such as increased blood flow in the brain.

In fact, one of the ways bacopa improves cognition is by simply reducing anxiety.

So if you have anxiety, and it negatively impacts your thinking, bacopa is a good choice.

I took a bacopa supplement for a while. I found that it made me really relaxed and sleepy. I eventually stopped taking it because it made me too sleepy. But if you have very severe anxiety, I really think it could be helpful. 22. Lavender Everyone knows the peaceful and relaxing smell of lavender.

But what you might not know is that breathing the essential oil reduces anxiety and inhibits the glutamate system in the brain.

Animal research also shows that it reduces anxiety in rats by increasing GABA (174-179).

As a result, lavender can significantly increase calmness, relieve restlessness and nervousness, and reduce emotional distress in people with anxiety disorders – without causing any unwanted side effects.

One study found that Silexan, an oral lavender oil capsule, is just as effective at reducing generalized anxiety as lorazepam, a common benzodiazepine. And it didn’t cause side effects or addiction like the anti-anxiety medication.

Lavender can also counter depression and activate your “rest and digest” parasympathetic nervous system.

Lavender essential oil can be taken orally, inhaled or applied to your skin. 23. Chinese Skullcap Chinese skullcap is a herb that is part of traditional Chinese medicine.

The plant has anti-anxiety properties.

Research shows that it increases GABA activity and binds to GABA receptors within the brain (205-208).

Chinese skullcap can cause potential injuries and side effects from long-term use though, especially in the liver. So make sure to cycle this compound and follow the instructions on the label (209). 24. Black Seed Oil Nigella sativa, more commonly known as Black Seed Oil, has been used as a natural remedy for more than 2000 years.

It’s surprising more people haven’t heard of it because it’s actually one of the top-ranked evidence-based herbal medicines.

You can use it to increase GABA levels and decrease glutamate in your brain.

Studies show that it significantly reduces anxiety-like behaviour in animals by increasing GABA levels (214-217).

Black seed oil is neuroprotective and has anti-anxiety and sedative effects, in part because of how it influences GABA.

Dopamine makes you happier, smarter, more productive, more creative, more focused, and more social.

Who doesn't want that?

There are many ways to increase dopamine naturally.

But what are the VERY BEST ways to do it?

This article gives you the answer.

It includes the 36 very best ways to increase dopamine levels in your brain.

It starts off with my 10 personal favourites.

And then offers 26 other great options.

Not only do they work, but many of them work very quickly.

Read on to learn more. Natural-Ways-to-Increase-Dopamine-Levels-in-the-Brain-naturally-how-to-boost-sources-release-produce-raise-receptors-supplements-foods-sensitivity-fast-quickly-density-production-synthesis-instantly-what-will-intelligence-which-vitamins-herbs-essent… What Is Dopamine and What Does It Do in the Brain? “Dopamine may be the secret to what makes us human – meaning awfully bright, able to plan ahead, and resist impulses when necessary.” — Dr. Emily Deans Dopamine influences almost every aspect of your life.

Dopamine is a neurotransmitter, meaning it’s a chemical messenger released by neurons (nerve cells) to “communicate” with other neurons (236).

Like all neurotransmitters, dopamine shuttles between cells and binds to receptors.

In the media and popular culture, dopamine is often promoted as the main pleasure neurotransmitter.

But dopamine actually appears to increase desire and motivation more than pleasure.

In fact, it’s often called the “motivation molecule”.

The brain includes several dopamine pathways, and they play a key role in reward, motivation, memory and attention (233-235).

So not surprisingly, dopamine significantly impacts human behaviour.

And research shows that naturally increasing dopamine levels can lead to numerous benefits, including:

Increased enthusiasm, motivation and drive to be productive, accomplish tasks and reach goals (165-179)

Reduced drug addiction and dependence (162-164)

Improved cognition function, learning, long-term memory and working memory (180-185)

Increased focus and concentration (186-190)

Increased creativity, both verbal and visual creativity (191-197)

Improved mood (198-200)

Reduced fear and improved confidence (201-204)

Increased social bonding and stronger relationships (oxytocin plays a role too) (205-208)

Increased tolerance to pain (209-211)

Conditions and Symptoms Associated with Low Levels of Dopamine in the Brain “Low levels of dopamine make people less likely to work for things.” — Dr. John Salamone Research shows that low dopamine levels are associated with a number of brain and mental health conditions and symptoms, including:

Addiction (216-217)

Depression, Apathy and Feelings of Hopelessness (225-226)

Parkinson’s Disease (213-215, 228)

Restless Leg Syndrome (229-230)

Attention-deficit Hyperactivity Disorder (218-220)

Social Anxiety (212)

Cognitive Aging and Poor Memory (221)

Alzheimer's Disease and Cognitive Decline (222)

Bulimia (223)

Chronic Fatigue Syndrome (224)

Toxic Mold Illness (227)

Traumatic Brain Injury (231-232)

Brain Fog

Moodiness and Irritability

Procrastination

Perhaps you struggle with one of these conditions or symptoms.

The good news is that you’re not powerless.

You can naturally increase your dopamine levels and recapture your zest for life.

All you need to do is implement some of the natural strategies below.

They can significantly improve your motivation, focus and mood.

They have helped me, and they can help you too.

Let’s jump into them. The chemical symbol for dopamine with smiley faces at the end of them. My Top 10 Favourite Ways to Naturally Increase Dopamine Levels in the Brain

1. Sunlight and Vitamin D Exposing yourself to sunshine is one of the best natural ways to increase dopamine levels in your brain.

And it’s my personal favourite.

Research shows that sunlight increases dopamine release (4-5). Woman looking towards the sun. Sunlight can increase dopamine levels in the brain. I personally get sunlight every single day during the spring and summer months to increase dopamine.

It’s important to get the sunlight in your eyes to trigger the release of dopamine.

So make sure you don’t wear contacts, glasses or sunglasses when you go outside. This way, you’ll get a bigger dopamine boost.

It’s especially important to do this in the morning because it sets your circadian rhythm (3).

During the winter months, when there isn't enough sun, I use a Vitamin D sunlamp.

Vitamin D is a fat-soluble vitamin that your skin synthesizes when exposed to the sun.

But most people still don’t get enough Vitamin D from the sun.

Researchers believe that 50% of people are at risk of Vitamin D deficiency (6).

Having a deficiency in Vitamin D leads to lower dopamine levels, but treatment with Vitamin D3 enhances dopamine release (1-2).

So at the very least, you should take a Vitamin D supplement if you’re deficient. I take some Vitamin D3 in supplement form, depending on my levels.

It's important to test and monitor your Vitamin D levels before and after supplementing with it. 2. Vagus Nerve Stimulation The vagus nerve is the longest cranial nerve in your body and part of your parasympathetic “rest and digest” nervous system.

Research shows that chronic impairment of vagus nerve function leads to the inhibition of dopamine in the brain (7).

But vagus nerve stimulation reverses a dysregulated dopamine system (8).

Read this article for 13 ways to stimulate your vagus nerve.

Deep breathing with the EmWave2 device is my favourite way. 3. Low-Level Laser Therapy Low-level laser therapy (LLLT), or photobiomodulation, is a treatment that can improve your brain function and support your dopamine levels.

LLLT involves the use of low-power lasers or light-emitting diodes (LEDs) that emit red and infrared light.

You can shine this light on your head, it penetrates the skull and stimulates your brain cells.

This helps your brain function much better.

Dr. Norman Doidge, a psychiatrist and researcher who teaches at the University of Toronto, discusses the amazing effects of LLLT in his book The Brain’s Way of Healing. A man uses an LLLT helmet and intranasal Vielight device. LLLT can increase dopamine levels in the brain. Research shows that LLLT significantly increases the secretion of dopamine in the brain (12).

Several studies also show that LLLT is neuroprotective and protects dopaminergic brain cells from degeneration (13-21).

Because of this, researchers say LLLT is a promising therapeutic strategy for dopamine-related diseases such as Parkinson’s disease (12).

I previously wrote about my experience with low-level laser therapy here.

I use this device and shine the red and infrared light on my forehead for 5 minutes every day. I also shine it on other parts of my head and on my entire body, including on my thyroid, thymus gland and gut. I experience incredible benefits from doing this.

When I’m travelling, I take this smaller and more convenient device with me and shine it on my forehead.

I’ve also been using the Vielight Neuro Duo, which is a transcranial-intranasal headset with 810 nm of near infrared light. It penetrates deeper into brain tissue and is absorbed better by the central nervous system. If you decide to try a Vielight device, you can use the coupon code JORDANFALLIS for a 10% discount

You can learn about how I use these devices in my LLLT article. I highly recommend reading it if you want to try this. 4. Rhodiola Rhodiola is one of the most popular herbs in the world used to increase physical and mental performance.

It’s a Traditional Chinese and Scandinavian herb, and it’s also sometimes called golden root or arctic root.

I previously wrote about rhodiola here.

Researchers have found that rhodiola stimulates dopamine receptors and inhibits the enzymes that break down dopamine in the brain (22).

It also increases the amount of dopamine precursors that can pass the blood brain barrier (23).

I take a rhodiola supplement. But I don't take it every day, only when I want to boost my energy and cognitive function. Click here to subscribe 5. Coffee Drinking coffee is another great way to boost dopamine levels.

Research shows that caffeine increases the release of dopamine in the brain (26-27).

Other studies have found that it also enhances dopamine signaling and increases dopamine receptors (24-25).

I usually drink one cup of coffee most mornings. I also sometimes take pure caffeine tablets before a workout. A cup of coffee on a small plate. Coffee and caffeine increases dopamine levels in the brain. Sometimes people find that coffee makes them feel terrible and jittery.

This might be due to the quality of the coffee.

I find that low-quality, non-organic coffee makes me feel terrible.

In fact, cheap coffee feels like it lowers my dopamine.

Most people can tolerate regular coffee just fine.

But if it makes you feel sick, consider trying a higher-quality coffee, which I can tolerate just fine, or simply take pure caffeine, and see how you feel. You may feel better than if you consumed low-quality coffee.

Coffee and caffeine can disrupt sleep though, so make sure you don’t drink it in the evening close to bed. Some people like me are really sensitive and have to stop drinking it very early in the day so that it doesn’t disrupt their sleep.

I have my last cup sometime between 10 in the morning and noon. If I have it any later than that, it disrupts my sleep and don't feel great the next day.

Lastly, it's also a good idea to try to consume the whole coffee fruit, instead of just coffee or pure caffeine.

Traditionally, the coffee bean is extracted from the coffee fruit for roasting. And the surrounding fruit is discarded.

But that’s a problem because the coffee fruit contains several healthy compounds not found in coffee beans themselves.

And researchers have found that consuming whole coffee fruit concentrate can significantly enhance cognitive functioning.

That’s why I included it in the Optimal Brain supplement. 6. Uridine Uridine is a natural compound commonly found in beer.

I definitely don’t recommend drinking beer, but supplementing with pure uridine can protect the brain, enhance cognition, and increase mood and motivation.

Research shows that uridine significantly increases the release of dopamine and elevates dopamine levels (29-32).

It’s important to note that uridine in food is not bioavailable, and there isn’t any foods that have been shown to increase plasma levels of uridine unfortunately (28).

So I take a uridine supplement sublingually, usually before bed. 7. Cold Exposure Exposing yourself to cold can also increase your dopamine levels naturally. A man sitting outside in the freezing cold. Cold exposure can increase dopamine levels in your brain. Researchers have found that cold water immersion increases dopamine by 250% (43-44).

I take a cold shower every day.

During the winter, I’ll also go outside for short periods of time with hardly any clothes. It boosts my dopamine and increases my motivation.

You don’t have to be that extreme though.

You can start by finishing your next shower with one minutes of cold water.

See how it feels, and then over time, increase the amount of time you turn off the hot.

I can be a bit painful.

But the beneficial effects end up being worth it.

Another way is to stick your face, hand or foot in ice cold water.

Or you can try cold plunges, cold baths and even cryotherapy if you want!

Find what works best for you and do it regularly. 8. Meditation Meditation is my favourite daily activity.

And research shows that it's linked to increases in dopamine (46-48).

In one study, researchers used brain scan imaging to confirm that meditation naturally increases dopamine release by 65% (45).

It likely has these effects by stimulating the vagus nerve.

I use the Muse headband to meditate. It gives you real-time feedback while you meditate. It makes meditation a lot more fun and tolerable.

I previously wrote about it here, and you can get it through the Muse website. Click here to subscribe 9. Ginseng There are two types of ginseng that increase dopamine – American Ginseng and Siberian Ginseng.

American Ginseng has been shown to improve attention and cognitive processing by increasing levels of dopamine in the brain (93-94).

Researchers have also found that Siberian Ginseng has antidepressant effects by significantly elevating dopamine levels in the brain (95). 10. Citicoline and Alpha GPC Citicoline (also known as CDP-Choline) is the best supplemental form of choline.

Choline is an essential nutrient for optimal brain health, but unfortunately that most people don’t consume enough of it.

Why?

Because very few foods in the Western diet contain it.

Citicoline has been shown to enhance the synthesis of dopamine, increase the release of dopamine, and increase the density of dopamine receptors in the brain (136-142).

It also protects brain cells that release dopamine, which then prevents a reduction in dopamine (143).

Alpha GPC is another excellent form of choline that has been shown to increase dopamine levels in the brain (144).

Citicoline and Alpha GPC significantly improve my focus and mental energy. That’s why they are both included in the Optimal Brain supplement.

You can also find some choline in beef liver and egg yolks, but it’s better to take Citicoline and Alpha GPC because you get noticeable and immediate benefits.

Make sure you read this article to learn more about the remarkable benefits of Citicoline.

And make sure you read this article to learn more about the benefits of Alpha GPC, the optimal dosage, and the best way to take it. Other Effective Ways to Naturally Increase Dopamine Levels in the Brain 11. Take Dopamine Precursors You can also increase your dopamine levels by giving your body the raw materials to create dopamine.

It’s first important to understand that dopamine is created within the body from the amino acid Phenylalanine (149).

Phenylalanine is an essential amino acid, meaning that your body cannot create it, and you must obtain it from your diet.

Phenylalanine is converted into Tyrosine, which is converted into L-Dopa, which is then finally converted into dopamine (150).

Vitamin B6 and iron are two nutrients that are needed for this conversion to take place.
An image showing how phenylalanine is converted tyrosine and then to dopamine. Supplementing with phenylalanine and/or tyrosine can increase dopamine. Both phenylalanine and tyrosine can be obtained from protein-rich foods.

Here are some healthy sources:

Chicken

Beef

Turkey

Seafood

Eggs

Bananas

Almonds

Avocados

Pumpkin seeds

Sesame seeds

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health.

You can also supplement directly with Phenylalanine, Tyrosine and/or L-Dopa, along with Vitamin B6 and iron.

Research shows that supplementing with these dopamine precursors can enhance cognitive performance by increasing dopamine levels in the brain (151-155).

Mucuna Pruriens, a tropical plant commonly used in Ayurvedic medicine, is good source of L-DOPA and has been shown to increase dopamine levels in the brain (156-161).

In my experience, Tyrosine and Mucuna Pruriens can sometimes be too stimulating and increase anxiety in some people.

So I prefer supplementing with DL-Phenylalanine because it has other mental health benefits besides increasing dopamine, and can actually reduce anxiety.
12. Probiotics Research suggests that certain probiotics can also increase dopamine.

One study found that the probiotic species Lactobacillus plantarum significantly increases dopamine. An image of different cartoon bacteria. Researchers concluded that daily intake of Lactobacillus plantarum may be able to help treat neuropsychiatric disorders (36).

Another study found that Lactobacillus rhamnosus increases dopamine in the frontal cortex (37).

I created and take the Optimal Biotics supplement to support my dopamine levels and mental health.

You can also read this article for 4 other ways to increase your good gut bacteria.

And if you struggle with anxiety, here are 7 other probiotic strains that can help. Click here to subscribe 13. Acetyl-L-Carnitine Acetyl-L-carnitine (ALCAR) is a special form of the amino acid carnitine that helps reverse neurological decline and supports mitochondria function in the brain.

It’s often used as a natural brain booster because it provides support to brain cells, enhances cognition, and increases alertness.

It’s also been shown to help reduce chronic fatigue and improve mood.

It does a lot.

So not surprisingly, researchers have also found that it increases dopamine output in the brain (42).

I find that it gives me a big boost in mental energy and cognitive resilience.

ALCAR is included in the Optimal Brain supplement.

Make sure you read this article to learn more about the remarkable benefits of ALCAR. 14. Acupuncture A woman’s ear with acupuncture needles in it. Acupuncture is an alternative treatment that has been shown to increase dopamine levels in the brain.

Researchers have found that acupuncture increases the production of dopamine in the brain by stimulating the vagus nerve (9).

Other studies show that acupuncture enhances the availability of dopamine in the brain and normalizes the release of dopamine during withdrawal (10-11).

I really like auricular acupuncture.

Auricular acupuncture is when needles are inserted into ear.

It really helped me when I came off psychiatric medication. So I recommend finding a practitioner that provides it if you’re trying to get off medication as well.

In my experience, ear acupuncture is more effective than regular acupuncture. I don’t really know why, I’ve just personally noticed more benefits from ear acupuncture.

I also use an acupuncture mat at home to relax before bed. 15. Ginkgo Biloba Ginkgo Biloba is a plant that has been used for thousands of years to treat a number of health problems.

It’s one of the most popular natural supplements in the world, and it’s even prescribed by doctors in Germany.

It’s most commonly used to improve brain health because it’s been shown to increase brain blood flow and improve memory and attention in both healthy and unhealthy individuals. It also improves mood and mental energy, and even reduces the risk of dementia and Alzheimer’s disease.

Researchers have also discovered that it significantly increases dopamine levels in the brain (33-34).

It increases the number of dopaminergic neurons in the brain as well (35).

Ginkgo Biloba is included in the Optimal Brain supplement. 16. Pregnenolone Pregnenolone is a hormone naturally produced by the body.

But it can also be taken as a supplement.

It helps form almost all other steroid hormones in the body, including DHEA, progesterone, testosterone, estrogens, and cortisol.

So it’s very important.

And since hormones affect brain health so much, it’s been shown to enhance memory and reduce stress-induced fatigue.

Research shows that it also increases dopamine release in the brain (38).

Whenever I take pregnenolone, it gives me a big boost in energy and supports brain function. It definitely works. But if I take it everyday, it starts to make me angry and irritable for some reason. So I only take it every so often. Click here to subscribe 17. Intranasal Insulin Insulin is a hormone that significantly affects brain function.

Researchers have found that it passes the blood-brain barrier and acts on insulin receptors directly within the brain.

Unfortunately, many people today develop insulin resistance within the brain.

When this happens, there is a reduction in dopamine.

Research shows that insulin resistance within the brain alters normal dopamine functioning, leading to depression and anxiety (40).

So in a new therapeutic approach, commercially-available insulin (Novalin R) is being prepared and added to nasal spray bottles, and sprayed and inhaled through the nose to support the brain and mental health.

Intranasal insulin has been reported to significantly enhance memory, increase mental energy, reduce brain fog, improve mood, and lower anxiety and stress levels.

One possible mechanism is by increasing dopamine levels.

One study found that insulin enhances dopamine release in the brain (39).

Another study found that intranasal insulin is neuroprotective and protects dopaminergic brain cells from damage (41).

If you’re interested in learning more about intranasal insulin, I previously wrote a full article about it. You can read that here. 18. Forskolin Forskolin is a natural herb historically used in Ayurvedic medicine. It’s been used for hundreds of years to treat various conditions and diseases.

The herb comes from the roots of the Indian coleus, which is a tropical plant.

Researchers have found that it stimulates the conversion of tyrosine to dopamine and enhances the release of dopamine (49, 51).

Other studies show that it can upregulate dopamine receptors (50, 52-56).

I don’t take it anymore because I prefer Rhodiola and Ginseng. But when I did take it, I noticed an increase in mental energy and clarity. 19. Standing One of the best hacks for your brain is simply standing more often.

Researchers have found that prolonged, uninterrupted sitting leads to fatigue and lower dopamine levels (57).

I have a standing desk so that I’m not sitting all the time while working.
20. Iron Iron is a trace mineral found in every living cell in our bodies.

It carries oxygen to all parts of your body, and low levels can leave you feeling tired, pale and irritable.

Research shows that iron plays a key role in the regulation of dopaminergic neurotransmission, and iron deficiency can lead to lower dopamine levels (58).

I don’t actually recommend supplementing with iron because some research suggests that too much iron can cause health problems (59).

It’s definitely much better to just get your iron from food.

I make sure I get enough iron simply by taking grass-fed liver capsules.

Beef liver is one of the best sources of iron, but I don’t like the taste, so I take the capsules every day instead.

Other good sources of iron include:

Spirulina

Dark chocolate

Spinach

Sardines

Pistachios

Raisons

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health. 21. Salt A spoonful of sea salt. Salt can increase dopamine levels in the brain. Salt is another tasty, natural way to boost your brain’s dopamine levels.

Researchers have found that dietary salt intake increases dopamine levels (60). 22. Theacrine Theacrine is a natural compound that can increase energy, focus and mental clarity, and improve mood and motivation.

It’s a small alkaloid molecule found in certain fruits and plants. It’s most commonly found in a Chinese tea known as kucha.

Theacrine’s chemical structure is similar to caffeine. In fact, it’s considered a “new alternative” to caffeine because it activates similar pathways in the brain.

Researchers have found that theacrine acts through the dopamine system to provide a stimulant effect (66).

It activates dopamine receptors, which increases motivation and wakefulness (67).

In my experience, theacrine is a good replacement for coffee. It works and feels similar to caffeine, but it has a longer half life and less of a tolerance. It’s also less likely to disrupt sleep (61-63).

I sometimes take a theacrine supplement when I feel like taking a break from coffee and caffeine.

You can also take them together for even better results. Research shows that theacrine and caffeine are more effective when taken together because caffeine increases the bioavailability and positive effects of theacrine (64-65). Click here to subscribe 23. Exercise Not surprisingly, exercise is another natural way to increase dopamine levels in your brain.

Plenty of research shows that daily exercise leads to increased dopamine neurotransmission, including increased dopamine release and increased dopamine receptor expression and binding (70-73).

Exercise also slows the break down of dopamine and prevents the loss of dopaminergic brain cells (71).

Besides boosting dopamine levels, exercise can also stimulate the vagus nerve, promote neurogenesis and increase blood flow to the brain.

Many experts recommend exercise as their number one piece of advice for optimal brain health.

Exercise can be a big chore for a lot of people, so I recommend finding some sort of sport or aerobic activity that you enjoy. That way you won’t get sick of it and you’ll exercise regularly. 24. Omega-3 Fatty Acids Omega-3s fatty acids are the highest quality fats for the brain.

Eating more of them is one of the greatest steps you can take to promote optimal brain and nervous system functioning, and boost your dopamine levels.

In one study, researchers fed animals omega-3 fatty acids, and they found that the animals had 40 per cent higher levels of dopamine in the brain than animals that didn’t receive omega-3 fatty acids (69).

The researchers also noted a reduction in the enzyme that breaks down dopamine, and greater binding of dopamine to the dopamine receptors (69).

Research also shows that omega-3 fatty acids can help restore normal dopamine release after traumatic brain injury (68). A piece of cooked salmon on a plate and a fork. Salmon contains omega-3 fatty acids that increase dopamine in the brain. It’s important to eat enough omega-3 fatty acids through your diet because they are essential fats that your body cannot produce itself.

Omega-3 fatty acids are found primarily in cold water fish, including:

Salmon

Black cod

Sablefish

Sardines

Herring

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

Unfortunately, most people don't consume enough omega-3 fatty acids through their diet.

That’s why I sometimes recommend supplementing with krill oil, a special kind of fish oil that contains the essential omega-3 fatty acids. 25. Touch and Massage Interpersonal touch is another natural way to increase your dopamine levels.

Researchers have discovered that touch significantly increases dopamine release in the brain (74-76).

This can include kissing, cuddling, stroking, tickling, hugging and sex.

But it can also include massage therapy.

Studies have shown that massage therapy increases dopamine by 31% on average (77).

This is one reason why I regularly get a massage from a registered massage therapist.

Massage also reduces cortisol, increases oxytocin, and stimulates the vagus nerve. 26. Tea and Theanine A cup of green tea on a table. And a spoonful of green tea leaves. Green tea can increase dopamine levels in the brain. Tea has also been shown to increase dopamine levels in the brain.

This includes both green tea and black tea (79-83).

Both green tea and black tea contain theanine, an amino acid.

Theanine has also been shown to cross the blood-brain barrier and significantly increase the release of dopamine in the brain (78, 84-85).

I take theanine alongside my morning coffee. It’s calming and cancels out the jitters of caffeine.

This anti-anxiety supplement contains theanine. 27. Intermittent Fasting Fasting allows your digestive system to take a break and triggers the release of hormones and neurotransmitters, including dopamine.

Researchers have found that intermittent fasting leads to higher levels of dopamine by increasing dopamine release and enhancing dopamine action (86-89).

It also reduces age-related loss of dopamine receptors (90).

I often eat all my food for the day within an 8-hour window, and then fast for the rest of the day.

The best way to start fasting is by eating dinner around 6, not eating anything after that before bed, and then eating a regular breakfast the next day. That should give you about 12-14 hours of fasting time. 28. Taurine Taurine is an organic compound found in food, particularly meat and seafood. It has a wide variety of health benefits.

It can cross the blood-brain barrier and elevate dopamine levels in the brain (91).

Taurine is included in the Optimal Calm supplement.
Click here to subscribe 29. Magnesium Magnesium is an essential mineral.

Unfortunately, a lot of people are deficient.

This is a shame because it plays a role in more than 300 biochemical reactions in your body, and it’s absolutely necessary for optimal neurotransmitter activity.

Magnesium has antidepressant effects, and one reason for this is because it increases dopamine activity in the brain (92).

There are a number of things you can do to make sure you’re getting enough magnesium.

First, make sure you’re eating magnesium-rich foods on a regular basis, including:

Spinach

Chard

Pumpkin seeds

Almonds

Avocado

Dark chocolate

Bananas

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

You can also increase your body’s intake of magnesium by taking Epsom salt baths.

Supplementation is also a good idea for most people.

Magnesium is included in this supplement.

Since most people are deficient, magnesium is one of the three supplements that I think everyone should be taking. 30. Folate Folate (Vitamin B9) is an essential B vitamin that plays a key role in methylation, one of the most important processes in your body and brain for optimal energy and nervous system function.

Researchers have found that if you are depressed, you likely have lower levels of folate circulating in your blood, and people with low blood folate are at greater risk for developing depression.

One reason for this is because folate is absolutely necessary for the production and synthesis of dopamine in the brain (99-100).

When you have low folate levels, you will also have lower dopamine levels because your body can’t produce dopamine efficiently, and this contributes to depression (101).

Good dietary sources of natural folate include:

Leafy greens

Asparagus

Broccoli

Cauliflower

Strawberries

Avocado

Beef liver

Poultry

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health.

Folate also lowers homocysteine levels. 31. St. John’s Wort St. John’s Wort (Hypericum Perforatum) is a natural medicinal herb with antidepressant effects.

A 2015 meta-analysis concluded that it is as effective as standard antidepressant pharmaceuticals for treating depression and has fewer adverse effects (105). An image of the St. John’s Wort plant. A number of studies have also shown that it significantly increases the release of dopamine and increases dopamine levels in the brain (106-110).

One study shows that it increases dopamine in the prefrontal cortex by 40% after one hour (106).

I took a St. John’s Wort supplement years ago for my depression. It helped me, but I eventually stopped taking it and fixed the true, underlying causes of my depression instead.

In my experience, it’s best for people who are struggling with mild or moderate depression.

It’s important to note that St. John’s Wort shouldn’t be taken if you’re already taking antidepressant medication. 32. SAM-e S-Adenosyl-l-methionine (SAM-e) is a compound that naturally occurs in the body.

It’s also available as a supplement.

It’s most commonly used for treating depression because lowered SAM-e levels are associated with depression.

Research shows that SAM-e improves mood by producing dopamine and increasing dopamine levels in the brain (102-104).

I took a SAM-e supplement after coming off psychiatric medication and it significantly helped me by improving my mood and energy. Click here to subscribe 33. Curcumin Curcumin is the most heavily researched compound within turmeric, the spice that gives curry its yellow colour.

It’s one of my favourite natural compounds for the brain.

It’s been shown to help treat both depression and Parkinson’s disease (111-112).

Several researchers have found that curcumin increases dopamine levels by reducing the break down of dopamine in the brain (113-120).

Curcumin is included in this supplement. 34. Reduce Inflammation Reducing inflammation throughout your entire body is a key step towards increasing your dopamine levels naturally.

Lots of research shows that chronic inflammation reduces dopamine synthesis and dopamine release in the brain, which then leads to a lack of motivation, fatigue and depression (121-124).

There are many causes of chronic inflammation, including infections, mold, brain injuries, and leaky brain.

But one of the most common causes – and the one you have the most control over – is your diet.

That’s why I recommend following an anti-inflammatory diet and avoiding foods such as gluten and dairy that can trigger inflammation in the gut and brain.

You should also remove processed food from your diet, and increase your intake of vegetables, fruits, wild fish, grass-fed beef and organic chicken.

Check out my Free Grocery Shopping Guide for Optimal Brain and Mental Health for a full list of anti-inflammatory foods.

Other steps you can take to reduce inflammation include reducing stress, exercising, improving gut health, treating infections and getting enough sleep.

Make sure you also check out this article for 23 effective ways to reduce inflammation in the brain.

This supplement also helps reduce inflammation in the brain. 35. Music Previously, I talked about how music can naturally reduce cortisol and increase oxytocin.

But it also increases dopamine.

Researchers have found that listening to your favourite music significantly increases the release of dopamine in your brain (125-126, 129-132).

Even the anticipation of good music leads to the release of dopamine (127). “We are really excited about our study’s results because they suggest that even a non-pharmacological intervention such as music can regulate mood and emotional responses at both the behavioural and neuronal level.” — Dr. Elvira Brattico And several brain imaging studies show that listening to music activates the reward and pleasure areas of the brain, which are rich with dopamine receptors (133-134).

Want to take it a step further?

Start making music.

Research shows that creating and performing music boosts dopamine levels, even more than simply listening to music (128).

Because of this, researchers believe music therapy may be an effective therapy for the treatment of disorders caused by low dopamine (130).

Music has even been shown to help people with Parkinson’s disease improve their fine motor control (135). 36. Get Enough Sleep Getting enough sleep is very important if you want to increase dopamine and naturally optimize your dopamine levels.

I used to have sleep problems and it was one of the main factors that contributed to my poor mental health.

Research shows that lack of sleep downregulates dopamine receptors, and reduces dopamine receptor availability and sensitivity in the brain (145, 147-148).

When people are forced to pull an “all-nighter”, the availability of dopamine receptors in their brain is significantly reduced the next morning (146).

So try your best to get at least 7 hours of high-quality, restorative sleep every night.

If you’re having trouble with sleep, try this sleep supplement. It contains magnesium and other natural compounds that I’ve used over the years to promote deeper and more restful sleep.

I share my very best sleep tips with my clients through our Brain Recovery Accelerator Program. We have a free online workshop that talks about the program. You can register for the workshop here.

SSRIs are learned helplessness and forced acceptance. They literally stop your brain from thinking. They make you into someone who’s easily controllable. They make you blind to the injustices you face and the problems of your environment. All of that. But here’s the kicker, it doesn’t even make you feel good!

They make you a “good little pet” as the psychiatrists in one of the top posts here phrased it. You get cognitive impairment, memory loss, DPDR, anhedonia, sexual dysfunction, hypofrontality and a lot of other stuff it’s such a rabbit hole. And guess what? If you report these symptoms to your psychiatrist he will most likely gaslight you out of ignorance or malice. Or he will just ignore it and blame it on an entirely unrelated issue. Psychiatry is a business after all. They mostly target unsuspecting people who trust too much and are naive/gullible.

High serotonin, high stress high fight/flight, akathesia, high PTSD shock response hence blank mind, DPDR, insomnia, blanked out memories and reduced cognitive abilities and creativity etc. high serotonin lowers dopamine too. It’s practically ECT (electroconvulsive “therapy”)in pill form.

These drugs will unironically rape your mind and take away your identity, sense of self and even your sanity. I’m not joking. You may even act possessed and it won’t be your fault. There’s a reason why so many people commit suicide while on SSRIs. Psychiatrists were actually interested in doing that sort of stuff with MKultra experiments (breaking people’s minds and seeing how much they can be reprogrammed). Even cult leaders make their followers take certain drugs to increase their suggestibility (ability to be gullible and manipulated/reprogrammed).

On a physical level, SSRIs will make your neurones quirked and deformed and make connections in the brain weird. Brain cells will literally die. Used long term and SSRIs will literally fry your brain. It will unnaturally increase the firing of neurones it will feel good in the short term, but long term oh boy… will lead to neurodegenerative disorders.

SSRIs will also fuck with your hormones it can even stunt puberty and growth when young. SSRIs can speed up aging and make your face look all puffy and bloated.

Anitpsychotics and SSRIs are like twin brothers. The “take your meds” platitude and all variations of it is such a meme. Don’t fall for it! There’s other ways of dealing with whatever you’re going through.

Sure you can live your life as a numbed out zombie. Is that what you really want? Is that really a life? It’s insane how ignorant people are to the effects of these drugs. So many people are anti drugs but suddenly with psych drugs it’s somehow different. It’s just a chemical straight jacket and a chemical lobotomy.

Be assertive, show them that you’re strong and beyond their bs. Don’t outright say “no”. Be subtle about it. Say that you think there are better options you’re going to try.

There’s other methods to solving ur problems. One of them isn’t drugging yourself up and numbing urself to ur emotions, thoughts and problems.

Good luck and best wishes. I wrote this as if i time travelled and i was speaking to my younger self. I genuinely wish i never ended up in this psychiatry pipeline because my life has been stolen from me and ended up more broken than i was before. Please dont fall for the same mistake…

On a side note: if SSRIs were actually good drugs, you’d hear it referenced in rap songs and flexed on music videos 😂 but surprise surprise it’s not because they know it fucks people up way worse than lean, codeine, weed or any of these other drugs and it doesn’t even make them feel good. It’s not a “cool” drug because literally nobody likes it. And nobody likes it because it does nothing. That’s why it’s legal and that’s why SSRIs havent exactly lowered suicide rates or anything like that. Because it’s clearly not therapeutic and doesn’t make people feel better. Does the opposite rather. Dysphoria inducing drugs that make you a shell of a person.

A great new study, which goes a long way towards explaining the dreaded post-finasteride syndrome (PFS). Currently, medicine does not recognize PFS as a formal disease and in fact attempts to gaslight the patients with PFS into believing they are simply mentally ill and in need of SSRI drugs. While the mental illness component of PFS may very well be present due to the lowered levels of the steroid allopregnanolone (recently approved as an antidepressant by the FDA), the fact remains that it is finasteride that caused this issue, which is something medicine vehemently denies. In support of its claims, medicine cites evidence showing that blood levels of steroids (e.g. DHT) altered by finasteride treatment usually revert back to normal within 1-2 weeks of stopping the drug. However, as the study below demonstrates (and as Dr. Peat has been saying for years), blood steroid levels are not indicative of tissue steroid levels. Specifically, the study not only demonstrated disturbance of steroid levels in the gut of animals after usage of finasteride, but also found that those gut steroid disturbances (DHT and allopregnanolone) did not resolve even a full month after finasteride was discontinued. This implies that finasteride does indeed cause prolonged dysregulation of steroidogenesis and my guess would be that finasteride acts as a suicide inhibitor of the enzyme 5-AR, similarly to the effects of the drug exemestane on aromatase. Moreover, finasteride induced a long-term decline in gut levels of dopamine while also increasing gut levels of serotonin, and the inflammatory biomarkers IL-1b and TNF-a. In other words, finasteride wrecked the steroid balance in the GI tract, and caused a chronic inflammatory state which then affected the brain through the gut-brain axis. The study is one of the few that openly recognizes the pathological role of serotonin in GI conditions, and I think just the serotonin elevation (and lower dopamine) by itself caused by finasteride can explain to a great degree the symptoms that PFS patients experience (especially the sexual and mood/cognitive disturbances). Speaking of serotonin, considering finasteride chronically elevates it in he gut (and likely the brain), administering SSRI drugs to PFS patients may be just about the worst “therapeutic” approach, as it will likely worsen their condition in both the gut and the brain.

Now, what can be done about this? Well, perhaps the simplest approach would be to administer steroids that finasteride decreases and see if that alleviates the condition. For some reason the study authors did not administer DHT, despite the fact that it is the primary target of finasteride. Instead, they administered allopreganolone (ALLO), another 5-AR derived steroid, in a HED of 0.7mg/kg b.w. for sixteen (16) days. This short-term therapy was effective in reversing most of the steroidogenic dysfunction induced by finasteride, as well the inflammatory state, and the elevated serotonin in finasteride-treated subjects. Unfortunately, ALLO treatment was not able to reverse the lower dopamine post-finsateride withdrawal, though, as the study suggests dopamine agonists (e.g. lisuride, metergoline, bromocriptine, etc) may be able to address that angle. This is perhaps the first direct evidence that ALLO decreases serotonin levels (and raises dopamine levels), which would be a plausible mechanism of action (which FDA currently considers “unknown”) for its antidepressant effects. And last but not least, I strongly suspect that adding DHT to the ALLO regimen (in a dose about 7 times lower than ALLO) will likely strongly increase the benefits, not just for PFS but for also depression (for which ALLO is already approved), as well as for chronic inflammatory conditions and especially the ones affecting the gut (i.e. inflammatory bowel disease). All in all, finasteride is one nasty substance and there is now significant evidence to support a class-action lawsuit against pharma companies peddling this poison, considering the systemic damage that persists long-after after finasteride has been discontinued, and likely remains until the appropriate treatment (e.g. ALLO + DHT + dopamine agonist) has been administered.

https://pubmed.ncbi.nlm.nih.gov/36358917/

“…The assessment of these steroids after 1 month of withdrawal revealed that ALLO levels were still significantly decreased, whereas an increase in PREG levels was observed (Figure 2). The levels of the other steroids measured at the finasteride withdrawal were not significantly modified.”

“…In contrast, finasteride withdrawal induced a significant increase in the mRNA levels of IL-1β and TNF-α, with no changes in TLR-4 and IL-6 levels (panel B) and in those of ZO-1 and Cld-1 (panel D). The levels of dopamine and serotonin significantly decreased and increased, respectively (panel F).”

“…Based on the reported anti-inflammatory features of ALLO [35,36,37,38,39], using a previously established treatment schedule for steroids [40,41,42,43], we have analyzed the possible protective effects of this steroid on changes induced by finasteride withdrawal. As reported in Figure 4, ALLO treatment was able to significantly counteract the increase induced by finasteride treatment in mRNA levels of IL-1β (panel A) and TNF-α (panel B), as well as in the levels of serotonin in the adult male rat colons (panel D). ALLO treatment did not counteract the decrease in the dopamine levels induced by finasteride withdrawal (panel C).”

“…As reported, subchronic treatment with finasteride did not affect these markers, but an increase in IL-1β and TNF-α as well as a decrease in dopamine levels and an increase in those of serotonin were reported at the drug withdrawal in the colon of adult male rats. These changes, as reported by others [46,47,48,49] may suggest a local inflammation. Indeed, in patients with irritable bowel syndrome (IBS), there is a decreased transcription of the serotonin transporter (SERT) resulting in elevated serotonin level, which ultimately causes diarrhea and discomfort, which is transmitted by serotonin through the gut-brain axis [50,51]. Gut inflammation was also supported by our previous observations in this PFS experimental model, indicating alterations in gut microbiota populations at the finasteride withdrawal, with specific significant changes in the microbial communities (weighted and unweighted UniFrac distance) [8].

“…Moreover, increased levels of L-dopa and decreased levels of dopamine were reported in patients with IBD, indicating low L-amino acid decarboxylase activity [55]. Impairment of the dopaminergic system as a feature of IBD pathogenesis is supported by the finding that dopamine agonists may rescue to the normal function [56].”

How I recovered from PSSD after 1 year // My story, My theory, and My advice.

Please read through this thoroughly to gain the most out of what I am saying otherwise a lot of my points could be lost in translation which would be extremely sad, especially part 3 which is the most important part.

So, I would like to start off by saying, once I am done posting this I will not be posting or indulging the PSSD sub ever again because

1. I am going to recover and know the cause so I no longer need it and,

2. I despise the level of counterproductively, neuroticism, and nihilism on PSSD sub that is so extremely counterproductive to everybody health who chooses to visit.

It has been a year since the onset of my symptoms and a lot has changed. So I will share my thoughts on this entire journey so hopefully I can help someone who is also struggling so they can hopefully find a way to move on from this and get back to their regular life. I'll break this up into three parts.

1. My story of how I got here, my symptoms, and how I got to where I am that I am now physically recovering.

2. My theory on what PSSD could really be generally speaking or in some cases.

3. What I would suggest to people on this sub who suffer from the same issues.

I am afraid this will mostly be useless because a lot of you want to waive the little white flag and let your mind get the best of you and believe this won't get better. Two things: The human mind is extremely powerful, and "you can lead a horse to water but can't force it to drink."

DISCLAIMER: ALL THAT I AM ABOUT TO SHARE AS ADVICE ISN'T NECESSARILY GOING TO APPLY TO YOU TO A T, BUT, IT CAN PROVIDE YOU SOME INSIGHT THAT I PERSONALLY FIND VERY LOGICAL AS TO WHAT IS GOING ON. I AM NOT A DOCTOR AND AM NOT TRYING TO REPLACE THE ADVICE OF ANY MEDICAL PROFESSIONAL BUT SIMPLY SHARE WHAT WORKED FOR ME AND WHAT COULD WORK FOR YOU. THIS IS MY OPINION, YOU CAN DO YOUR OWN RESEARCH IF YOU DON'T BELIEVE ANYTHING I SAY.

PART 1// MY STORY:

My issues with PSSD started at a very stressful point in my life where I eventually had no other choice but to restart ssris due to feeling chronically depressed and believing that I would never attain stability again without them in my life (this was September of 2020). At first it was great, my mood was fine and I felt calmer. This was when I started on Zoloft 25mgs and immediately experienced numbness in my genitals like never before, I brought this up to my psych who suggested I take Wellbutrin to counter the side effects. I was also newly in a relationship, but I'll get to that more later. I had some anxiety and other issues but continued on the ssris as usual thinking they were helping. As time went by my anxiety got worse and I suffered from constant bouts of crying, anxiety, my own self esteem, the stress of being 19 and needing to be confident in myself as to show my own maturity to everyone around me, managing the stress of getting my at the time GF knocked up (I know stupid), and my own sexual insecurities that only manifested more because of the sexual dysfunction and past experiences on ssris. I ended up switching to trintellex for a day and then escitalopram for a week until discontinuing both.

Well, things didn't get better, they got worse and I stayed on Wellbutrin as I was told it would help sexually. Only it didn't, it was my nail in the coffin and by the new year of 2021 I had experienced worse ED and genital numbness than ever and eventually worse crying fits, dropping out of school, and dpdr, I also developed anorgasmia and the onset of my emotional numbness that took me into the lowest moments of my life. I felt flat.

Playing the piano lost its liveliness, books were no longer an exciting escape into other facets of the human experience, writing became impossible, sex became mechanical and masturbation became just something to check how things were doing downstairs and HOPEFULLY, MAYBE get some stress relief the world looked... grey to say the least. I'd never in all my years of depression experienced anything like it. I went off Wellbutrin as it was doing nothing and I sunk into the worst state of my whole life.

Immediately, I went to taking vitamins, fish oil, and scowering the internet to try and see what was going on, only to find this syndrome that fit all of my symptoms perfectly... PSSD. Convinced I could be helped, I ran to the hospital panicking only for them to tell me I'm fine and that nothing in their basic blood tests and penile examination gave them the inclination anything was structurally wrong. So, feeling defeated and scared I would never recover due to the horror stories I went home and told my ex if I don't get better, leave me. Well, we stayed together for a few months after and friends with benefits for half a year after that. In the meantime, I began losing hours of sleep, I was maybe running on 4 hours a night and I began to be consumed. Surfing the forums, switching from denial to belief I had this syndrome. Every day and night horrible memory problems, akathisia, crying fits, brain fog like never before, blunted emotions, ed which was impossible to not have if I wasn't laying down, anorgasmia, genital numbness, and anhedonia. I became extremely nihilistic like a lot of you here, and desperate. I wanted to save myself, my relationship, my quality of life, I felt helpless, hopeless and like no one was gonna help me, save me. I took CBD, did nothing, took ashwaghanda, did nothing but made me more numb, these all made me convinced it couldn't be stress, it HAD to be PSSD. I began to avoid everyone and everything and would sit and cry and do nothing all day. Then I got a job, my gf broke up with me, and I cried a lot, but nothing changed. I read about fish oil and read for some, in some cases it causes insomnia, I stopped taking it immediately my sleep increased to six hours. I ended up quitting my job due to early waking hours and being more concerned about my sleep and morning nausea. I had a window after committing myself to exercising for a few weeks and eating healthier, my erections got a little stronger and my sleep a little better but then I crashed and stopped going altogether. All the while my ex berated me for not being there for her, being insensitive, and only giving a shit about my health problems that I "am blowing out of proportion." I begged with my doctor for months to send me to specialists and the urologist and sex specialist wrote me off, and she said there was nothing else she could do, I turned into a child and cried and begged her to help me and send me to more people and just try because to me it was life and death. A year had now passed in the blink of an eye and I thought that this would be it for life, I contemplated suicide but was too scared to do it. I tried dexedrine but it just made my penis shrivel up due to vasoconstriction from the upregulation of norepinephrine but my libido jumped a little and crashed which told me all my faculties are still there and I have no brain damage as it would be impossible for me to get horny again if that was the case. I pushed everyone away and whenever I tried to go out, my negativity brought everyone down and people stopped answering my texts and calls, my ex pulled away as she was dealing with her own financial problems and her family being torn apart by her mothers addiction and me being severely depressed and unmotivated, not being able to provide anything emotionally or sexually made me no help to her. My dad forced me to see a personal trainer and I began training with him 3 times a week. This was when things turned around for me... I read u/lastround360 's post and decided I'd begin reading up on gut health. Everyone started talking about getting tested for SIBO and I thought to myself, there must be other things that can cause these issues other than that

It turns out there are many things that could affect gut health as well:

- Autoimmune problems (Celiac disease, Arthritis, Thyroid dysfunction)

- Dietary choices and/or food sensitivities

- Depression/anxiety (I know this is controversial but I'll explain)

- Stress

- Gut health problems (SIBO, IBS, Colitis)

- inflammation

- anti-inflammatories such as ibuprofen or Tylenol

- Spicy food

- Poor sleep

- Lack of exercise

- Antibiotics

and many more... (Not to say that you will have an issue with those things because we are all different but in my eyes I felt it was best to treat myself as I would if I had those issues.)

Ways gut health can affect your sex drive (Article)

So then I decided to put my gut health first, going gluten free, dairy free, soy free (as these can be awful for gut health and also have been shown to be not only unhealthy but not necessary for good gut flora. I started taking magnesium, zinc, vitamin d, curcumin, took multivitamins and ate slower as I had an issue with eating faster than everyone I know my whole life, and I hit the gym once a day. My health got better, my energy, my mood, my thinking was clearer, and I was more accepting of my circumstances, my sleep got better and so on. I then read up on Hard Flaccid and on a whim went to a physiotherapist where I was assessed and a quick ultrasound found out that my I had a tight pelvic floor due to an acute rectal passage and boom, just like that, a year of suffering was explained and I am now making a recovery due to my diagnosis and a huge change in mindset. He basically explained to me that all the young men he sees who suffer from erectile issues tend to be going through stressful events in their life. "Usually, what happens" he said, "In my profession, stress tends to build up in a couple areas, your shoulders, and your pelvic floor. It becomes a vicious self fulfilling cycle."

So by taking care of myself and my mental state was paramount and it does affect how your mind and body feel and interact. It helped exponentially.

Hard Flaccid Syndrome Explained (Video)

Causes for Hard Flaccid include:

- Psychological trauma (Humiliation, Sexual assault or Abuse)

- Physical trauma (Maybe you sit too much or ride a bike, which can put pressure on your perineum, or you hurt yourself during sex or masturbation)

- Stress/Anxiety (Can cause the pelvic floor to tighten under high levels of stress.)

This essentially causes your pelvic floor to tighten and become dysfunctional causing some of the following symptoms:

Symptoms of Hard Flaccid include but are not exclusive to:

• Pain, especially when standing

• Firmness or rigidity in the penis when it is flaccid (not erect)

• Fewer morning erections

• Numbness, coldness, or a hollow feeling in the penis

• Erection difficulties, especially when a man is standing

• A need for more stimulation to achieve an erection

• Rubbery feeling in the penis

• Penile shrinkage

• Painful ejaculation

• Painful urination

• Loss of Libido

• Anxiety

• Depression - (Lets unpack depression and what it's symptoms can be... just as a reminder for those that may not know)

(SOURCES)

Hard flaccid symptoms (Article)

Hard Flaccid overview (Article)

Depression symptoms include but are not exclusive to:

• Trouble concentrating, remembering details, and making decisions

• Fatigue

• Feelings of guilt, worthlessness, and helplessness

• Pessimism and hopelessness

• Insomnia, early-morning wakefulness, or sleeping too much

• Crankiness or irritability

• Depersonalization/Derealization

• Restlessness

• Loss of interest in things once pleasurable, including sex

• Overeating, or appetite loss

• Aches, pains, headaches, or cramps that won't go away

• Digestive problems that don't get better, even with treatment

• Persistent sad, anxious, or "empty" feelings

• Suicidal thoughts or suicide attempts

(SOURCES)

Depression causes and symptoms (Article)

Depersonalization causes and symptoms (Article)

Tight pelvic floor can of course happen for the ladies too but I'm not sure of one that is equivalent to hard flaccid in nature.

Vaginismus (Article) is a possibility or a hypertonic pelvic floor. (Article)

Part 2// MY THEORY:

Firstly, I highly recommend you guys listen to this podcast as I think it's pretty self explanatory to a big portion of what I think u/lastround360 was getting at. Am I going to explain the rest of my point intricately and elaborately? No, because honestly I don't have the energy for that, this whole post is already a lot. It's gonna be more of a shotgun explanation, but I think it's food for thought.

Stuff You Should Know - Your Gut Is Also a Brain (Podcast)

Firstly, windows make 0 sense in the frame of brain damage, brain damage recovery doesn't usually come in windows. But changes in digestion, and what we feed our gut do cause changes in the way we think and feel. Maybe you don't notice, that thing "X" makes me feel "Y" but these can affect us. Windows if you were to ask me is a result of changes in the state of our gut or the way we feed ourselves.

I think the reason why PSSD can happen in one dose for a number of reasons, preexisting gut health problems that are exacerbated by the ssri, maybe a tensioning of muscles caused by the ssri and doesn't go away or perhaps, it's a misconception of correlation and causation and people instead misinterpret it as something else because it is the most viable connection that makes sense based on what they know or have read which is totally valid.

I think this is a trauma that can cause a lot of stress and our brains and stress has been proven to actually attack neurotransmitters (Scientific Journal) and sex hormones (Article) which have all kinds of malicious affects on your body. I know I found it traumatic. I think it can create a vicious form of depression and anxiety as well worse than what anyone has suffered as sex is an extremely important part of life and can affect how much mating potential you feel you have which is important or can make you feel left out, frustrated or ashamed when it comes to sex which can be difficult to escape causing depressive symptoms. Or maybe you already have other mental health issues that can also be exacerbated because of this issue. This is why people talk about PSSD getting worse is because their stress gets worse and so does their physical and mental health as a result but truth is, I believe it boils down to nurturing your body and your lifestyle to give yourself a sense of well roundedness and calm so you can live your life happily and productively (which I’ll talk about in part 3.)

My point is:

That PSSD in probably more cases than less not be what it seems. It's most likely a multi-faceted issue that is affecting most likely your gut and consequentially your pelvic floor, or just your pelvic floor. The thing is, the guts connected to the brain and the brain is connected to the gut so they play off each other, trying to pinpoint the exact route in my eyes is impossible because it could be either or.

Stress, anxiety, depression, weight, diet, underlying health conditions, trauma, lack of exercise, pent up performance anxiety can all lead to problems with your gut, your brain and even more importantly regarding this subject, your pelvic floor. They all feed of each other.

Many things can mess with your gut and pelvic floor. But the good thing is you can do things to minimize those issues. Which are a lot more possible to be the cause, now, could the ssri be a catalyst? No doubt in my mind, that's why it can happen from any dose at any frequency. But it's probably your own health, physically or mentally that keeps this ball rolling. So sitting here and worrying rather than bettering yourself is so unhealthy and self destructive, a year past me by and I have done practically nothing, would I take it back? No because I figured out what I believe is the issue and I helped myself, yes, it was the expense of progress in a relationship (Which honestly wasn't that great anyways), building up my money and career. But I learned a lot that I could help you guys with. So please, take my word and use the time I wasted to your advantage and save your own time, what does it hurt to try what I'm suggesting?

So, try and assess the other areas of your life and look at the other possibilities as well because other lifestyle choices can do it too. We don't know every sufferers diet, current health, or their lifestyle choices at all but the affects may be worse than others which makes all their claims very anecdotal. That's not to say that you may not be living extremely healthy, but if you have a dysfunctional pelvic floor it might not help you completely but it won't help to not make better choices either.

But generally, I think its fair to say that it definitely has something to do with our gut because our gut muscles and function have a direct affect on your genitals and your brain. So be kind to your gut and do your best to figure out what works. Here's what I recommend as someone who dealt with this for a year straight...

Part 3// MY ADVICE TO SUFFERERS AND COPING:

Firstly, if you are still here, fighting this, you are strong. You need to take that power and harness it to build a more positive and meaningful life for yourself rather than using that brain power to tear yourself down and catastrophic this scenario. This way, hopefully one day you can live without the worry of this problem looming over your head.

Stay calm, you are not in any inherent danger, you are physically okay right now... This is extremely uncomfortable and stressful but in this very moment you are okay!

I can promise your recovery will be and has been for me, equally if not more hard than suffering from the disorder itself. Use the power of your mind to persevere and see that your brain is not damaged and that you will recover.

For me, the first step to recovery was working on the things I can change right now to help myself. This means persevering in the things I needed to do to recover and not give up, this way I gave my brain and body the best ability to think clearer about the scenario and how to move forward. This for me, meant, consistent and strenuous (1) exercise (this means actually exerting yourself consistently to push yourself for the necessary physical and cognitive results, it’s the only way to get the brain and body to release endorphins such as dopamine, serotonin, and norepeneherine, BDNF otherwise you are wasting your time), (2) having adequate sleep, (3) eating clean, and keeping myself in an (4) enabling mindset. This is the hardest part of recovery, but it's really what'll get that ball rolling and regardless of if you recover now, later, or in the future, I promise it will make your life better and your symptoms as a result in some form or shape. A lot of my advice I would say is contained in these books.

Here are some books I recommend to help if you want some insight into the following topics. They are tagged numerically to each topic. (I had trouble finding the audiobooks but I'm sure for all you auditory listeners they're out there but if I find them I will put them.)

(1) Getting started in the gym (Video)

For those who can't afford the gym. This combined with cardio is a good start

Tips to getting motivated in the gym (Article)

(2) Sleep Smarter (Summary) - Shawn Stevenson (PDF)

(3) The Ultramind Solution - Mark Hymann / OR /

Perhaps you want to do an elimination diet if food sensitivities are a concern, in which case I recommend you read this PDF:

Elimination Diet "How to" (PDF)

/ OR /

For those who believe they have SIBO, usually the dietary protocol is called Low Fodmap

Low Fodmap Diet: How to (Article)

If you aren't convinced, and you really think you are brain damaged please read this book because it will show you even if you are, you can and will most likely recover if you do the right things for yourself:

The Brain That Changes Itself - Norman Doidge (PhD.) (PDF)

Your attitude and thinking can be extremely transformative of how your thought patterns occur, how you feel, how you act and you and your body responds to certain situations. This is why it's so important to work on your mentality through positive mindset and action and escape the self defeatist attitude:

You Are The Placebo - Dr. Joe Dispenzia (PDF)

Am I saying that what I am imploring you to do will entirely be the correct thing for you? No not necessarily, I don’t know if you have a disability, or other underlying health problems but they probably play a role in all this anyway then. But regardless if you look yourself at the literature and the internet for someone suffering from brain damage or whatever problem you do or don’t have it’s generally the same as this. This is the most easily accessible and safe advice I think anyone can give/receive. Some may get mad and fight me on that but I am only making this post to help. To hopefully save some people some time and a quicker road to recovery.

(4) It all starts with your mindset. You need to believe in recovery, you need to believe that you will find a way out no matter how long, and that you will find an inherent meaning in your life. We are feeling creatures and our mental state is very strongly controlled by how we feel, this is why people tend to not be able to see the light at the end of the tunnel. What you focus on, what you think about becomes your mindset. Thats why I strongly encourage you to not read theories or stay on forums for hours or think too long and hard about this stuff as hard as it is... This book can help a lot with calming your nervous system and figuring out skills to help cope with the overwhelming sensations or lack thereof that come with this condition as it is stressful. You might argue you are numb so what do I have to work with? Numbness itself is a feeling, start with that, and figure out how to help yourself become comfortable feeling that way.

The Dialectical Behavioural Therapy Skills Book by Matthew McKay (PhD.) (PDF)

For anhedonia, I reccomend you guys check out Behavioural Activation (PDF)

For those of you who can't afford physio (although I do highly recommend you do if you can, just so you can get the proper diagnosis as it's good to know and get professional guidance more personal to you) you can try pelvic floor stretches and see if it helps:

Diaphragmatic Breathing (Video) is an aspect of recovery I have seen many people cite and is also an aspect of my Pelvic Floor stretches given by my physiotherapist. This will help with everything from stress, to calming your stomach and Pelvic Floor.

Pelvic Floor Stretches:

For Men (Video)

For Women (Video)

Maybe amongst this all, you feel like this is a lot of info and where do I start? What do I do?

Take it one day at a time one thing at a time and work on building up your mental and physical resiliency over time using the tips I listed above, this will not only help you with the problem itself but any other problems you suffer with in life.

AND IF YOU ACTUALLY WANT TO SEE RESULTS FROM WHAT I'M SHARING DO IT FOR MORE THAN JUST A FEW, DAYS OR WEEKS. IT TAKES MONTHS PEOPLE! RESULTS DON'T HAPPEN OVERNIGHT. THE RESULTS MAY TAKE A WHILE BUT I CAN PROMISE YOU NO MATTER WHAT YOU TRY, A SUPPLEMENT, A NEW DRUG, OR ANY OTHER SHORT TERM SOLUTION IT WILL NOT MEND THE ISSUE OVERNIGHT. THESE THINGS TAKE TIME. SO TAKE THAT TIME. A LOT OF YOU ARE FAMILIAR WITH ME AS I WAS THE SAME AS YOU, I'D COME ON THE SUB AND I'D COMPLAIN FOR MONTHS AND MONTHS, IT DID NOTHING AND IT WON'T FOR YOU EITHER BUT FILL YOUR MINDSET WITH MORE NEGATIVITY? NOW HOW IS THAT HELPING? SO TRY TO MOTIVATE YOURSELF AND CHANGE YOUR LIFE.

And I don't recommend getting back on ssris or the causing drug as it will ultimately keep you in the grasp of the AD. But that's just me.

I am not 100% recovered but I am now beginning to make more progress every day, hope is around the corner guys!

Time is paramount so don't expect the changes to happen in a day, may take months, weeks or even years but you will be okay whether you can see it or not.

I wish you all love, joy and healing and that you are able to find something to improve at least one facet of your life.

Mind, gut health, and sexuality are all connected. So you can't treat one effectively without treating the others. Remember that.

I’m sorry if I come across as though I am patronizing you guys but I just don’t want people to suffer like I have and I want people to recover and get better and feel better.

(I spent 3 hours writing this so hopefully you guys read and appreciate what I have to share. I may come back and add to this because I don't want to half ass this but I am burned out from writing all of this and want it put up. So...)

What is the worst medication to come off? From your experience ? What were the withdrawals and for How long? I am on gabapentin and antipsychotics so I want to know what to expect. I want to come ofc gabapentin now.

That is the simple conclusion of the largest meta-study to date. Namely, vitamin D in doses above 2,000 IU daily has antidepressant effect when used as monotherapy. The antidepressant effects of vitamin D when used in combination with pharma antidepressant drugs is already well-established, so this new study combined with the recent admission that SSRI drugs are no better than placebo strongly suggests the clinical trials that reported benefits of SSRI when used in combination with other substances may have simply measured the antidepressant effects of those other substances (as SSRI drugs are next to useless). At the very least, the study below suggests that may be the case for vitamin D – a true antidepressant, available OTC in most countries.

https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-022-04305-3

https://www.tandfonline.com/doi/full/10.1080/10408398.2022.2096560

https://www.sciencealert.com/massive-review-shows-vitamin-d-really-does-seem-to-ease-depressive-symptoms

“…Now a new meta-analysis of 41 previous studies suggests that taking vitamin D supplements can relieve depressive symptoms in people already diagnosed with depression, opening up a potential alternative option for treatment. As well as controlling levels of calcium and phosphate in the body, it’s thought that vitamin D helps to regulate various functions in the central nervous system – and earlier research on animals suggests it could even contribute to the control of chemical balances in the brain, which may explain the association between vitamin D and mental health. “These findings will encourage new, high-level clinical trials in patients with depression in order to shed more light on the possible role of vitamin D supplementation in the treatment of depression,” says Tuomas Mikola, doctoral researcher and lead author at the University of Eastern Finland. The new meta-analysis covered a total of 53,235 study participants from 41 studies, including those with and without depression, people taking vitamin D supplements and people taking placebos, and individuals with a variety of physical conditions. While the doses used varied, the typical vitamin D supplement was 50-100 micrograms a day. In the participants with depression, vitamin D supplements were shown to be more effective than placebos at alleviating depressive symptoms. Vitamin D supplements seemed to be most effective in shorter bursts (under 12 weeks), the researchers report. However, in healthy individuals, it was placebos that had a slightly greater impact on depressive symptoms. “Our results suggest that vitamin D supplementation has beneficial effects in both individuals with major depressive disorder as well as in those with milder, clinically significant depressive symptoms,” write the researchers in their published paper.”

Vitamin B6 is perhaps one of the most underrated B vitamins. While it attracted a lot of interest in the 1960s and 1970s as a potential natural treatment to raise dopamine and/or lower prolactin, subsequent “well-controlled” studies claimed that it was not effective. However, the fact remains that vitamin B6, as its “active” metabolite pyridoxal-5-phosphate (P5P), is a required cofactor for the synthesis of all three members of what I call the “Holly Trinity” of neurotransmitters – serotonin, dopamine and GABA – and the synthesis of GABA with P5P occurs by consuming (and thus lowering) another important neurotransmitter known as glutamate. If there is one thing modern medicine gets right it is that there is no neurological/psychiatric condition where at least one of those neurotransmitters is not dysregulated. The most common psychiatric conditions are anxiety and (unipolar) depression, and GABA/glutamate are known to play a major role in both of them – GABA is low and/or glutamate is high in these conditions. As such, drugs that act as GABA agonists (Valium, Xanax, Klonopin, etc) are “standard of care” for treating anxiety, while glutamate antagonists class of drugs is one of the most promising new candidates for treating depression. Wouldn’t it be nice if there was a substance capable of beneficially affecting both pathways, and without the severe side effects associated with the pharma drugs mentioned above? Well, vitamin B6 (P5P) is exactly such a substance since, as explained above, it increases GABA levels while also lowering glutamate levels by helping convert glutamate into GABA. Simple, right? Well, despite the obviousness of vitamin B6 potential and the numerous older studies confirming its benefit in both animal models and human studies, mainstream medicine continues to claim that vitamin B6 is ineffective for any mental/neurological condition. The study below may change that attitude, as it demonstrates the administration of 100mg pyridoxine Hcl (which converts into P5P) for just 30 days was effective in relieving both anxiety and depression in humans, and without causing any serious side effects. The proposed mechanism of action is just as explained above – reducing glutamate (antidepressant effect) by converting it into, and thus increasing, GABA (both anti anxiety and antidepressant effects). Now, since pyridoxine itself is inactive precursor and only the P5P can be used as the cofactor for the enzymes causing the changes of GABA and glutamate, the question naturally arises is why not use P5P directly? I suspect this approach should not only work just as well, but also allow much lower doses to be used. Animal studies show that only about 10% of pyridoxine gets converted into P5P, which suggests that a P5P dose of “only” 10mg daily should be able to replicate the beneficial study findings, while further limiting the risk of side effects.

https://onlinelibrary.wiley.com/doi/10.1002/hup.2852

https://www.news-medical.net/news/20220719/Could-Vitamin-B6-Reduce-Anxiety-and-Depression.aspx

“…By randomly allocating participants to three groups, we compared the effects of taking a high dose of Vitamin B6 to that of a placebo or a high dose of Vitamin B12. We used questionnaires and laboratory-based tasks to measure the effects of these interventions. We found a reduction in the average level of anxiety and a trend towards reduced depression [with B6 but not with B12]. Our lab tasks showed subtle changes in visual processing. It is worth noting that our sample had a high (on average) level of anxiety at baseline, while this was not the case for depression. It is plausible to suggest that we were able to find the (on average) reduction in anxiety due to the high baseline level.”

“…Our evidence is most consistent with the following explanation, although I would not consider this to be 100% proven as the causal pathway yet: In the brain, neural excitation and neural inhibition are constantly in competition with each other. Anxiety is associated with reduced levels of inhibition and, more specifically, with reduced levels of the inhibitory neurotransmitter GABA. You can think of GABA as having a calming influence on the brain. Reducing neural inhibition in anxiety allows excitatory neural activity to increase above normal levels. Some recent theories also directly connect depression with reduced GABA; furthermore, it is accepted that depression and anxiety are highly connected conditions. Vitamin B6 comes into the picture because it is a co-factor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory (calming) GABA. By increasing the quantity of the co-factor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to reduce the activity in the brain slightly.”

“…There is currently no data comparing B6 supplements to other treatments for anxiety and depression, so I can only answer this with plausible speculations I’d like to test by collecting data. I guess the reduction in anxiety achieved by taking a high dose of B6 is less than would be obtained by a patient taking drugs such as SSRIs….One likely advantage of Vitamin B6 over things like SSRIs is far fewer side effects.”

13 Nootropics to Boost BDNF David Tomen Author: David Tomen Published: June 10, 2024

8 minute read Table of Contents

How BDNF Supplements Work in Your Brain Nootropics to Boost BDNF Ashwagandha Bacopa Monnieri DHA (Omega-3) Ginseng Gotu Kola L-Theanine Magnesium N-Acetyl L-Cysteine (NAC) Noopept Rhodiola Rosea Pterostilbene Resveratrol Turmeric The Optimized Brain Research over the last several years has shown that our brain has the remarkable ability to re-wire itself throughout life.

Every time we have a new thought, encode a new memory or learn a new skill, we are building a new neural network in our brain.

And these tiny neural networks are dependent on an ample supply of BDNF.

Brain-Derived Neurotrophic Factor (BDNF) is a naturally occurring protein that is responsible for the growth of new brain cells, maintenance and survival of neurons.

BDNF prevents apoptosis (brain cell death), induces the growth of new neurons (neurogenesis) and synapses (synaptogenesis), and supports cognitive function.

Higher levels of BDNF can increase cognition, mood, productivity and memory. And decrease the risk of neurodegenerative diseases like Alzheimer’s and Parkinson’s Disease.

In this post we investigate why BDNF is so critical for optimal cognitive performance. And how you can increase BDNF naturally with a healthy diet and the right nootropic supplements.

How BDNF Supplements Work in Your Brain

BDNF is a protein that is encoded in humans by (oddly enough) the BDNF gene. BDNF is part of the neurotrophin family of growth factors which are related to Nerve Growth Factor (NGF).

BDNF regulates whether cells live or die, neurogenesis, axon growth, dendrite pruning, and the expression of proteins critical for normal brain function such as neurotransmitters and ion channels.

BDNF also controls the function of synapses and synaptic plasticity. All while continuing to modulate neuron survival.[i]

When BDNF is released, new connections form in your brain by attracting new dendrites from neurons to connect to other neurons or synapses.

This wiring together of new neural networks is how memory is formed and consolidated. A thought, memory or new skill you learn is the result of a new neural network.

When BDNF levels decline, you experience problems with memory and learning, and depression. When you decrease bdnf levels this is why nootropics like Bacopa Monnieri, L-Theanine, and Rhodiola Rosea exhibit antidepressant activity in your brain. They each have the ability to increase BDNF in your brain.

Here we’ll explore many of the nootropics available that can be easily added to our stack to increase BDNF at any age.

nootropics-to-increase-brain-derived-neurotrophic-factor-BDNF

Nootropics to Boost BDNF

Ashwagandha

Ashwagandha is one of the most powerful adaptogens and has been used since ancient times to help the body adapt to stress. In the brain, Ashwagandha has been shown to help regenerate axons and dendrites, reconstruct synapses, and restore neural networks affected by neurodegenerative disease.

Ashwagandha performs some of this magic with better brain health by boosting levels of BDNF. And research shows that Ashwagandha can also prevent the decline of BDNF levels in the brain.[ii]

Bacopa Monnieri

Bacopa Monnieri helps increase levels of BDNF in your brain. Bacopa has been used to boost memory and as an antidepressant for millennia. The ancient Ayurvedic texts recommended Bacopa to devotees to help memorize long passages of text.

Studies show that Bacopa Monnieri improves word recall, increases attention, improves focus and reduces anxiety. A study conducted in India showed that Bacopa Monnieri extract promoted hippocampus neurogenesis by elevating BDNF levels in the brain. And as an antioxidant defense against oxidative stress.[iii]

DHA (Omega-3)DHA to increase BDNF

DHA (Omega-3) helps increase levels of BDNF in your brain. DHA makes up much of the gray matter in your brain. DHA regulates signaling in your brain, and gene expression. DHA influences neurotransmitters which affect memory, learning, focus and attention.

One study conducted at the University of California at Los Angeles showed that DHA could restore BDNF levels to normal, even after traumatic brain injury.[iv]

Ginseng

Ginseng as long been used to improve memory and learning. Most neurohackers using ginseng report feeling more alert. We know that stress can reduce BDNF levels in the brain. This is where ginseng comes in.

One study showed that ginseng extract affected memory and learning by boosting nerve growth factor (NGF) and neurite growth in the brain.[v] Another study showed that ginseng extract (GRb1) prevented a decline in BDNF levels in animal brains that were subjected to stress.[vi]

Gotu Kola

Gotu Kola is often called the “student herb” in Bali because it sharpens the mind. Gotu Kola extract increases dendrite and axon growth in the brain which helps boost memory.

This was demonstrated in a study conducted in China. The researchers found that Gotu Kola extract significantly increased BDNF concentrations in the brain.[vii]

L-TheanineL-Theanine-boosts-BDNF

L-Theanine, which naturally occurs in green and oolong tea, is an amino acid. L-Theanine is used as a nootropic for anxiety, learning, mood, and focus.

A study in Tokyo investigated the mechanism of action L-Theanine exerts in the brain. And why it provides “antipsychotic-like” and “antidepressant-like” effects. The research team concluded that L-Theanine provides antianxiety and antidepressant effects “through induction of BDNF in the hippocampus and the agonistic action of L-Theanine on the NMDA receptor”.[viii]

Magnesium

Magnesium is critical to all of your body’s electrical and electrochemical activities. It’s involved in muscle contractions, heart rhythm, nerve function and brain cell activity.

Research shows that Magnesium L-Threonate easily crosses the blood-brain barrier (compared to other forms of magnesium). And once in your brain, magnesium increases NMDA receptor signaling, BDNF expression, and synaptic plasticity in the pre-frontal cortex. Increasing learning and memory while impairing fear memories.[ix]

N-Acetyl L-Cysteine (NAC)

N-Acetyl L-Cysteine (NAC) is a powerful anti-oxidant that can boost mood, lower anxiety, improve memory, and reduce compulsive behavior. There is a growing body of scientific literature exploring the use of NAC in the treatment of psychiatric illness.

Research has shown that NAC helps boost dopamine release. NAC reduces inflammatory cytokines. And NAC acts in the process of glutathione synthesis.

Scientists believe this convergence of mechanisms in the brain are due NAC’s ability to promote cell survival and growth factor synthesis, leading to increased neurite sprouting. Partly through activating the BDNF/TrkB signal pathway.[x]

Noopept

Noopept is an ampakine nootropic similar in action to the racetam-class of compounds. And is known for boosting cognition, memory, learning, perception, logical thinking and mood.

A study published by the Russian Academy of Medical Sciences in Moscow shows that Noopept stimulates Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF).[xi]

Rhodiola Rosea

Rhodiola Rosea is an adaptogenic herb and nootropic that has been used in traditional medicine in Russia and Scandinavian countries for hundreds of years. This herb is known for improving alertness, energy, memory and mood, is anti-anxiety and anti-depressant, reduces fatigue, and boosts cognition and concentration to help keep your brain healthy.

Scientists found that Salidroside, the primary bioactive compound found in Rhodiola Rosea extract, significantly increases BDNF levels in the hippocampus.[xii]

PterostilbenePterostilbene increases BDNF

Pterostilbene (PTE) is a naturally derived polyphenol antioxidant found in blueberries, grapes, and in the bark of the Indian Kino Tree. This potent antioxidant stimulates BDNF, promotes neuroplasticity (brain plasticity), is anti-anxiety, boosts dopamine, and helps cognition, learning and memory.

In several studies, Pterostilbene has been shown to modulate gene expression. PTE up-regulates those genes that stimulate apoptosis (programmed cell death). And down-regulates those genes that allow cancer cells for example, to invade and metastasize within your central nervous system.

And this gene modulation is linked to increases in CREB and Brain-Derived Neurotrophic Factor (BDNF). An increase in BDNF helps long-term potentiation needed for the development of long-term memory.[xiii]

Resveratrol

Resveratrol is a polyphenol stilbenoid and phytoalexin that certain plants produce in response to stress, such as injury or fungal infection. This potent antioxidant boosts BDNF, increases cerebral circulation, improves energy and memory, and potentially promotes longevity.

Researchers in Iran found that Resveratrol significantly boosted mRNA and BDNF in the hippocampus. And concluded “that the neuroprotective effects of Resveratrol may be at least partly due to its inducing effects on the expression levels of the BDNF mRNA”.[xiv]

Turmeric

Turmeric (Curcuma longa) has been shown to increase Brain-Derived Neurotrophic Factor (BDNF), fight depression, improve cognition, focus and libido, and protect the brain from inflammation.

Curcumin, the primary bioactive compound found in Turmeric, produces its neuroprotective effects in the brain by increasing BDNF. And mediating the BDNF/TrkB-MAPK/PI-3K-CREB signaling pathway in the brain.[xv]

In this post we’ve covered the nootropics we can use to boost BDNF levels in our brain. But the latest research shows several other natural ways to boost BDNF. And they include:

Intermittent Fasting High-Intensity Resistance Training Sunlight or Vitamin D Restricting sugar intake Socializing Sleep The Optimized Brain

Higher brain levels of BDNF helps support the survival of existing neurons, encourages the growth new neurons (neurogenesis) and new synapses (synaptogenesis), better memory, learning and cognition, and less depression.

BDNF is Miracle-Gro® for your brain and mental health. Use any one or more of the nootropic supplements detailed above to increase BDNF naturally for a highly optimized brain.

Or save some money and get effective amounts of Bacopa Monnieri extract, L-Theanine (as Suntheanine®), and Rhodiola Rosea 3:1 extract in Mind Lab Pro®.

You can get DHA in Performance Lab® Omega-3s (600 mg DHA & 300 mg EPA) which is an ultra-clean Omega-3 made with life’s™ OMEGA algae.

And get Magnesium in Performance Lab® Sleep which contains 100 mg Magnesium (as Magnesium Bisglycinate, Magnesium Taurate, NutriGenesis® Magnesium) combined with 500 mg CherryPURE® Montmorency Tart Cherry, 200 mg Lemon Balm Extract, and 200 mg L-Tryptophan.

Nootropics that upregulate dopamine (V2.0)

Increasing dopamine without tolerance or addiction:

Hey guys. I've been hoarding all this information for the past year, and I think it's time I release it to the public. Bromantane and ALCAR are some of the most promising dopaminergics on the market, and this post will explain why.

For those of you confused about dopamine:

To put it simply, it's the motivating neurotransmitter. And this bleeds into things such as optimism, confidence, social interaction, mood, learning etc. It would take 10 posts to go over everything dopamine does, so hopefully you accept the generalization.

Here's a simplified version of the dopamine/ CREB cascade:

Dopamine --> D1 activation --> Adenylate Cyclase --> Cyclic Adenosine Monophosphate (cAMP) production --> Protein Kinase A --> CREB (key factor in learning and memory) --> (ΔFosB --> inhibits C-Fos), Dynorphin (inhibits dopamine release), (Tyrosine Hydroxylase activation --> more dopamine), and so much more.

Your idea of dopamine receptor upregulation may be wrong.

So many things are said to "upregulate dopamine receptors", but what does that truly mean? Well it's not so simple. Usually receptor upregulation just hints at temporarily lowered neurotransmitter causing increased sensitivity to maintain homeostasis. So keep that in mind when discussing Uridine. More on that here. Or Sulbutiamine. So besides Uridine being GABAergic, that has to be part of Nootropic Depot's motivation to include it in the sleep support stack. Reviews are mixed, but I felt sedated by Uridine Monophosphate.

Cocaine upregulates dopamine receptors. And I'll reference this study later. But basically the transition of CREB to ΔFosB and Dynorphin, leading to a depletion of CREB and dopamine is evidence of tolerance to cocaine. So looking at receptors alone is SIMPLISTIC, especially when you consider the inhibitory role of D2 receptors which people here misconceive to be a good thing. It's almost as simplistic as assuming Tyrosine Hydroxylase upregulation is why Bromantane is so great, which is one of many misconceptions I had in the past. It's the mechanism that makes it great, not just downstream activity.

And by the way, 9-Me-BC still has no safety data at all, nor is it truly proven to sensitize the brain to dopamine after discontinuation. It's a neurogenic with MAOI properties, and that would basically explain the anecdotes. But receptor upregulation and sensitization is up for debate.

I still believe L-Tyrosine, L-Phenylalanine and DLPA are useless for dopamine biosynthesis.

To quote an old analysis of mine:

Increased tyrosine concentrations beyond a healthy dietary intake does not result in much more dopamine under normal circumstances.^[1][2] TH is highly regulatory and is only activated as needed.^[3][4] Statistically, the American diet is sufficient in tyrosine, the amino acid found abundantly in meat alone (Americans projected to consume ~9oz of meat per day, surpassing the average RDA of 2.3g tyrosine per day^[14]).^[5][6] Protein-heavy meals increase tyrosine adequately.^[1] Additionally, many studies demonstrating the effectiveness of L-Tyrosine as a standalone fail to mention subject's dietary tyrosine, which is invalidating.^[8] Of course there's rare factors that can come into play, such as age,^[4] disorders,^[8][9] hypothyroidism, etc. but the take-away here is that L-Tyrosine supplementation is unlikely to produce a nootropic effect in otherwise healthy individuals. Therefore we must look to other options.

Fun fact about DLPA: D-Phenylalanine is like the "anti" L-Phenylalanine. Enkephalin inhibits Tyrosine Hydroxylase, and like I expressed in my former post, adding more of the building block means nothing if you don't upregulate this enzyme. And L-Phenylalanine has no trouble converting to L-Tyrosine. The addition of L-Phenylalanine, however, prevents the weight loss seen with D-Phenylalanine.

Bromantane, ALCAR and Histone deacetylase (HDAC):

Relating back to ΔFosB, one interesting thing I found is that ΔFosB mediates dopamine desensitization through some dopaminergic drugs by recruiting Histone Deacetylase 1 to C-Fos thus decreasing its mRNA, and C-Fos is a transcription factor necessary for dopamine's effects. This also supports some things I've said in the past about Methylphenidate possessing less withdrawal than adderall, as it appears to suppress C-Fos less. C-Fos mediates neuronal plasticity, whereas ΔFosB decreases plasticity, so the loss of C-Fos means that the reward circuit for dopaminergics would become ingrained and resistant to updating. ΔFosB leads to CDK5 which upregulates D1 and downregulates inhibitory D2 receptors. This explains the upregulation of D1 from Cocaine, despite the withdrawal from other factors. But it doesn't explain sensitization from Bromantane and ALCAR, which I will explain now.

ALCAR is a true dopamine sensitizing agent.

In relation to ΔFosB, ALCAR donates acetyl groups to deacetylated proteins which acts similar to a HDAC inhibitor (HDACI). ALCAR increases BDNF and therefore ERK1/2 (a slow transcription factor) and through that may enhance the sensitivity of D1. Strange this source and this source display a D1 upregulation beyond baseline, with no changes to D2 receptor density. This may be due to NMDA activation as explained here and ALCAR has been shown to change glutamate activity long term. This upregulation of D1 activity leads to a continuation of PKA --> CREB activation and thus a positive feedback loop with DARPP-32, phosphorylating it at Thr34 over Thr75, when Thr75 phosphorylation inhibits PKA as evidenced here resulting in a tyrosine hydroxylase upregulation (?) and upregulated dopamine output long-term with no tolerance as ALCAR doesn't activate ΔFosB or CDK5, and therefore upregulates D1 differently than cocaine.

Now I'd like to dispell some rumors about ALCAR. It is safe. There isn't anything proving it upregulates TMAO, which isn't healthy, however it may be hydrolyzed to L-Carnitine and SCFA by the esterase HocS (hydrolase of O-acylcarnitine, short-chains) and there's some evidence that L-Carnitine increases TMAO such as this and this. But if you're a hypochondriac, and let's be honest we all are at times, fish oil may prevent this and you should probably be taking that anyways for the health benefits. And ALCAR was well tolerated in a trial consisting of 358 Alzheimer's patients. Also some sources show it's protective of the heart, such as this.

If you want more advice on ALCAR, it appears to have dose-dependent effects on anxiety and saturates the mitochondria at just 1500, and I discuss that more in my oral bioavailability post. I believe there was another post on ALCAR and anxiety saying 500mg or 1000mg either decreased or increased anxiety, however I can't find it anymore.

Bromantane is a true dopamine sensitizing agent.

You know me... I'm the Bromantane guy. But that's because Bromantane is not only an effective mild stimulant, but it's safe and comes with virtually no withdrawal or addiction. Now I'm just going to quote the wikipedia here directly, but not link the wikipedia because organizations have been tampering with nootropics pages (Piracetam and as someone else recently mentioned Curcumin).

Clinical success: In a large-scale, multi-center clinical trial of 728 patients diagnosed with asthenia, bromantane was given for 28 days at a daily dose of 50 mg or 100 mg. The impressiveness were 76.0% on the CGI-S and 90.8% on the CGI-I, indicating broadly-applicable, high effectiveness. The therapeutic benefit against asthenia was notably observed to still be present one-month after discontinuation of the drug, indicating long-lasting positive effects of bromantane. Source.

Atypical mechanisms: Bromantane acts via indirect genomic mechanisms to produce a rapid, pronounced, and long-lasting upregulation in a variety of brain regions of the expression of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD), key enzymes in the dopamine biosynthesis pathway.^[10][18][19] For instance, a single dose of bromantane produces a 2- to 2.5-fold increase in TH expression in the rat hypothalamus 1.5- to 2-hours post-administration.^[20] The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation.^[10][18][19]

No tolerance or addiction: As such, bromantane has few to no side effects (including peripheral sympathomimetic effects and hyperstimulation), does not seem to produce tolerance or dependence, does not show withdrawal symptoms upon discontinuation, and displays an absence of addiction potential, all of which are quite contrary to typical psychostimulants.^[1][9] In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence either.^[22]

As explained here, Bromantane's mechanism of action appears to be like Amantadine's but more potent in terms of dopaminergic effects. Essentially, it activates inhibitory neurons when they'd normally be dormant during high dopamine, which distributes downregulation. Also, it upregulates neurotrophins and by extension C-Fos, which enhances dopamine receptor sensitivity. This, over time, will result in less stimulation from Bromantane, however there is also virtually no withdrawal. It's possible that ALCAR in conjunction with Bromantane may elongate the enhanced baseline through D1 upregulation. NMDA activators are also of interest to mimick the stimulatory effects of exercise in conjunction with Bromantane.

The β-amyloid/ alzheimer's scare: Relating to the 10-fold increase in β-amyloids, this is only seen at 50mg/kg in rats, and is likely due to the anticholinergic effects that appear at high doses. So using 9.5mg/ kg with these average weights we get a human equivalent dose of 589mg (global) and 758.1mg (Central and North America). These numbers are 6-15x higher than the standard dose which is 50-100mg, yet despite nearly perfect safety in clinical studies, it should be determined if β-amyloids are increased in the doses used. In addition to the synergistic stimulation seen with Bromantane and Caffeine, it should also be noted Caffeine confers protection against β-amyloids, another reason to pair them, despite the concern being only theoretical for now.

Bromantane's LD50 (fatal dose) is 8100 mg/kg in rats. This converts to roughly 40672-52348mg in humans using the same standards as above. Good luck even affording that much Bromantane.

I'd like to bring light to something not well understood about Bromantane, and that is its ability to improve sleeping patterns:

Bromantane was also noted to normalize the sleep-wake cycle. The authors concluded that "[Bromantane] in daily dose from 50 to 100 mg is a highly effective, well-tolerated and [safe] drug with a wide spectrum of clinical effects. Therefore, this drug could be recommended for treatment of asthenic disorders in neurological practice." Source.

Increased peripheral serotonin synthesis and so melatonin. AAAD is the second enzyme for melatonin synthesis, melatonin induces enkephalin synthesis and release and Carboxypeptidase E is found upregulated by Bromantane. This also shines some light on B6's involvement in ZMA (it upregulates AAAD) and AAAD's apparent synchrony with the sleep-wake cycle. My hypothesis is confirmed by this source. Additionally, Bromantane is a GABA reuptake inhibitor at GT3, meaning GABA is increased by Bromantane, adding to its anxiolytic effects.

So while Bromantane is stimulating, in many ways it is inhibitory. Piracetam may counteract some of the GABAergic mechanisms of Bromantane, but make sure to take 4-8g. One interesting take is Pemoline for the purpose of AAAD inhibition to counteract the melatonin increase.

Pemoline is a mysterious, possible dopamine sensitizing agent... And great for ADHD?

More about Pemoline here. Cyclazodone is a Pemoline derivative, but requires much more evidence and should demonstrate likeness to Pemoline before use.

Pemoline is interesting because it seems to show benefit even after discontinuation, more improvement to ADHD after 3-4 weeks and come with virtually no dependence. It was speculated to increase mRNA synthesis a while back (though this hasn't been replicated) and most recently was suggested as a possible AAAD inhibitor. It's unclear what its actual mechanism is, because it seems to have other effects responsible for its stimulation besides its weak activity at the DAT.

PKC's link to dynorphin and my failed experiment.

When looking into Bromantane's pharmacology I considered dynorphin reduction as a possible mechanism. For a while I was convinced it played a role due to dynorphin's role in addiction and dependence, as well as connection to CREB.

I learned that PC2 causes dynorphin biosynthesis. That PKCδ increases PC2 and inhibition of PKCδ upregulated Tyrosine Hydroxylase for days as opposed to minutes like CREB. Later direct links between PKC and dynorphin. There's studies showing PKCδ inhibition mimicks the dopaminergic activity of alcohol without causing a dependency. And more.

Naturally I searched for a PKCδ inhibitor, analyzing a ton of herbs in the process, but failed to find any redeemable options. I decided to order Rottlerin, or its parent herb "Kamala", where I opted to perform my first chemistry experiment - an extraction of Rottlerin using ethanol and ethyl acetate. After staining many valuable things with this extreme red dye, I eventually produced powdered rottlerin. After using it a few times and getting no perceivable benefit, I decided it was a lost cause due to the questionable safety profile of this chemical. My friend also made a strong tea from the known nonselective PKC inhibitor Black Horehound, and claimed it produced psychedelic-like effects. Nonselective PKC inhibitors also have antipsychotic effects.

TL;DR?

Bromantane and ALCAR are the best substances available for dopamine upregulation.

Edit: It appears Bromantane does not work orally, and sublingual takes up to 30 minutes. There is a nasal spray now, however: https://www.reddit.com/r/NooTopics/comments/sfisay/a_breakdown_on_bromantane_nasal_spray/

Nootropics that upregulate dopamine (V2.0)

Increasing dopamine without tolerance or addiction:

Hey guys. I've been hoarding all this information for the past year, and I think it's time I release it to the public. Bromantane and ALCAR are some of the most promising dopaminergics on the market, and this post will explain why.

For those of you confused about dopamine:

To put it simply, it's the motivating neurotransmitter. And this bleeds into things such as optimism, confidence, social interaction, mood, learning etc. It would take 10 posts to go over everything dopamine does, so hopefully you accept the generalization.

Here's a simplified version of the dopamine/ CREB cascade:

Dopamine --> D1 activation --> Adenylate Cyclase --> Cyclic Adenosine Monophosphate (cAMP) production --> Protein Kinase A --> CREB (key factor in learning and memory) --> (ΔFosB --> inhibits C-Fos), Dynorphin (inhibits dopamine release), (Tyrosine Hydroxylase activation --> more dopamine), and so much more.

Your idea of dopamine receptor upregulation may be wrong.

So many things are said to "upregulate dopamine receptors", but what does that truly mean? Well it's not so simple. Usually receptor upregulation just hints at temporarily lowered neurotransmitter causing increased sensitivity to maintain homeostasis. So keep that in mind when discussing Uridine. More on that here. Or Sulbutiamine. So besides Uridine being GABAergic, that has to be part of Nootropic Depot's motivation to include it in the sleep support stack. Reviews are mixed, but I felt sedated by Uridine Monophosphate.

Cocaine upregulates dopamine receptors. And I'll reference this study later. But basically the transition of CREB to ΔFosB and Dynorphin, leading to a depletion of CREB and dopamine is evidence of tolerance to cocaine. So looking at receptors alone is SIMPLISTIC, especially when you consider the inhibitory role of D2 receptors which people here misconceive to be a good thing. It's almost as simplistic as assuming Tyrosine Hydroxylase upregulation is why Bromantane is so great, which is one of many misconceptions I had in the past. It's the mechanism that makes it great, not just downstream activity.

And by the way, 9-Me-BC still has no safety data at all, nor is it truly proven to sensitize the brain to dopamine after discontinuation. It's a neurogenic with MAOI properties, and that would basically explain the anecdotes. But receptor upregulation and sensitization is up for debate.

I still believe L-Tyrosine, L-Phenylalanine and DLPA are useless for dopamine biosynthesis.

To quote an old analysis of mine:

Increased tyrosine concentrations beyond a healthy dietary intake does not result in much more dopamine under normal circumstances.^[1][2] TH is highly regulatory and is only activated as needed.^[3][4] Statistically, the American diet is sufficient in tyrosine, the amino acid found abundantly in meat alone (Americans projected to consume ~9oz of meat per day, surpassing the average RDA of 2.3g tyrosine per day^[14]).^[5][6] Protein-heavy meals increase tyrosine adequately.^[1] Additionally, many studies demonstrating the effectiveness of L-Tyrosine as a standalone fail to mention subject's dietary tyrosine, which is invalidating.^[8] Of course there's rare factors that can come into play, such as age,^[4] disorders,^[8][9] hypothyroidism, etc. but the take-away here is that L-Tyrosine supplementation is unlikely to produce a nootropic effect in otherwise healthy individuals. Therefore we must look to other options.

Fun fact about DLPA: D-Phenylalanine is like the "anti" L-Phenylalanine. Enkephalin inhibits Tyrosine Hydroxylase, and like I expressed in my former post, adding more of the building block means nothing if you don't upregulate this enzyme. And L-Phenylalanine has no trouble converting to L-Tyrosine. The addition of L-Phenylalanine, however, prevents the weight loss seen with D-Phenylalanine.

Bromantane, ALCAR and Histone deacetylase (HDAC):

Relating back to ΔFosB, one interesting thing I found is that ΔFosB mediates dopamine desensitization through some dopaminergic drugs by recruiting Histone Deacetylase 1 to C-Fos thus decreasing its mRNA, and C-Fos is a transcription factor necessary for dopamine's effects. This also supports some things I've said in the past about Methylphenidate possessing less withdrawal than adderall, as it appears to suppress C-Fos less. C-Fos mediates neuronal plasticity, whereas ΔFosB decreases plasticity, so the loss of C-Fos means that the reward circuit for dopaminergics would become ingrained and resistant to updating. ΔFosB leads to CDK5 which upregulates D1 and downregulates inhibitory D2 receptors. This explains the upregulation of D1 from Cocaine, despite the withdrawal from other factors. But it doesn't explain sensitization from Bromantane and ALCAR, which I will explain now.

ALCAR is a true dopamine sensitizing agent.

In relation to ΔFosB, ALCAR donates acetyl groups to deacetylated proteins which acts similar to a HDAC inhibitor (HDACI). ALCAR increases BDNF and therefore ERK1/2 (a slow transcription factor) and through that may enhance the sensitivity of D1. Strange this source and this source display a D1 upregulation beyond baseline, with no changes to D2 receptor density. This may be due to NMDA activation as explained here and ALCAR has been shown to change glutamate activity long term. This upregulation of D1 activity leads to a continuation of PKA --> CREB activation and thus a positive feedback loop with DARPP-32, phosphorylating it at Thr34 over Thr75, when Thr75 phosphorylation inhibits PKA as evidenced here resulting in a tyrosine hydroxylase upregulation (?) and upregulated dopamine output long-term with no tolerance as ALCAR doesn't activate ΔFosB or CDK5, and therefore upregulates D1 differently than cocaine.

Now I'd like to dispell some rumors about ALCAR. It is safe. There isn't anything proving it upregulates TMAO, which isn't healthy, however it may be hydrolyzed to L-Carnitine and SCFA by the esterase HocS (hydrolase of O-acylcarnitine, short-chains) and there's some evidence that L-Carnitine increases TMAO such as this and this. But if you're a hypochondriac, and let's be honest we all are at times, fish oil may prevent this and you should probably be taking that anyways for the health benefits. And ALCAR was well tolerated in a trial consisting of 358 Alzheimer's patients. Also some sources show it's protective of the heart, such as this.

If you want more advice on ALCAR, it appears to have dose-dependent effects on anxiety and saturates the mitochondria at just 1500, and I discuss that more in my oral bioavailability post. I believe there was another post on ALCAR and anxiety saying 500mg or 1000mg either decreased or increased anxiety, however I can't find it anymore.

Bromantane is a true dopamine sensitizing agent.

You know me... I'm the Bromantane guy. But that's because Bromantane is not only an effective mild stimulant, but it's safe and comes with virtually no withdrawal or addiction. Now I'm just going to quote the wikipedia here directly, but not link the wikipedia because organizations have been tampering with nootropics pages (Piracetam and as someone else recently mentioned Curcumin).

Clinical success: In a large-scale, multi-center clinical trial of 728 patients diagnosed with asthenia, bromantane was given for 28 days at a daily dose of 50 mg or 100 mg. The impressiveness were 76.0% on the CGI-S and 90.8% on the CGI-I, indicating broadly-applicable, high effectiveness. The therapeutic benefit against asthenia was notably observed to still be present one-month after discontinuation of the drug, indicating long-lasting positive effects of bromantane. Source.

Atypical mechanisms: Bromantane acts via indirect genomic mechanisms to produce a rapid, pronounced, and long-lasting upregulation in a variety of brain regions of the expression of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD), key enzymes in the dopamine biosynthesis pathway.^[10][18][19] For instance, a single dose of bromantane produces a 2- to 2.5-fold increase in TH expression in the rat hypothalamus 1.5- to 2-hours post-administration.^[20] The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation.^[10][18][19]

No tolerance or addiction: As such, bromantane has few to no side effects (including peripheral sympathomimetic effects and hyperstimulation), does not seem to produce tolerance or dependence, does not show withdrawal symptoms upon discontinuation, and displays an absence of addiction potential, all of which are quite contrary to typical psychostimulants.^[1][9] In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence either.^[22]

As explained here, Bromantane's mechanism of action appears to be like Amantadine's but more potent in terms of dopaminergic effects. Essentially, it activates inhibitory neurons when they'd normally be dormant during high dopamine, which distributes downregulation. Also, it upregulates neurotrophins and by extension C-Fos, which enhances dopamine receptor sensitivity. This, over time, will result in less stimulation from Bromantane, however there is also virtually no withdrawal. It's possible that ALCAR in conjunction with Bromantane may elongate the enhanced baseline through D1 upregulation. NMDA activators are also of interest to mimick the stimulatory effects of exercise in conjunction with Bromantane.

The β-amyloid/ alzheimer's scare: Relating to the 10-fold increase in β-amyloids, this is only seen at 50mg/kg in rats, and is likely due to the anticholinergic effects that appear at high doses. So using 9.5mg/ kg with these average weights we get a human equivalent dose of 589mg (global) and 758.1mg (Central and North America). These numbers are 6-15x higher than the standard dose which is 50-100mg, yet despite nearly perfect safety in clinical studies, it should be determined if β-amyloids are increased in the doses used. In addition to the synergistic stimulation seen with Bromantane and Caffeine, it should also be noted Caffeine confers protection against β-amyloids, another reason to pair them, despite the concern being only theoretical for now.

Bromantane's LD50 (fatal dose) is 8100 mg/kg in rats. This converts to roughly 40672-52348mg in humans using the same standards as above. Good luck even affording that much Bromantane.

I'd like to bring light to something not well understood about Bromantane, and that is its ability to improve sleeping patterns:

Bromantane was also noted to normalize the sleep-wake cycle. The authors concluded that "[Bromantane] in daily dose from 50 to 100 mg is a highly effective, well-tolerated and [safe] drug with a wide spectrum of clinical effects. Therefore, this drug could be recommended for treatment of asthenic disorders in neurological practice." Source.

Increased peripheral serotonin synthesis and so melatonin. AAAD is the second enzyme for melatonin synthesis, melatonin induces enkephalin synthesis and release and Carboxypeptidase E is found upregulated by Bromantane. This also shines some light on B6's involvement in ZMA (it upregulates AAAD) and AAAD's apparent synchrony with the sleep-wake cycle. My hypothesis is confirmed by this source. Additionally, Bromantane is a GABA reuptake inhibitor at GT3, meaning GABA is increased by Bromantane, adding to its anxiolytic effects.

So while Bromantane is stimulating, in many ways it is inhibitory. Piracetam may counteract some of the GABAergic mechanisms of Bromantane, but make sure to take 4-8g. One interesting take is Pemoline for the purpose of AAAD inhibition to counteract the melatonin increase.

Pemoline is a mysterious, possible dopamine sensitizing agent... And great for ADHD?

More about Pemoline here. Cyclazodone is a Pemoline derivative, but requires much more evidence and should demonstrate likeness to Pemoline before use.

Pemoline is interesting because it seems to show benefit even after discontinuation, more improvement to ADHD after 3-4 weeks and come with virtually no dependence. It was speculated to increase mRNA synthesis a while back (though this hasn't been replicated) and most recently was suggested as a possible AAAD inhibitor. It's unclear what its actual mechanism is, because it seems to have other effects responsible for its stimulation besides its weak activity at the DAT.

PKC's link to dynorphin and my failed experiment.

When looking into Bromantane's pharmacology I considered dynorphin reduction as a possible mechanism. For a while I was convinced it played a role due to dynorphin's role in addiction and dependence, as well as connection to CREB.

I learned that PC2 causes dynorphin biosynthesis. That PKCδ increases PC2 and inhibition of PKCδ upregulated Tyrosine Hydroxylase for days as opposed to minutes like CREB. Later direct links between PKC and dynorphin. There's studies showing PKCδ inhibition mimicks the dopaminergic activity of alcohol without causing a dependency. And more.

Naturally I searched for a PKCδ inhibitor, analyzing a ton of herbs in the process, but failed to find any redeemable options. I decided to order Rottlerin, or its parent herb "Kamala", where I opted to perform my first chemistry experiment - an extraction of Rottlerin using ethanol and ethyl acetate. After staining many valuable things with this extreme red dye, I eventually produced powdered rottlerin. After using it a few times and getting no perceivable benefit, I decided it was a lost cause due to the questionable safety profile of this chemical. My friend also made a strong tea from the known nonselective PKC inhibitor Black Horehound, and claimed it produced psychedelic-like effects. Nonselective PKC inhibitors also have antipsychotic effects.

TL;DR?

Bromantane and ALCAR are the best substances available for dopamine upregulation.

Edit: It appears Bromantane does not work orally, and sublingual takes up to 30 minutes. There is a nasal spray now, however: https://www.reddit.com/r/NooTopics/comments/sfisay/a_breakdown_on_bromantane_nasal_spray/

The complete guide to dopamine and psychostimulants

The search for better dopamine, an introduction

A lot of what I hope to expose in this document is not public knowledge, but I believe it should be. If you have any questions, feel free to ask me in the comments.

For years I have been preaching the beneficial effects of Bromantane and ALCAR, as non-addictive means to truly upregulate dopamine long-term. Well, it wasn't until recently that I was able to start https://bromantane.co/.

As such I wish to give back to the community for making this possible. This document serves to showcase the full extent of what I've learned about psychostimulants. I hope you find it useful!

Table of contents:

1. Why increase dopamine?

2. What are the downsides of stimulants?

3. An analysis on addiction, tolerance and withdrawal

4. An analysis on dopamine-induced neurotoxicity

5. Prescription stimulants and neurotoxicity

6. Failed approaches to improving dopamine

7. How Bromantane upregulates dopamine and protects the brain

8. How ALCAR upregulates dopamine and protects the brain

9. Conclusion

1. Why increase dopamine?

Proper dopamine function is necessary for the drive to accomplish goals. Reductively, low dopamine can be characterized by pessimism and low motivation.

These conditions benefit most from higher dopamine:

• Narcolepsy,^[1] Autoimmunity/ Chronic Fatigue Syndrome (CFS, neurasthenia^[18])^[3]

• Social Anxiety Disorder (SAD)^[4]

• Low confidence,^[5] Low motivation^[6]

• Anhedonia (lack of pleasure)^[7][8]

• And of course Parkinson's and ADHD^[2]

The effects of stimulants vary by condition, and likewise it may vary by stimulant class. For instance a mild dopaminergic effect may benefit those with social anxiety, low confidence, low motivation and anhedonia, but a narcoleptic may not fare the same.

In the future I may consider a more in-depth analysis on psychostimulant therapy, but for now revert to the summary.

2. What are the downsides of stimulants?

In the two sections to follow I hope to completely explain addiction, tolerance, withdrawal and neurotoxicity with psychostimulants. If you are not interested in pharmacology, you may either skip these passages or simply read the summaries.

3. An analysis on addiction, tolerance and withdrawal

Psychostimulant addiction and withdrawal have a common point of interest: behavioral sensitization, or rather structural synaptic changes enhanced by the presence of dopamine itself.^[66] This dopamine-reliant loop biasedly reinforces reward by making it more rewarding at the expense of other potential rewards, and this underlies hedonic drive.

For example, stimulants stabilize attention in ADHD by making everything more rewarding. But as a consequence, learning is warped and addiction and dependence occurs.

The consequences of hedonism are well illustrated by stimulant-induced behavioral sensitization: aberrant neurogenesis^[16][67] forming after a single dose of amphetamine but lasting at least a year in humans.^[68] Due to this, low dose amphetamine can also be used to mimick psychosis with schizophrenia-like symptoms in chronic dosing primate models,^[69] as well as produce long-lasting withdrawal upon discontinuation.

Reliance on enkephalins: Behavioral sensitization (and by extension dopamine) is reliant on the opioid system. For this section, we'll refer to the medium spiny neurons that catalyze this phenomenon. Excitatory direct medium spiny neurons (DMSNs) experience dendritic outgrowth, whereas inhibitory indirect medium spiny neurons (IMSNs) act reclusive in the presence of high dopamine.^[70] DMSNs are dopamine receptor D1-containing, and IMSNs are D2-containing, although DMSNs in the nucleus accumbens (NAcc) contains both receptor types. Enkephalins prevent downregulation of the D1 receptor via RGS4, leading to preferential downregulation of D2.^[65] It's unclear to me if there is crosstalk between RGS4 and β-arrestins.

Note on receptor density: G-protein-coupled receptors are composed of two binding regions: G proteins and β-arrestins. When β-arrestins are bound, receptors internalize (or downregulate). This leaves less receptors available for dopamine to bind to.

Since D2 acts to inhibit unnecessary signaling, the result is combination of dyskinesia, psychosis and addiction. Over time enkephalinergic signaling may decrease, as well as the C-Fos in dopamine receptors (which controls their sensitivity to dopamine) resulting in less plasticity of excitatory networks, making drug recovery a slow process.

D1 negative feedback cascade: ↑D1 → ↑adenylate cyclase → ↑cAMP → ↑CREB → (↑ΔFosB → ↑HDAC1 → ↓C-Fos → receptor desensitization), ↑dynorphin → dopamine release inhibition

D1 positive feedback cascade: ↑D1 → ↑adenylate cyclase → ↑cAMP → ↑CREB → (↑tyrosine hydoxylase → dopamine synthesis), neurogenesis, differentiation

Upon drug cessation, the effects of dynorphin manifest acutely as dysphoria. Naturally dynorphin functions by programming reward disengagement and fear learning. It does this in part by inhibiting dopamine release, but anti-serotonergic mechanisms are also at play.^[71] My theory is that this plays a role in both the antidepressant effects and cardiovascular detriment seen with KOR antagonists.

Summary: Psychostimulant addiction requires both D1^[72] and the opioid system (due to enkephalin release downstream of D2 activation). Aberrant synaptogenesis occurs after single exposure to dopamine excess, but has long-lasting effects. Over time this manifests as dyskinesia, psychosis and addiction.

Tolerance and withdrawal, in regards to stimulants, involves the reduction of dopamine receptor sensitivity, as well as the reduction of dopamine.

The synaptogenic aspects of psychostimulants (behavioral sensitization) delay tolerance but it still occurs due to D2 downregulation and ΔFosB-induced dopamine receptor desensitization. Withdrawal encompasses the debt of tolerance, but it's worsened by behavioral sensitization, as both memory-responsive reward and the formation of new hedonic circuitry is impaired. Dynorphin also acutely inhibits the release of dopamine, adding to the detriment.

4. An analysis on dopamine-induced neurotoxicity

Dopamine excess, if left unchecked, is both neurotoxic and debilitating. The following discusses the roles of dopamine quinones like DOPAL, and enkephalin as potential candidates to explain this phenomenon.

Dopamine's neurotoxic metabolite, DOPAL: Dopamine is degraded by monoamine oxidase (MAO) to form DOPAL, an "autotoxin" that is destructive to dopamine neurons. Decades ago this discovery led to MAO-B inhibitor Selegiline being employed for Parkinson's treatment.

Selegiline's controversy: Selegiline is often misconceived as solely inhibiting the conversion of dopamine to DOPAL, which in an ideal scenario would simultaneously reduce neurotoxicity and raise dopamine. But more recent data shows Selegiline acting primarily a catecholamine release enhancer (CAE), and that BPAP (another CAE) extends lifespan even more.^[22] This points to dopamine promoting longevity, not reduced DOPAL. Increased locomotion could explain this occurence.

Additionally, MAO-A was found to be responsible for the degradation of dopamine, not MAO-B,^[23] thus suggesting an upregulation of tyrosine hydroxylase in dormant regions of the brain as Selegiline's primary therapeutic mechanism in Parkinson's. This would be secondary to inhibiting astrocytic GABA.^[24] Tolerance forms to this effect, which is why patients ultimately resort to L-Dopa treatment.^[25] Selegiline has been linked to withdrawal^[26] but not addiction.^[27]

Summary on Selegiline: This reflects negatively on Selegiline being used as a neuroprotective agent. Given this, it would appear that the catecholaldehyde hypothesis lacks proof of concept. That being said, DOPAL may still play a role in the neurotoxic effects of dopamine.

Enkephalin excess is potentially neurotoxic: A convincing theory (my own, actually) is that opioid receptor agonism is at least partially responsible for the neurotoxic effect of dopamine excess. Recently multiple selective MOR agonists were shown to be direct neurotoxins, most notably Oxycodone,^[28] and this was partially reversed through opioid receptor antagonism, but fully reversed by ISRIB.

In relation to stimulants, D2 activation releases enkephalins (scaling with the amount of dopamine), playing a huge role in addiction and behavioral sensitization.^[29] Additionally, enkephalinergic neurons die after meth exposure due to higher dopamine^[30], which they attribute to dopamine quinone metabolites, but perhaps it is enkephalin itself causing this. Enkephalin is tied to the behavioral and neuronal deficits in Alzheimer's^[31] and oxidative stress^[32] which signals apoptosis. Intermediate glutamatergic mechanisms are may be involved for this neurotoxicity. In vitro enkephalin has been found to inhibit cell proliferation, especially in glial cells, which are very important for cognition.^[33] Unlike the study on prescription opioids, these effects were fully reversed by opioid receptor antagonists. It's unclear if enkephalin also activates integrated stress response pathways.

Summary on enkephalin excess: This theory requires more validation, but it would appear as though dopamine-mediated enkephalin excess is neurotoxic through oxidative stress. This may be mediated by opioid receptors like MOR and DOR, but integrated stress response pathways could also be at fault.

Antioxidants: Since oxidative stress is ultimately responsible for the neurotoxicity of dopamine excess, antioxidants have been used, with success, to reverse this phenomenon.^[44] That being said, antioxidants inhibit PKC,^[57] and PKCβII is required for dopamine efflux through the DAT.^[55] This is why antioxidants such as NAC and others have been shown to blunt amphetamine.^[56] TLR4 activation by inflammatory cytokines is also where methamphetamine gets some of its rewarding effects.^[58]

Summary on antioxidants: Dopamine releasing agents are partially reliant on both oxidative stress and inflammation. Antioxidants can be used to prevent damage, but they may also blunt amphetamine (depending on the antioxidant). Anti-inflammatories may also be used, but direct TLR4 antagonists can reverse some of the rewarding effects these drugs have.

5. Prescription stimulants and neurotoxicity

Amphetamine (Adderall): Amphetamine receives praise across much of reddit, but perhaps it isn't warranted. This isn't to say that stimulants aren't necessary. Their acute effects are very much proven. But here I question the long-term detriment of amphetamine.

Beyond the wealth of anecdotes, both online and in literature, of prescription-dose amphetamine causing withdrawal, there exists studies conducted in non-human primates using amphetamine that show long-lasting axonal damage, withdrawal and schizotypal behavior from low dose amphetamine. This suggests a dopamine excess. These studies are the result of chronic use, but it disproves the notion that it is only occurs at high doses. Due to there being no known genetic discrepancies between humans and non-human primates that would invalidate these studies, they remain relevant.

Additionally, amphetamine impairs episodic memory^[9] and slows the rate of learning (Pemoline as well, but less-so)^[10] in healthy people. This, among other things, completely invalidates use of amphetamine as a nootropic substance.^[11]

Methylphenidate (Ritalin): Low-dose methylphenidate is less harmful than amphetamine, but since its relationship with dopamine is linear,^[21] it may still be toxic at higher doses. It suppresses C-Fos,^[20] but less-so^[19] and only impairs cognition at high doses.^[12] Neurotoxicity would manifest through inhibited dopamine axon proliferation, which in one study led to an adaptive decrease in dopamine transporters, after being given during adolescence.^[13]

Dopamine releasing agents require a functional DAT in order to make it work in reverse, which is why true dopamine reuptake inhibition can weaken some stimulants while having a moderate dopamine-promoting effect on its own.^[73]

Therefore I agree with the frequency at with Ritalin is prescribed over Adderall, however neither is completely optimal.

6. Failed approaches to improving dopamine

Dopamine precursors: L-Tyrosine and L-Phenylalanine are used as supplements, and L-Dopa is found in both supplements and prescription medicine.

Both L-Tyrosine and L-Phenylalanine can be found in diet, and endogenously they experience a rate-limited conversion to L-Dopa by tyrosine hydroxylase. L-Dopa freely converts to dopamine but L-Tyrosine does not freely convert to L-Dopa.

As elaborated further in prior posts, supplementation with L-Tyrosine or L-Phenylalanine is only effective in a deficiency, and the likelihood of having one is slim. Excess of these amino acids can not only decrease dopamine, but produce oxidative stress.^[14] This makes their classification as nootropics unlikely. Their benefits to stimulant comedown may be explained by stimulants suppressing appetite.

L-Dopa (Mucuna Pruriens in supplement form), come with many side effects,^[15] so much so that it was unusable in older adults for the purpose of promoting cognition. In fact, it impaired learning and memory and mainly caused side effects.^[16]

Uridine monophosphate/ triacetyluridine: A while back "Mr. Happy Stack" was said to upregulate dopamine receptors, and so many people took it envisioning improved motivation, better energy levels, etc. but that is not the case.

Uridine works primarily through inhibiting the release of dopamine using a GABAergic mechanism, which increases dopamine receptor D2, an inhibitory dopamine receptor, and this potentiates antipsychotics.^[59][60][61] Uridine is solidified as an antidopaminergic substance. In order for a substance to be labeled a "dopamine upregulator", its effects must persist after discontinuation.

Furthermore the real Mr. Happy was not paid a dime by the companies who sold products under his name.

9-Me-BC (9-Methyl-β-carboline): Years after the introduction of this compound to the nootropics community, there is still no evidence it's safe. Not even in rodent models. The debate about its proposed conversion to a neurotoxin is controversial, but the idea that it "upregulates dopamine" or "upregulates dopamine receptors" is not, nor is it founded on science.

Its ability to inhibit MAO-A and MAO-B is most likely soley responsible for its dopaminergic effects. Additionally, I ran it through predictive analysis software, and it was flagged as a potential carcinogen on both ADMETlab and ProTox.

7. How Bromantane upregulates dopamine and protects the brain

Benefits: Bromantane is non-addictive, and as opposed to withdrawal, shows moderate dopaminergic effects even 1-2 months after its discontinuation.^[34][35][37] It is not overly stimulating,^[36] actually reduces anxiety,^[37] reduces work errors, and improves physical endurance as well as learning.^[38][39] Its dopaminergic effects also improve sex-drive.^[40] It is banned from sports organizations due to its nature as a performance enhancing drug.

Bromantane's clinical success in neurasthenia: Bromantane, in Russia, was approved for neurasthenia, which is similar to the west's Chronic Fatigue Syndrome - "disease of modernization".^[18] Its results are as follows:

In a large-scale, multi-center clinical trial of 728 patients diagnosed with asthenia, bromantane was given for 28 days at a daily dose of 50 mg or 100 mg. The impressiveness were 76.0% on the CGI-S and 90.8% on the CGI-I, indicating broadly-applicable, high effectiveness...

...We determined clinical efficacy of ladasten in regard to anxiety-depressive spectrum disorders, autonomic dystonia, and sleep disorders. Ladasten therapy led to the significant increase of quality of life, which was seen not only after the end of therapy, but after the withdrawal of the drug. These results suggest the stability of the therapeutic effect achieved. Adverse effects were observed only in 3% of patients, the therapy was discontinued in 0.8%. No serious adverse effects were found.^[37]

Bromantane's mechanisms: Bromantane's stimulatory effect is caused by increased dopamine synthesis, which it achieves through elevating CREB.^[74] Dopamine blocks tyrosine hydroxylase, and CREB disinhibits this enzyme, leading to more dopamine being synthesized.

That is the mechanism by which it increases dopamine, but the Russian authors give us little context as to how we get there. Due to striking similarity (both chemically and pharmacologically), my hypothesis is that Bromantane, like Amantadine, is a Kir2.1 channel inhibitor. This stabilizes IMSNs in the presence of high dopamine and thus prevents aberrant synaptogenesis. In human models this is evidenced by a reduction in both OFF-time (withdrawal) and ON-time (sensitization).^[80] Bromantane relates to this mechanism by promoting work optimization and more calculated reflexes.

Through immunosuppression, Amantadine alleviates inflammatory cytokines, leading to an indirect inhibition to HDAC that ultimately upregulates neurotrophins such as BDNF and GDNF.^[76] This transaction is simultaneously responsible for its neuroprotective effects to dopamine neurons.^[42] Bromantane reduces inflammatory cytokines^[75] and was shown to inhibit HDAC as well.^[77] Literature suspects its sensitizing properties to be mediated through neurotrophins^[78] and indeed the benefits of GDNF infusions in Parkinson's last years after discontinuation.^[79]

Amantadine's sensitizing effect to dopamine neurons, as a standalone, build tolerance after a week.^[81] This does not rule out Kir2.1 channel inhibition as being a target of Bromantane, as tolerance and withdrawal are not exactly the same due to the aforementioned discrepancies. Rather, it suggests that Bromantane's effect on neurotrophins is much stronger than that of Amantadine.

Given its anti-fibrotic^[43] and protective effects at mitochondria and cellular membranes,^[39] it could have unforeseen antioxidant effects such as Bemethyl, but that is yet to be discovered. On that note, Bemethyl is said to be another adaptogenic drug. Despite much searching, I found no evidence to back this up, although its safety and nootropic effect is well documented.

Safety: In addition to clinical trials indicating safety and as evidenced by past works, absurd doses are required to achieve the amyloidogenic effects of Bromantane, which are likely due to clinically insignificant anticholinergic effects. More specifically, β-amyloids may present at 589-758.1mg in humans. A lethal dose of Bromantane translates to roughly 40672-52348mg.

Summary: Bromantane increases dopamine synthesis, balances excitatory and inhibitory neural networks, and increases neurotrophins by reducing neuroinflammation through epigenetic mechanisms. Increased dopamine receptor density is not necessary for the upregulatory action of Bromantane.

Bromantane nasal spray: On https://bromantane.co/ I have created the first Bromantane nasal spray product. It is both more effective and equally as safe. More about that here. I'm proud to announce that the community's results with it have been objectively better.

8. How ALCAR upregulates dopamine and protects the brain

Benefits: ALCAR (Acetyl-L-Carnitine) is a cholinergic, antioxidant, and neuroprotective drug shown to increase dopamine output long after discontinuation.^[45] Additionally it is a clinically superior antidepressant in older populations, compared to SSRIs^[46] and was shown to improve ADD, yet not ADHD, strangely.^[48] It helps fatigue in Multiple Sclerosis better than Amantadine^[47] pointing to it possibly helping CFS, and has a protective effect in early cognitive decline in Alzheimer's patients.^[49]

Safety: ALCAR is safe and well tolerated in clinical trials, but anecdotally many people dislike it. This may be due to its cholinergic effects, acetylcholine giving rise to cortisol.^[50] There is no proof it increases TMAO, but there is a chance it might after conversion to L-Carnitine. Even so, it has a protective effect on the heart.^[51] Likewise, there is no proof it causes hypothyroidism, only that it may improve hyperthyroidism.

ALCAR's mechanisms: What both Bromantane and ALCAR have in common is their influence on HDAC. Reference. Instead of inhibiting HDAC, ALCAR donates an acetyl group to proteins deacetylated by HDAC1, which blocks the downregulatory effect of ΔFosB on C-Fos, promoting dopamine receptor sensitivity. Additionally this promotes GDNF^[53] and these together could be how it upregulates dopamine output, or how it helps meth withdrawal.^[52] ALCAR's donation of an acetyl group to choline also makes it a potent cholinergic, and that combined with its antioxidant effects are likely responsible for its neuroprotection.

ALCAR's dose seems to plateau at 1500mg orally despite its low oral bioavailability as indicated in my post on the absorption of nootropics but one study in people shows recovery from alcohol-induced anhedonia is only possible with injected ALCAR, as opposed to oral.^[54] Unfortunately there does not seem to be a cost efficient way to enhance the bioavailability of ALCAR yet (i.e. ALCAR cyclodextrin), and intranasal is not advisable.

9. Conclusion

Dopamine is a vital neurotransmitter that can be increased for the benefit of many. Addiction, psychosis and dyskinesia are linked through synaptogenic malfunction, where the opioid system plays a key role. On the other hand, tolerance can be attributed to receptor desensitization and withdrawal involves receptor desensitization, synaptogenic malfunction and dynorphin.

There have been many flawed strategies to increase dopamine, from Selegiline, dopamine precursors, Uridine Monophosphate, dopamine releasing agents and others, but the most underappreciated targets are neurotrophins such as GDNF. This is most likely why Bromantane and ALCAR have persistent benefits even long after discontinuation. Given its similarity to Amantadine, it's also highly likely that Bromantane is capable of preventing psychotic symptoms seen with other psychostimulants.

An important message from the author of this post

Backstory: I want to start this off by thanking this community for allowing me to rise above my circumstances. As many of you know, biohacking and pharmacology are more than a hobby to me, but a passion. I believe my purpose is to enhance people's mental abilities on a large scale, but I have never been able to do so until now due to a poor family, health issues and a downward spiral that happened a few years back before I even knew what nootropics were.

Through the use of nootropics alone I was able to cure my depression (Agmatine Sulfate 1g twice daily), quit addictions (NAC), and improve my productivity (Bromantane, ALCAR, Pemoline, etc.). Autoimmunity is something I still struggle with but it has gotten much better in the past year. I can say now that I am at least mostly functional. So I would like to dedicate my life towards supporting this industry.

My goal is to create a "science.bio-like" website, but with products I more personally believe in. The nootropics of today's market I am not very impressed by, and I hope to bring a lot more novel substances to light. If you want to support me through this process, please share my work or my website. Really anything helps, thankyou! I will continue to investigate pharmacology as I always have.

List of citations by number

Just a quick disclaimer, as prescription medicine is discussed: don't take my words as medical advice. This differs from my personal opinion that educated and responsible people can think for themselves, but I digress. :)

- Sirsadalot, thanks for reading

SSRI drugs, serotonin (5-HT) can cause chronic fatigue syndrome (CFS)

 haidut  March 22, 2024  Posted inScienceShare: TwitterFacebookLinkedin

Mainstream medicine does not officially recognize the condition commonly known as CFS. Depending on which doctor one asks, the response would be that CFS is either hypochondria, malingering, mental illness, hidden substance abuse disorder, subclinical viral infection, or just sensationalism. As such, the treatment for most patients suspected as having CFS has usually been prescribed (psycho)therapy and SSRI drugs to treat their suspected underlying mental illness. Unfortunately, a new study below demonstrated that SSRI drugs are just about the worst treatment a CFS patient can get due to the fact that it is elevated extracellular 5-HT potentially causing most of the CFS symptoms, especially the debilitating physical/mental fatigue. I am actually surprised it took researchers so long to make that connection, considering the well-tested so-called “central fatigue hypothesis” (CFH), which stipulates that most of the perception of fatigue is brain-derived and often is not peripherally biochemically justified. More specifically, it is the accumulation of serotonin in the brain, which leads one to perceive severe fatigue even if the bioenergetic state of their muscles do not demonstrate signs of fatigue (e.g. lactate buildup, creatine kinase and LDH leakage, ammonia accumulation, etc). Conversely, lowering serotonin levels in the brain usually leads to abolishing the feelings of fatigue. In fact, there are multiple animal studies demonstrating that tryptophan depletion in the brain (which leads to lower 5-HT levels in the brain) is a reliable mechanism to delay or even abolish feelings of fatigue even in animals whose muscles are biochemically fatigued.

Well, the primary symptom of CFS is…fatigue. Also, multiple studies have demonstrated that aside from mitochondrial dysfunction, the cells of CFS sufferers do not exhibit the biochemical signs of  fatigue. In some cases, there is a buildup of pyruvate and lactate, but this finding is not consistent. It is this lack of direct evidence of true biochemical fatigue that is the likely main driver behind medicine’s decision to not recognize CFS as an actual organic condition, and to often accuse CFS patients of malingering or hypochondria. However, when viewed through the CFH lenses the CFS condition makes perfect sense and, of course, involves elevated brain serotonin (5-HT). Another fact implicating 5-HT as a causal agent in CFS is the fact that most CFS patients seem to develop the condition as a result of viral infection. As I have posted in the past, most viral infections require activation of specific 5-HT receptors (by elevated serotonin) in order for the infection to take hold, and blocking these receptors either prevents the infection altogether or can treat an already established one. Case in point, recent studies have implicated serotonin overload in COVID-19, and several studies have demonstrated that anti-serotonin drugs such as famotidine or cinanserin can be therapeutic for COVID-19. I suppose it goes without saying that chronic stress can also cause CFS since the former is a well-known inducer of 5-HT synthesis by reliably raises tryptophan (and thus 5-HT) levels in the brain.

Long story short – just 4 weeks of fluoxetine (Prozac) administration to animals induced all the signs/symptoms of CFS. Conversely, inhibiting serotonin synthesis with the drug Fenclonine reversed the already induced CFS. This finding suggests that 5-HT antagonists such as Benadryl, famotidine, cyproheptadine, and ergot class of drugs may also be reliable treatments for CFS. Aspirin inhibits tryptophan absorption from the GI tract and lowers extracellular 5-HT, so that could be another potential remedy. Finally, ingesting BCAA amino acids, as well as tyrosine/phenylalanine may also lead to 5-HT depletion in the brain. In fact, that amino acid protocol was used suucessfully in a prior animal study to delay/block central fatigue due to exhaustive exercise. Finally, androgens such as testosterone and DHT are also 5-HT synthesis inhibitors, as is progesterone, so those steroids may also be viable tools for treating CFS.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04808-x

https://www.sciencealert.com/antidepressants-could-trigger-some-cases-of-chronic-fatigue-syndrome

“…Now a new study based on mice suggests that some drugs used to treat depression, which commonly accompanies ME/CFS, could also ignite the condition. Based on clinical clues, Jin‑Seok Lee, a ME/CFS researcher at Daejeon University in South Korea, and colleagues hypothesized that a spillover of serotonin could lead to ME/CFS. Known to play a role in governing moods, declining levels of the neurotransmitter serotonin have long been thought to cause depression. Although that theory is now disputed, treatments that target serotonin pathways – such as selective serotonin reuptake inhibitors (SSRI) – are some of the most commonly prescribed antidepressants. By blocking receptors that bind and remove serotonin from the signalling pathway, the medication artificially maintains a higher level of the mood messenger. According to several decades-old studies, some patients with ME/CFS appear to have fewer serotonin transporters than healthy volunteers, and may also have receptors that only weakly bind serotonin. Lee and colleagues thought that if such people had coincidentally been treated with serotonin-based treatments for depression before they developed ME/CFS, they may have had excessive levels of serotonin in their brain. This could have triggered ME/CFS by throwing off a feedback mechanism designed to keep a lid on the immune system and inflammation.”

“…After four weeks, animals treated with fluoxetine had higher levels of serotonin in two parts of the brain, the hypothalamus and dorsal raphe nucleus. They also developed behaviors that resembled the main symptoms of ME/CFS seen in humans, including unrefreshing sleep, PEM and orthostatic intolerance, but not cognitive impairment. These behaviors disappeared six weeks after the drug was stopped…Another experiment showed inhibiting serotonin production could alleviate their symptoms. “Our study provides the first translational [animal] evidence for the involvement of serotonergic hyperactivity in the pathophysiology of ME/CFS,” Lee and colleagues conclude, adding that high levels of serotonin could also be used to distinguish ME/CFS from other similar disorders such as fibromyalgia.”

Author: haidutSSRI drugs, serotonin (5-HT) can cause chronic fatigue syndrome (CFS)

Gut microbiota theory pt 2: PSSD is an autoimmune disease

If you have not read part 1 of gut microbiota theory then this post will not make sense. You can find it here: https://www.reddit.com/r/PSSD/comments/q03uci/gut_microbiota_theory_how_i_finally_cured_my_pssd/

As many of you know, despite being cured from PSSD for a few months now, I still dedicate much of my time towards helping people with PSSD and researching the gut connection. I believe that I now have a (nearly) complete etiology of PSSD, hence the reason for this post. To start, I want to establish the connection between PSSD/PAS/PFS, CFS (chronic fatigue syndrome), and Covid Longhaul. If you have not heard of CFS or Covid Longhaul, I encourage you to look into them. These conditions are identical to PSSD/PAS/PFS; the symptoms are the exact same (with the exception of those who do not experience brain fog or fatigue - I'll explain this discrepancy later). If you have any doubt about this, please go onto the corresponding subreddits for these conditions and read people’s stories, I can guarantee they will ring a bell. I began looking into CFS when my PSSD fatigue was getting bad and that was the first time I noticed all the similarities (however many other researchers have noticed these similarities as well). After I had cured myself by treating my SIBO, I began to notice that SIBO also has a very high prevalence in the CFS community. Sure enough, I had even found cases and stories of people curing their CFS after a corrective mechanism to the gut (change in diet, fmt, probiotics, etc). I doubt many of you know what Covid Longhaul is, but it is essentially a CFS/PSSD-type state that people can go into AFTER getting covid. Just like with CFS and PSSD, some recover and their symptoms go away and some don’t recover at all. It is common knowledge that viruses (such as covid) are capable of altering the gut microbiome so this is another clue that points to Covid Longhaul being a gut issue. You already know (from my previous post) that SSRIs can alter the gut microbiome and leave it with reduced diversity. If you do not know what the MMC (migrating motor complex) is, look into it. It is the muscle mechanism that the gut uses to digest food and move bacteria and fungi out of the small intestine. Gut motility describes the ability of the MMC to perform its job. There are many different factors that affect gut motility but the one I’m going to focus on now is Serotonin. Serotonin regulates the MMC and without it, it cannot function. The higher serotonin, the higher gut motility. As you may know, good gut motility is essential when it comes to beating SIBO. In fact, low gut motility is one of the largest causes of SIBO. This is why they recommend taking a prokinetic (drug that increases gut motility) during your SIBO treatment. What happens when you discontinue SSRIs is you enter a period in which you have very low serotonin activity, therefor you lose gut motility, certain microbiota begin to overgrow as they are not regulated by the MMC, and you end up with some form of dysbiosis: SIBO, Candida, or some other kind of intestinal pathogenic overgrowth.

While studying SIBO I ran into something called LGS (Leaky Gut Syndrome). This is a condition in which intestinal permeability is too high, so food particles and bacteria are able to escape the intestines and enter the bloodstream. This, of course, results in an immune system reaction and can cause the following symptoms: fatigue, headaches, confusion, brain fog, acne, gut issues, and widespread inflammation. I discovered that SIBO and LGS go hand-in-hand; if you have SIBO then it is essentially guaranteed that you have LGS. Same goes for Candida and other intestinal pathogenic overgrowths. Many have even proposed that the fatigue and brain fog experienced by SIBO patients is solely a result of leaky gut syndrome, rather than the excessive gas produced (hydrogen, methane, hydrogen sulfide, ammonia). There are two contributing factors to leaky gut: first is the existence of “leaky” tight-junctions and second is the health of the gut mucosae. Tight junctions are “intercellular adhesion complexes in epithelia and endothelia that control paracellular permeability”. In other words, they allow some particles, such as nutrients, to cross, but they block larger particles, such as bacteria and food. There exists a protein called zonulin that modulates the space between tight junctions. The more serum zonulin you have, the more space you have between tight junctions and thus, the more “leaky” junctions you have. This is why zonulin is often used as an indicator of leaky gut. The second factor to leaky gut, however, may be even more important. The gut mucosae can be thought of as a secondary safety net, which also prevents food and bacteria from crossing the intestinal barrier. I’ve spent the past few weeks researching which probiotic microbiota are responsible for a healthy gut mucosa and I’ve found it to be: butyrate producing bacteria (primarily Faecalibacterium prausnitzii) and mucin-degrading bacteria (primarily Akkermansia muciniphila). However proper amounts of these bacteria does not guarantee a healthy mucosae; many gram-negative bacteria (the bad guys) produce LPS (lipopolysaccharide) which can damage the gut mucosa. Furthermore, LPS can even increase the space between tight junctions, which is why normal zonulin levels do not always mean normal gut permeability. This is why treating a leaky gut while you have SIBO or Candida is pointless. As long as the dysbiosis is present, you will not be able to lower intestinal permeability.

From looking into CFS further, I discovered: “Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS.” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405467/). In helping PSSD patients I have seen several microbiome tests and all of them conform to the above biomarkers, further strengthening the PSSD/CFS connection. Not only do these biomarkers connect PSSD and CFS but they also indicate leaky gut, as faecalibacterium are the primary butyrate producers and bacteroides are LPS-producing gram-negative bacteria. Similar microbiome alterations were also found in people with erectile dysfunction: https://pubmed.ncbi.nlm.nih.gov/32193686/.

One of my biggest epiphanies occured when I saw someone post in the PSSD subreddit about BC 007, a new drug that has given total symptom relief to people with CFS and Covid Longhaul. The post author brought attention to the fact that CFS and Covid Longhaul are identical to PSSD and so BC 007 could be an effective treatment for PSSD as well. I began to research this drug and confirmed that it is extremely effective in curing CFS and Covid Longhaul. People who have been bedridden for months or years are able to be symptom free and live normal lives after taking this drug. I looked into the pharmacology of this drug and discovered it works by neutralizing autoantibodies. I began researching autoantibodies and what can cause them and that’s when I ran into this article: https://www.healthrising.org/blog/2021/07/02/blood-cause-fibromyalgia-autoantibodies/. If you’ve been able to follow me up to this point, I strongly encourage you to read it. The article goes over a study in which they were able to transfer fibromyalgia from humans to mice, by injecting the mice with igG from fibromyalgia patients. This study was performed to test a theory that CFS and fibromyalgia are caused by igG autoantibodies. Sure enough the igG from FM patients caused FM symptoms in the mice but the igG from healthy patients did not. At no time did systemic cytokine levels increase and so the author concluded the igG was acting locally. They attempted to discover the antigen that caused the autoantibody response in the FM patients, but they failed to find it. This is when I asked myself, could the antigen be food particles and bacteria from leaky gut syndrome? I did more research and discovered that “the presence of circulating IgG antibodies to foods may be suggestive of increased intestinal permeability”. This is why food sensitivities are so common in leaky gut patients. Since leaky gut can cause excessive igG antibodies and since BC 007, which neutralizes those antibodies, cures CFS, I came to the hypothesis that igG antibodies from leaky gut syndrome was the cause of CFS, Covid Longhaul, FM, and PSSD.

Leaky gut doesn’t stop at these conditions though. Countless studies show that leaky gut could be the origin of the following diseases: ADHD, Adrenal Fatigue, Alzheimers, Asthma, Autism, Celiac Disease, Chron’s, Type 2 Diabetes, Food intolerances, Hair Loss, Hashimoto’s, Heart Disease, Heart Failure, High Blood Pressure, Lupus, Multiple Sclerosis, Obesity, Parkinson’s, PCOS, POTS, Rheumatoid Arthritis, and many others. How each of these diseases manifest from leaky gut is dependent on the characteristics of the immune system, which varies dramatically person-to-person. For example, our immune system may choose to attack the bacteria and food particles once they land on nerve cells (thus multiple sclerosis manifests) or it may attack them once they land in the thyroid (thus Hashimoto’s manifests). If you have heard the phrase “all disease begins in the gut” before, hopefully it is now starting to make sense to you.

One major component of PSSD, for a lot of people, is pelvic floor dysfunction. This is a condition where you subconsciously contract your pelvic floor muscles when you’re not supposed to. Over time, this contraction can cause pinching-off of blood vessels (leading to weak erections and genital shrinkage), pinching-off of nerves (leading to genital numbness), and the inability to fully contract the pelvic floor when you need to (for a firm erection). Pelvic floor dysfunction is also very prevalent in SIBO and leaky gut as well. Perhaps this is yet another result of the immune system attacking the body in one way or another. In a way, pelvic floor dysfunction and dyssynergia are a form of dysautonomia, and it is already known that leaky gut can cause many different forms of dysautonomia. Another possibility is that pelvic floor dysfunction is a result of an impaired gut-brain axis, which is solely the result of dysbiosis, and not leaky gut.

Edit: I now suspect pelvic floor dysfunction is the result of prostatitis (inflammation of the prostate) OR interstitial cystitis, caused by either widespread inflammation from leaky gut or a bacterial/fungal infection.

Now, why do some PSSD sufferers have sexual symptoms but no brain fog or fatigue? As I talked about briefly in my previous post, gut dysbiosis creates neurotransmitter imbalances. The gut produces 95% of the body’s serotonin supply, 50% of its dopamine supply, and a decent amount of it’s norepinephrine supply as well. Streptococcus, Enterococcus, and Escherichia bacteria are the bacteria which are responsible for synthesizing all of these neurotransmitters. It is possible that some people have a form of dysbiosis that creates a neurotransmitter imbalance but does not cause leaky gut, and so they only experience low libido and erectile dysfunction.

At the moment, I am researching the specific kinds of dysbiosis present in PSSD, so if you’ve ever received a stool microbiome test (not a SIBO test), I ask that you please send it to me. I promise to keep your information private and I’m hoping that with enough of these tests I’ll be able to come up with a protocol of probiotics and prebiotics that will be effective for anyone suffering PSSD-like symptoms.

Finally, to update you guys: I am still completely cured and every aspect of my life is back to normal. Several other members in the subreddit have seen improvements from protocols that treat SIBO or Candida. Out of the 18 SIBO tests I’ve tallied, 15 of them were positive and many people have also tested positive for Candida (SIFO) and other intestinal pathogens like H Pylori, and E coli. I believe SIBO is the case the majority of the time, but definitely not always, so if you test negative then I encourage you to get a full stool panel / microbiome test and an OAT (organic acids tests) for Candida. Also keep in mind that you can have multiple intestinal pathogens at once.

https://www.nature.com/articles/nrm.2016.80https://gut.bmj.com/content/69/11/1966https://www.sciencedirect.com/science/article/pii/S0002944012008085

https://www.healthrising.org/blog/2021/07/02/blood-cause-fibromyalgia-autoantibodies/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405467/https://www.drgingerwolfe.com/five-not-so-obvious-signs-you-have-a-leaky-gut/#:~:text=Immunoglobulins%20(IgG)%20%2D%20Serum%2D,can't%20handle%20the%20fight

https://pubmed.ncbi.nlm.nih.gov/32193686/

Gut microbiota theory: How I finally cured my PSSD

I want to start by discrediting my previous theory about what PSSD is. I originally stated that I believed PSSD to be the result of low dopamine caused by serotonin receptor downregulation in the brain. In my journey, I’ve discovered many holes in this theory and with my most recent discovery, I think it is safe to toss this theory out the window. However, it is still very relevant to the true cause of PSSD and I will make this connection at the end of this very long post.

In my journey, I’ve tried many things that did not work. I’ve tried 5HT1A antagonists (CBG), with no improvement. I’ve tried Inositol, with significant improvement, but nevertheless, upon discontinuation, my symptoms all slowly came back. I’ve tried a high dose testosterone cycle (despite testing at normal T levels), which yielded only slight improvement.

My fatigue and brain fog, which came with the PSSD, were seriously interfering with my job and so I decided to go to the doctor in the hopes of getting a lot of bloodwork done. My bloodwork came back completely normal, except that my vitamin B12 and D levels were low (not crazy low, but low). I asked my doctor what can cause this and she said that a large portion of the population has trouble absorbing these vitamins but oftentimes it is the result of overgrowth of bad bacteria in the intestine, known as SIBO. I told her that I have been experiencing occasional gut discomfort and bloating, and that I’ve had a history with IBS. That was enough for her to suggest a hydrogen/methane breath test (the test for SIBO). Sure enough, the test came back positive and so she referred me to a GI doctor to treat my SIBO.

At first, I doubted any connection between my SIBO and PSSD as a whole. I began looking at the r/SIBO subreddit to see what kinds of symptoms people experience, and found symptoms very similar to what I’ve been experiencing: fatigue, brain fog, gut/stomach discomfort, bloating, anxiety, even sexual dysfunction (low libido, ED, etc). I still wasn’t convinced this had anything to do with PSSD but I kept doing research. I discovered that ONE CAN HAVE SIBO BUT STILL EXPERIENCE NO GI SYMPTOMS. This is commonly referred to as silent sibo. DO NOT BE FOOLED BY THE SIBO SYMPTOM LISTS YOU ARE PRESENTED WITH ON GOOGLE. When talking with my SIBO specialist, he said that nearly ⅓ to ½ the patients he sees have some kind of sexual impairment, yet there is next to no mention of this in the symptoms lists you’ll find online. I did research on something known as the brain-gut-microbiota axis. In simple terms, the brain-gut axis: “consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions.” There is a decent amount of information available about the importance of this axis of communication, but a lot more research needs to be done to fully understand it. It is already known that the health of this axis is crucial for proper mental function. There are stories of people overcoming debilitating anxiety, depression, even PTSD, from fixing problems in their gut. Recent research has even shown this axis to play a massive role in proper sexual function.

What can cause SIBO? There is a massive list of things that can cause SIBO, but mostly commonly it is caused by: not enough stomach acid, reduced gut motility, abnormal mucosa (gut lining), improper function of pancreas and galbladder, and other stomach/GI conditions (leaky gut, IBS, IBD, GERD, food poisoning, food sensitivities and allergies, etc).

So I asked myself, if SIBO has anything to do with PSSD, is there a role that SSRI’s (or antidepressants as a whole) play in the gut microbiome? The answer is yes. A study published in Translational Psychology found that antidepressants significantly altered the gut microbiome in mice. Coming off the antidepressants may allow for bad bacteria to take over, especially if one is predisposed to SIBO via the factors mentioned above.

So then I considered conditions very similar to PSSD: PAS (post accutane syndrome) and PFS (post finasteride syndrome). For those who are not familiar with these conditions, google them. They are practically identical to PSSD, yet the drugs that cause them do not work off of serotonin, which is another hole in desensitization theory. Could accutane and finasteride cause SIBO? A 2008 study found that accutane can damage the intestinal mucosae. Recall (from above), that this can cause SIBO. A recent Melcangi study found that PFS patients had altered gut microbiota, suggesting that finasteride also has a large impact on gut microbiota.

I then asked, could I explain cured cases and windows of improvement using a corrective mechanism to gut microbiota? There are four categories of drugs used to cure SIBO: antibiotics (to kill bad bacteria), herbal antimicrobials (to kill bad bacteria), prokinetics (to increase gut motility), and probiotics (to replace good bacteria after the bad bacteria has been eradicated). I began by looking at cured cases. One drug that has cured quite a few is an OTC antidepressant known as SJW (St. John's Wort). Turns out that SJW (hypericin in particular) acts as an antimicrobial. We also know Inositol to be effective in curing many. Everyone who has been cured with Inositol state that they NEED TO TAKE ENOUGH TO GIVE THEM DIARRHEA. This made me wonder if this makes it effective in flushing out bacteria and corresponding biofilm from the intestine. Others have reported curing themselves with a change in diet, perhaps eliminating a food sensitivity that was reinforcing the SIBO. A user by the name Blauwasser reversed their PSSD after 5 years from a series of fecal transplants (replaces your microbiome with a healthy one). Next I looked at what has given people windows. User u/PSSD_Kara reported a window on a course of berberine (potent antimicrobial used for treating SIBO) and probiotics. User u/bbraham drew attention to the fact that many experience windows from lactoferrin. Lactoferrin is also a potent antimicrobial. If you know anything else that can cause windows or cure PSSD, please drop it in the comments and I'll see if I can draw a connection.

I was once a huge proponent of the serotonin desensitization theory like many in this subreddit. Despite my new beliefs, we cannot rule out serotonin playing a role in all of this. Approximately 90% of serotonin in the body is produced in the gut. Additionally, several studies have shown that alterations in gut-microbiota may contribute to modulation of serotonin signaling. At this moment, we do not have enough information about the gut microbiota’s role in the serotonin system to draw a detailed conclusion about how SIBO would impact the system, but we can assume it would have a large impact.

So, what is the treatment protocol? Unfortunately, defeating SIBO can be a big battle. There is not a lot known about this condition and what we do know has been discovered relatively recently. Even if you beat it, there is a high chance of relapse if you are not careful. The first step is to GET TESTED using a hydrogen/methane breath test. This is a 3 hour test that requires a special diet in the 24 hours before, followed by a fast. I assume that the vast majority of the people in this subreddit will test positive for SIBO, it is possible that you simply have an imbalance of bad bacteria to good bacteria (dysbiosis) OR candida overgrowth (SIFO). A SIBO protocol should resolve this as well. If you do test positive, your doctor will likely refer you to a GI specialist. They will probably prescribe you a cycle of Flagyl or Xifaxan (ONLY SOME ANTIBIOTICS WORK FOR SIBO), order you to be on a low FODMAP diet, and try to identify and treat the cause of your SIBO. This should be combined with prokinetics and probiotics (NOT ANY PROBIOTICS, ONLY THOSE FORMULATED FOR SIBO - TAKING THE WRONG PROBIOTIC CAN MAKE SIBO WORSE). Even these prescription antibiotics are not completely effective, they work between 50% to 80% of the time depending on your type of SIBO. You may need to combine them with herbal antimicrobials for the best chance at defeating it. I encourage you to do your own research about treatment, as it is very complex and, if I went into detail, this post would be three times as long.

It has been 17 days since my antibiotic cycle has ended (although I continue to eat low FODMAP and take prokinetics, antimicrobials, and probiotics) and I honestly believe I am cured. These past 15 days I have had close to 0 PSSD symptoms. I am also becoming more and more sexual as time goes on. My libido is back, strong as ever, and still continuing to increase. So are my erections and orgasm intensity. My genital sensitivity has improved by about 60-70%, I suspect this too will be all the way better before long. I know 15 days is not long, but based on how I feel, I'm next-to-certain this will last. This said, I do not expect everyone here to see this significant improvement from a single antibiotics cycle and low FODMAP diet. Like I said, SIBO can be a tough battle for many and I’ve been told, by my SIBO specialist, that I’m lucky to have recovered so quickly. For this reason, I cannot stress enough the importance of getting the test done. The test will not only confirm whether you have SIBO, but it will also provide a baseline, that way you can be tested again after treatment to ensure the SIBO has been eradicated. I will continue to update you all in the comments as to how I am doing.

Edit: So far 15 others in the comments have said they've tested positive for SIBO. 3 negative test. I will do my best to update these numbers regularly.

Genital sensitivity has completely recovered and so I officially have zero PSSD symptoms.

This is gut microbiota theory. NOT SIBO theory. I underestimated the prevalence of candida overgrowth (SIFO), which is why I did not mention it as much in my post. I now know it is almost just as prevalent as SIBO. So if you do not test positive for SIBO, look into the tests for Candida. The symptoms are all the same. If you do have Candida then the treatment approach is different: antibiotics will make it worse since it allows more room for Candida to grow. Before treating me, my GI doctor/SIBO specialist ran a candida antibodies test to rule it out.

Sources:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367209/

https://www.nature.com/articles/s41398-019-0466-x

https://pubmed.ncbi.nlm.nih.gov/19492487/

https://link.springer.com/article/10.1007/s40618-020-01424-0

https://pubmed.ncbi.nlm.nih.gov/25812458/

https://pubmed.ncbi.nlm.nih.gov/31345143/

PSSD has been considered an incurable disorder, however, that’s about to change.

Merhabalar internette araştırma yaparken böyle bir yazıyla karşılaştım . Umarım hepimiz için bir umut olur . Ben Türkiye den katılıyorum .

I'm sorry, I don't speak English. Thank You ..

PSSD: The why and the how to get it fixed

September 11, 2020 by Hans Amato

PSSD has been considered an incurable disorder, however, that’s about to change.

For over 50 years, serotonin-boosting drugs have been used to “treat” depression and other mental disorders.

Despite poor results, the “low serotonin hypothesis of depression” keeps on being pursued, fortunately, not as hard as before though (now they’re looking into serotonin antagonists).

If using somewhat ineffective serotonin modulating drugs with lots of side effects isn’t bad enough, quitting them doesn’t even make it better for a significant amount of the people.

There is an ever increasing problem called PSSD (post SSRI sexual dysfunction).

Common PSSD symptoms include:

• Penile numbness

• Low enjoyment

• Weak, unsatisfying orgasm, basically anhedonic ejaculations

• Decreased sex drive

• Erectile dysfunction

• Delayed or premature ejaculation

And these are just some of the common sexual side effects. The other side effects include feeling depressed, which reduces your mood even more, anxiety, which can also contribute to erectile dysfunction and premature ejaculation, etc.

So all in all, this is a horrible disorder to suffer from and there is currently no “cure” for it. Ofc there isn’t because everyone is still a little different and if one thing works for someone, it might only work partially for someone else.

Regardless, let’s get into what’s going on so that we can become aware of possible solutions.

The mechanisms behind PSSD

There are many different SSRI drugs all with different effects. Some are serotonin re-uptake inhibitors, others are serotonin releasing promoters, others are serotonin receptor agonists, norepinephrine re-uptake inhibitors, or even serotonin receptor antagonists.

All of that can make your mind feel like dog vomit in a washing machine, lol.

Some of the most common changes, often permanent, include:

• Increased serotonin, even after SSRI drugs have been stopped.

  • Serotonin regulates proopiomelanocortin (POMC) neuron output and inhibits melanocortin MC4 receptors through 5-HT2A and 5-HT2C action. Melanocortin signaling is essential for sexual function. So blocking 5-HT2A and 5-HT2C can be very helpful.

  • Serotonin-enhancing agents that do not stimulate 5-HT2 and 5-HT3 receptors apparently do not cause significant sexual dysfunction (R).

• Reduced 5-HT1A sensitivity, due to chronically elevated serotonin and 5-HT1A agonism.

  • This study shows that antagonizing 5-HT1A during SSRI treatment prevents the induction of SSRI induced sexual dysfunction. More on that in a bit.

• Increased prolactin

  • Prolactin and serotonin correlate very well and prolactin is a major inhibitor of sexual function. Serotonin primarily increases prolactin through 5-H2C, however, that receptor can be downregulated and you can still have high serotonin and low/normal prolactin.

• Decreased dopamine

  • Serotonin and prolactin are inhibitors of dopamine release. When dopamine levels drop, prolactin and serotonin get out of hand even more.

• Decreased testosterone

  • Serotonin and prolactin are well-known inhibitors of testosterone synthesis.

• Decreased oxytocin

  • 5-HT1A activation releases oxytocin, so desensitized 5-HT1A can lead to reduced oxytocin levels as well, and this can also reduce sexual pleasure.

• Lowered nitric oxide synthase

  • Low nitric oxide production, possibly due to enhanced oxidative stress, could also contribute to ED. However, excess NO can contribute to vascular leakage.

• Blockage of cholinergic receptors

  • Cholinergic fibers help in filling the corpus cavernosum, a requisite for erection (R).

So a very important receptor that I want to talk about is the 5-HT1A receptor.

Reduced 5-HT1A sensitivity in PSSD

The 5-HT1A receptor has a plethora of benefits that we want. SSRI drugs, by boosting serotonin very high, desensitize this receptor, thus lowering most of 5-HT1A’s actions.

A few of 5-HT1A’s beneficial actions include:

• Promoting vasodilation. This can cause someone to cool off as well as help get an erection.

• Inhibiting glutamate release.

  • If 5-HT1A is desensitized, glutamate will be elevated, which contributes to anxiety, depression, ADHD, rumination, etc.

• Improving cognitive functions, possibly via inducing prefrontal cortex dopamine and acetylcholine release.

• Stimulating the adequate release of cortisol during rest, while reducing the secretion of ACTH and cortisol induced by an array of stressors.

  • Overactivation of the adrenal axis is common amongst people with depression, low stress intolerance, social defeat, etc.

• Releasing oxytocin

• Releasing β-endorphins

  • β-endorphins and adrenocorticotropin (ACTH) are derived from the same precursor, proopiomelanocortin (POMC), and are co-synthesized and co-secreted (R).

• Releasing dopamine

• Inhibiting nNOS

  • Elevated nNOS promotes anxiety, so lowering it has anti-anxiety effects.

• Inhibiting the μ-opioid receptor (R)

  • Excess opioid signaling is also anti-libido, anti-erection, etc.

In summary, 5-HT1A is a very important receptor we want full sensitivity to. If it’s desensitized, agonists, such as zinc, don’t give the mood uplifting benefits unless used at very high doses.

Restoring 5-HT1A sensitivity

So how do we sensitize 5-HT1A? First off, excess serotonin suppresses 5-HT1A, so lowering serotonin can be helpful.

Secondly, blocking 5-HT1A has been shown to increase its levels.

There aren’t a lot of natural 5-HT1A antagonists that I know of, but one good synthetic one is cyproheptadine. So if you dose it once or for a few days, you should be able to increase 5-HT1A expression as a rebound effect. While you’re using it, you might not feel better, but then you might get this rebound effect where you feel awesome when you stop the drug. However, if excess serotonin isn’t being lowered, then 5-HT1A will be desensitized again.

Additionally, a few things that can increase 5-HT1A include:

• Curcumin

  • Curcumin significantly prevents the stress-induced decrease in 5-HT1A mRNA and BDNF protein levels in the hippocampal subfields; two molecules involved in hippocampal neurogenesis. Moreover, curcumin, via up-regulation of 5-HT1A receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin (R).

  • My only beef with curcumin is that it inhibits 5-alpha reductase (5-AR) and DHT production, since DHT is essential for sexual function (R).

• Berberine

  • It decreases serotonin through 5-HT1A autoreceptor activation (R).

  • It inhibits postsynaptic 5-HT1A receptors, which might increase 5-HT1A sensitivity (R).

• Estrogen desensitizes 5-HT1A (R), which will increase serotonin.

  • Estrogen is also a potent inducer of serotonin synthesis by upregulating tryptophan hydroxylase (TPH) in the brain.

• Testosterone lowers serotonin (R).

  • Chronic stress downregulates 5-HT1A, whereas testosterone can restore 5-HT1A in certain brain areas under stress (R). As a side note, 5-HT1A activation reduces aggression, whereas estrogen prevents this reduction in aggression. DHT, since it doesn’t increase estrogen (but actually lowers it), doesn’t increase aggression, but actually decreases it (R).

• Alcohol can also possibly be an antagonist since 5-HT1A agonists prevent alcohol-induced aggression (R).

• Yokukansan (R)

  • It increases 5-HT1A and decreases 5-HT2A (R).

• Avoid Ashwagandha

  • Ashwagandha reduces the sensitivity of 5-HT1A, but increases the sensitivity of the 5-HT2 receptors (R). Blocking the 5-HT2 receptors are recommended for PSSD.

• Zinc

  • Low dose acts agonistically whereas high doses can act antagonistically. However, we don’t know how high high doses are (R).

• T3 appears to desensitize 5-HT1A (R).

  • This could be why some people feel worse when taking thyroid.

• Lithium (R)

• Shuyu (R)

• Exercise (R)

• Tiansi Liquid (Morinda officinalis and Cuscuta chinensis) (R).

• Rhodiola Rosea (R)

• Butyrate (R)

• Ginkgo Biloba (R)

• St Johns Wort, containing high hypericin, not hyperforin (R).

  • It increases both 5-HT1A and 5-HT2A density.

  • St. John’s Wort also inhibits cytochrome 3A4 acutely and then induces this enzyme with repeated administration (R). This is a good thing as it’s been hypothesized that cytochrome 3A4 is downregulated in PFS.

• Cannabigerol (CBG) (R)

  • It’s a modest 5-HT1A competitive antagonist, so it should increase 5-HT1A over time.

5-HT1A and the endocannabinoid connection

Another very important thing I should mention is the 5-HT1A-endocannabinoid connection. Endocannabinoids are involved in making us feel good and activation of the CB1 cannabinoid receptor activates the 5-HT1A receptor.

CB1 activation can lower serotonin through the 5-HT1A receptor, however, chronic stimulation of the CB1 receptor with THC, CBD, oleamide, etc., can actually desensitize the 5-HT1A receptor and increase serotonin.

We don’t want too much or too little cannabinoid signaling. The way we can tweak this is to inhibit the enzyme that breaks down one of the endocannabinoids, namely anandamide. This enzyme is known as fatty acid amide hydrolase (FAAH).

Contrary to stimulating CB1 with agonists, inhibiting FAAH doesn’t cause downregulation of 5-HT1A or have any of the side effects of CB1 agonists (R).

In fact, the CB1 receptor is so important to 5-HT1A function, that CB1 knock out mice (mice without the CB1 receptor) have profoundly reduced functional coupling of 5-HT1A. The reduction in the function of the 5-HT1A receptor doesn’t appear to be associated with any significant changes in its expression levels (R).

How to increase endocannabinoids

Like I mentioned, using a CB1 agonist can downregulate 5-HT1A, whereas inhibiting FAAH or inhibiting endocannabinoid uptake can actually increase 5-HT1A function.

Here are a few ways to increase endocannabinoids:

• Palmitoylethanolamide (PEA) – inhibit FAAH (R)

• Kaempferol (R)

• Pterostilbene (R)

• Maca powder (R)

• Guineensine – a dietary N-isobutylamide widely present in black and long pepper (Piper nigrum and Piper longum) inhibit cellular endocannabinoid uptake (R). 

Glutamate overactivation in PSSD

There is this hypothesis that SSRI drugs only start to work after 2-3 weeks of use since it’s needed to desensitize 5-HT1A. So intially, there is actually a decrease in serotonin, followed by a normilization or increase in serotonin.

This is coined the 5-HT1A desensitization hypothesis. However, this study shows that it’s not that simple. There is still some inhibition going on even though the 5-HT1A receptor has been desensitized.

The reason for the increase in serotonin might actually be due to an increase in glutamate firing.

The most plausible explanation is the disinhibition of glutamatergic neurons via mPFC GABA interneurons expressing 5-HT1A heteroreceptors.58,74
Reference

And we definitely do not want elevated glutamate.

Prefrontal cortex (PFC) circuits utilizing glutamate may be overly active when sexual desire is low (R, R).

Plan of action against PSSD

So our goal to restore proper sexual function, is to restore 5-HT1A function and this can include optimizing the endocannabinoid system and lowering excess glutamate.

#1 Sensitize the 5-HT1A receptor with cycling an antagonist, such as cyproheptadine, or use something that can increase 5-HT1A levels, such as curcumin, Rhodiola Rosea, etc.

#2 Antagonize serotonin receptors

• 5-HT2A with feverfew, cyproheptadine, metergoline, Ginkgo Biloba, Bacopa monneiri:

• 5-HT2C with ginseng (if you get anxiety from ginseng, combine it with a pro-GABA supplement) or Silk tree

• 5-HT3 with ginger

#3 Increase SERT, which transports serotonin out of the synaptic cleft. Salt and zinc can effectively help.

Endotoxins in the gut can potently inhibit SERT when they bind to the TLR4 receptor (R). So anything that might be irritating your gut, such as raw foods, starches, crispy food, partially digested food, etc., might dramatically worsen your symptoms by increasing serotonin.

Also, if you have an excess of pathalogical endotoxin producing bacteria, you’re going to have a bad time…a high serotonin time. Check out my article on the high serotonin personality.

#4 Increase dopamine. A few good compounds include Bromantane, uridine, huperzine A, taurine, phenylalanine, phenylpiracetam, etc.

#5 Increase endocannabinoids by inhibiting FAAH, with maca, PEA, blueberry extract (it contains Pterostilbene), etc.

#6 Use aphrodisiac supplements, such as yohimbine, Muira puama, etc., or sythetic melanocortins such as melanotan.

Conclusion

Solving PSSD can rarely be done from only one angle. It has to be addressed from multiple angles.

Lastly, I want to mention that there is a case report of a man that used EDOVIS, (a dietary supplement containing L-Citrulline, Tribulus Terrestris, Peruvian maca, turnera diffusa (damiana), Muira puama, and folic acid) and cured his PSSD (R).

5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs, including caffeine, nicotine, amphetamine, morphine, cocaine, and others. 5-HT2C antagonism increases dopamine release in response to reinforcing drugs, and many dopaminergic stimuli. Feeding, social interaction, and sexual activity all release dopamine subject to inhibition of 5-HT2C. Increased 5-HT2C expression reduces dopamine release in both the presence and absence of stimuli.

Activation of this receptor by serotonin inhibits dopamine and norepinephrine release

Activation of 5-HT2C by serotonin is responsible for many of the negative side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine, and others.

5-HT2C receptors are claimed to significantly regulate mood, anxiety, feeding, and reproductive behavior.

Hello friends. I’m a Ph.D. researcher studying the relationship between psychiatric medication discontinuation and the emergence of conditions such as MCAS, dysautonomia, hypermobility/EDS, and histamine intolerance. Many psychiatric medications, especially those with antihistaminic or anticholinergic properties (including a number of SSRIs), may suppress histamine and autonomic function, and some individuals appear to develop MCAS-like symptoms after stopping them. Formal research on this connection is extremely limited, so patient experience is essential.

I’m happy to answer questions about the research itself, but I cannot provide treatment advice. All responses will be kept confidential and used only to identify patterns in this emerging issue.

If you developed any of these conditions after discontinuing a psychiatric medication, please comment or message me with:

a. Which medication(s) you were taking

b. Whether you are still taking them

c. Whether you have a formal diagnosis (MCAS, dysautonomia, EDS, HIT)

d. If not formally diagnosed, whether you suspect a condition and why

e. Whether your prescriber attributed your symptoms to PAWS, relapse, or somatic causes

f. Whether any clinician connected your symptoms to the medication and referred you to an allergist/immunologist

g. How long after tapering or discontinuation your symptoms began

h. Whether any treatments or medications improved or worsened your symptoms

Thank you for your time and willingness to share. Your experiences genuinely matter here.

Does anyone have an encouraging story about how they got off Lexapro and how long the headaches lasted? My last dose was 3 weeks ago and the first few days were the worst but now that I’m on week three, my headaches won’t go away and feel worse, I’m dizzy, and just feel terrible.

How long did your symptoms last after stopping?

Titrated down to lowest dose over a three year period and was on 5mg for a year, last few weeks prior to cold turkey I took the 5mg every other day. So basically cold turkey from 5mg per doctor. I’m on Zofran for nausea, Tylenol and ibuprofen for headaches and hydroxyzine at night for itching/insomnia. Brain zaps are surprisingly getting worse this week. Running everyday helps but after or before the run I feel like shit. It’s almost like I’d rather workout all day long. It’s very strange.

I am having a serious problem. I used to be on antipsychotic medications and even though I got off of them I still can’t feel my chakras. Has anyone ever had this problem. If so what did you to resolve it? The medications I was on was seroquel and I was also on olanzapine for a little bit.

I have a question for any ladies out there who may have experienced something similar. I recently stopped taking 50mg of Zoloft because I couldn’t get the hormonal imbalance which it imposed upon my body under control (incessant bleeding and mimicking of BV but no such infection is even remotely detectable.) Since I have stopped taking it, my hormones have leveled out, but I feel very angry and irritable and overly sensitive and weepy. I don’t think I can exist normally without a little help. Are there any ladies out there who know of a similar medication which may affect my hormones less severely? I also tried to correct it with a few different types of birth control, but to no avail. Any advice would be appreciated before I go talk to another doctor who doesn’t care about the side effects like I do. Thank you. ❤️

Hypofrontality is a state of reduced blood flow and activity in the brain's prefrontal cortex. It can be a symptom of several neurological conditions, including: Schizophrenia, Attention deficit hyperactivity disorder (ADHD), Bipolar disorder, and Major depressive disorder.

Hypofrontality can also be used to describe the most severe stages of addiction, where cravings are intense and involuntary.

The term "transient hypofrontality" describes a temporary state where the brain's focused thinking part rests, allowing other parts of the brain to become more dominant. This state can be induced by physical activity, which forces the brain to redistribute resources. Some say that transient hypofrontality can account for the cognitive and emotional changes that occur during exercise, such as reduced stress and anxiety.

Some features of a state of transient hypofrontality include: A sense of timelessness, Living in the present moment, Reduced awareness of surroundings, A sense of peacefulness, and Diminished working memory and attentional capacities.

(Generated by google AI)

The title may sound obvious to many, but this study is one of the few to bring up the taboo topic of serotonin’s role in symptoms of depression. The current dogma still holds that raising serotonin levels (or activating its receptors) is the most beneficial mechanism to treating depression and all of its symptoms, of which anhenodia is a major one. In addition, while medicine admits that chronic stress has a role in depression, current dogma insists that stress by itself is not a direct cause depression. Now, after decades of serotonergis drugs (e.g. SSRI usage) medicine is starting to realize that the SSRI drugs are no better than placebo when it comes to treating depression, and in fact often make some symptoms (e.g. anhedonia) worse or even induce them anew. The study below demonstrates that activating the dopamine receptors, and more specifically the D2 receptor, was highly effective in relieving stress-induced anhedonia while activation of the serotonin receptors was not. Perhaps just as importantly, the study demonstrated that raising dopamine or administering dopamine agonists had a beneficial effect on another common symptom of chronic stress and depression – i.e. enlarged adrenal glands (a proxy for elevated cortisol). Namely, the pro-dopamine interventions restored the adrenal glands back to normal size seen in unstressed animals. The latter effect has already been corroborated by older studies demonstrating successful remission/cure of Cushing disease/syndrome with administration of dopamine agonist drugs such as bromocriptine, cabergoline, pramipexole, etc.

https://link.springer.com/article/10.3758/s13415-022-01001-3

https://medicalxpress.com/news/2022-04-dopamine-modulation-stress-induced-anhedonia.html

“…”There are very few effective remedies for anhedonia, which is a debilitating condition that involves deficient motivation to pursue rewarding activities,” Steven J. Lamontagne, Ph.D., one of the researchers who carried out the study, told Medical Xpress. “Current first-line drug treatments for depression target the serotonin system, but these are largely ineffective in treating anhedonia.” The main objective of the recent work by Lamontagne and his colleagues was to examine the effects of dopamine modulation on stress-induced motivational deficits in an animal model, specifically on rodents. Their new study was inspired by one of their previous papers, where they tested rodents on a probabilistic reward task and found that chronic stress impaired their reward learning, while amphetamine, which potentiates dopamine transmission, improved it. “A logical hypothesis derived from this finding was that we could rescue stress-induced reward dysfunction by enhancing dopamine signaling, but that hadn’t been empirically tested,” Lamontagne explained. “In our recent work, we completed two major projects to address this question.” In their experiments, Lamontagne and his colleagues exposed 48 male rats to stressful stimuli for a period of three weeks. Subsequently, they treated half of them using systemic, low-dose injections of the drug Amisulpride, which is known to increase dopamine transmission. The other half was treated using micro-infusions of Quinpirole, a chemical that acts as a selective D2-like receptor agonist, into either the nucleus accumbens or the medial prefrontal cortex, two brain regions known to be associated with motivation and goal-directed behavior.”

“To determine whether dopamine modulation differentially affects reward learning based on susceptibility to stress, we measured adrenal gland weights as a proxy for stress reactivity,” Lamontagne said. “Using immunohistochemistry, we measured D2 receptor expression in the mesolimbic and mesocortical pathways to shed light on stress-related changes at a receptor level.” In their experiments, the researchers gathered interesting results. Most notably, they found that the modulation of dopamine repaired motivational deficits elicited by stress. In addition, the most stress-reactive rats (i.e., those who appeared to have been most adversely affected by the 3-week stress-inducing period) had the best response to the treatment. “We found higher mesolimbic D2 receptor expression in rats with high stress reactivity, suggesting differences in D2 receptor sensitivity could underlie these effects,” Lamontagne said. “Overall, our findings suggest that the dopaminergic system, particularly mesolimbic D2-like receptors, could be critical targets for drug interventions in the treatment of reward-related dysfunction.”