Table of Contents
Key Takeaways
- SAM-e (S-Adenosyl Methionine) is a naturally occurring amino acid crucial for brain health and bodily functions.
- It regulates neurotransmitters, impacting mood, memory, and behavior.
- SAM-e treats depression and anxiety effectively, faster than traditional antidepressants and without their side effects.
- SAM-e enhances neuroplasticity, brain-cell membrane fluidity, and muscarinic receptors, leading to improved learning, memory, and mood.
- SAM-e supplementation with B vitamins at recommended dosages of 400 to 1600 mg daily benefits conditions like depression, anxiety, osteoarthritis pain, fibromyalgia, and chronic liver disease.
SAM-e (S-Adenosyl Methionine, Ademethionine, Adomet) is the naturally-occurring amino acid methionine bound to an ATP molecule. And is found in nearly every cell in your body.
SAM-e helps produce and breakdown the neurotransmitters acetylcholine, dopamine, serotonin, norepinephrine and melatonin in your brain. SAM-e maintains cell membranes and plays a role in a healthy immune system.
Studies show that SAM-e is very effective in treating depression without the side effects of prescription antidepressants. And while pharmaceutical antidepressants can take from 6 to 8 weeks to begin working, SAM-e can work much faster.
The latest research shows that SAM-e can be anti-anxiety, reduces pain including in fibromyalgia, and can improve learning, memory and mood.
SAM-e helps:
- Neuroplasticity. SAM-e is involved in the formation of myelin that surrounds and protects axons. And SAM-e can improve brain-cell membrane fluidity. Enhancing the function of neuroreceptors.
- Neurotransmitters. SAM-e is involved in the synthesis of acetylcholine, dopamine, serotonin, and norepinephrine. Helping to normalize mood, moderate behavior, and elevate emotions.
- Neuroprotectant. SAM-e helps produce the powerful antioxidant glutathione through a process called transsulfuration. SAM-e helps stabilize cell membranes and promotes the secretion of bile. And through a process called aminopropylation, SAM-e is converted into the antioxidant methylthioadenosine, which has anti-inflammatory and analgesic (pain-relieving) properties.
Overview
SAM-e (S-Adenosyl Methionine) is a naturally occurring coenzyme that plays many critical roles in your body.
SAM-e is made from methionine and ATP (adenosine triphosphate) during a cycle that recycles the amino acid homocysteine. This cycle requires Vitamin B6 and B12 and folate (B9) to work properly.
SAM-e is a precursor to the crucial antioxidant glutathione which is used in your brain and liver. When glutathione levels drop in your body, liver damage from oxidative stress begins within seconds of exposure to alcohol or toxins.
SAM-e is a methyl donor that contributes to several essential processes in your brain. As a methyl donor, SAM-e is involved in the production and recycling of hormones, cytokines, and the neurotransmitters acetylcholine, dopamine, norepinephrine, and serotonin.
This methyl donor process is call ‘methylation’, and contributes to gene expression. Affecting how your cells work and communicate including your cell DNA.
SAM-e modifies important molecules in cell membranes that control communications within and between brain cells. SAM-e boosts the number of muscarinic receptors in certain parts of your brain which are critical to this cellular communications network.
SAM-e is used to treat depression, anxiety, osteoarthritis pain, fibromyalgia, and chronic liver disease.
SAM-e is sold as an OTC dietary supplement in the United States and Canada. And as a prescription drug in several European Union countries, and Russia. SAM-e is marketed under the brand names Adomet, Gumbaral, Samyr, Heptral, Agotan, Donamet, Isimet and Admethionine.
How does SAM-e work in the Brain?
SAM-e boosts brain health and function in several ways. But two in particular stand out.
- SAM-e helps alleviate depression. SAME-e is one of the main building blocks your brain needs to produce the neurotransmitters acetylcholine, dopamine, serotonin, norepinephrine and melatonin. By raising the levels of dopamine in your brain, SAM-e helps enhance memory, motivation and learning.
Researchers at the West Los Angeles VA Medical Center studied the antidepressant effect of oral SAM-e in a randomized, double-blind, placebo-controlled trial for 15 patients with major depression.
The researchers found that SAM-e is a safe, effective antidepressant with few side effects and a rapid onset of action. And may be useful for those who cannot tolerate prescription tricyclic antidepressants.[i]
- SAM-e directly influences neuronal signaling. SAM-e increases the number of muscarinic receptors in the hippocampus. We have two kinds of acetylcholine (ACh) receptors in our brain. 1) Nicotinic receptors and 2) Muscarinic receptors
Most of the nootropics we investigate here at Nootropics Expert influence nicotinic receptors and ACh. Muscarinic receptors have a very different mechanism of action. They are part of a large family of G-protein-coupled receptors (GPCRs) which are used as an intracellular secondary messenger system.
Your brain has a very complex system of control to regulate different processes going on in different cells at different times. For this to work, there must be a sophisticated means of communication between cells.
GPCRs and their G proteins provide this intercellular communication. And form one of the most important signaling systems in your brain. They are involved in nearly every aspect of your physiology and behavior.
G proteins work by binding neurotransmitters, hormones, growth factors, cytokines, odorants and photons at the cell surface to the GPCR, and activating that receptor. Everything you see, hear, smell, or taste goes through this signaling process.
And SAM-e increases the number of these muscarinic receptors in parts of your brain, including your hippocampus. In one study, aged rats were given SAM-e for 30 days. Supplementation with SAM-e restored the number of muscarinic receptors to levels found in the same areas in young animals.[ii]
Supplementing with SAM-e to increase muscarinic receptors in your brain can boost neuroplasticity and increase learning, memory, mood and even smell and vision.
How things go bad
You have healthy levels of SAM-e throughout your body when you’re young. But as you age, your body makes less of it. This is why young people bounce back from difficult experiences more easily. They’ve got higher levels of dopamine and a higher pain threshold than adults.
SAM-e is a major methyl donor in your body. It is involved in the biosynthesis of hormones, neurotransmitters, proteins and phospholipids.[iii]
SAM-e participates in a sequence of events involving folic acid (folate) and Vitamin B12. Folate converts to 5-MTHF (5-methyltetrahydrofolate) which converts freely circulating homocysteine back into the amino acid Methionine (using Vitamin B12). L-Methionine then binds to an Adenosine group from ATP to create SAM-e.
SAM-e is then able to donate methyl groups (called methylation) to a variety of reactions including the production and breakdown of the neurotransmitters dopamine, serotonin, norepinephrine and melatonin in your brain.
This methylation process degrades SAM-e into S-Adenosylhomocysteine. Which is then fed back into this cycle from the beginning. This process is referred to as a ‘one-carbon cycle’.
If you don’t have enough folate or Vitamin B12 available, this SAM-e methylation process breaks down. And the result can be depression, brain fog, poor recall and memory, and pain.
This lack of folate and Vitamin B12 can affect you regardless of age. This is a big enough problem that the Canadian government mandated folate fortification of all flour, and some corn and rice products to address this issue in 1998.[iv]
Low levels of SAM-e, methylfolate, Vitamin B6 and B12 can lead to all kinds of problems. And genetic defects that don’t allow the use of these important vitamins can result in the same symptoms.
↓ Cognition, memory, recall, and mood diminish
↓ Methylfolate, Vitamin B6 & B12 absorption declines
↑ Homocysteine levels rise
↑ Pain levels rise
↓ Mental health, language and fine motor skills decline
All of these changes in brain energy metabolism are contributing factors to neurodegenerative diseases, including Alzheimer’s, Parkinson’s, ALS, epilepsy, dementia, and other cognitive symptoms.
But even if you’re not concerned with genetic defects, a lack of B-Vitamins, or the effects of aging, SAM-e can help.
SAM-e benefits
Stress-related disorders like anxiety, major depression and PTSD are some of the most debilitating illnesses known to man. And if you’re reading this, and dealing with any of these, supplementing with SAM-e may help.
To cope with stress requires changes in the expression of “immediate-early genes” in your hippocampus. The same area of your brain you use for learning and memory.
Stressful events result in epigenetic (gene) modifications within ‘immediate-early genes’ in your hippocampus neurons. DNA methylation acts to suppress the expression of these genes. This is where SAM-e comes in…
SAM-e is a methyl donor for the enzyme that methylates your DNA. When SAM-e levels are high enough, a stressful event will not result in DNA de-methylation.
Instead, a stressful event enhances DNA methylation of ‘immediate-early genes’. Which suppress their expression and allows you to adapt in a healthy way to this stressful situation.[v]
SAM-e is a powerful antidepressant. In 2005, researchers combed through the databases of Medline, Psychinfo, AMED, and Cochrane Controlled Trials Register. And collated the findings of randomized, controlled trials studying SAM-e for depression through to September 2001.
The team concluded after analyzing all the clinical evidence that SAM-e was effective in treating major depression in adults.[vi]
SAM-e is also a potent pain-killer. A recent study looked at 56 people with arthritis in their knees for 16 weeks. One group took the COX-2 inhibitor Celebrex while the other group took SAM-e.
Researchers found that SAM-e was as effective as Celebrex at eliminating pain. And without the potential side effects of heart attack or stroke that can be caused by using Celebrex.[vii]
Another study on the effect of SAM-e with 17 fibromyalgia patients confirmed a close relationship between primary fibromyalgia and psychologic problems including depression.
SAM-e treatment improved the depressive state of these patients. And SAM-e was found to be an effective and safe therapy in the management of fibromyalgia.[viii]
How does SAM-e feel?
For some, supplementing with SAM-e can be life-changing.
SAM-e can have a profound effect on emotions, depression, and feelings of anxiety. You may experience improved concentration, energy, alertness, and feelings of well-being. Even vision can become clearer.
Once you start supplementing with SAM-e, you should experience at the very least, a general sense of well-being.
SAM-e works particularly well for those who deal with depression or anxiety. Neurohackers report that they no longer have panic attacks. And the feeling of doom is gone.
Adding SAM-e to your nootropic stack can improve sociability, and not feeling overwhelmed by life. Brain fog lifts and thinking is clearer and faster.
Others say that the “dark cloud has lifted”, and all the negativity and stress is gone. Things that normally would irritate are just brushed off, and you move on.
One big word of caution: SAM-e needs Vitamins B6 & B12 and folate to work. Or supplementing with SAM-e may be a waste of time and money because without adequate levels of these B-Vitamins it will not provide any benefit.
You’ll notice reference to B-Vitamins several times in this article on SAM-e. It is that important. Use Vitamin B6 & B12 and folate every day that you supplement with SAM-e. Or use a B-Complex formula that contains methylfolate (B9) (avoid folic acid).
SAM-e Clinical Research
SAM-e Lifts Mood
We have made significant progress in the last 100 years in diagnosing and treating depression. And yet, 10’s of millions still suffer from depression. In 2014, an estimated 15.7 million adults in the United States had at least one major depressive episode in the past year.[ix]
In the United States, one in ten Americans are using antidepressants.[x] I don’t have statistics from other countries but I suspect many have similar problems. Unfortunately, antidepressants only work 30 – 50% of the time. And often come with a host of side effects.
One reason that many people continue to suffer from depression is that most doctors are not aware of the link between homocysteine and depression.
If you’re dealing with depression and have had little success with antidepressants, you may have something as simple (and as serious) as a folate deficiency. Or low levels of Vitamin B12. Studies show a link between folate deficiency and impaired metabolism of serotonin, dopamine, and norepinephrine.
One study looked at 46 patients with severe depression. 24 of these patients had raised levels of homocysteine. And significantly lower levels of folate, SAM-e, and other metabolites.
The researchers concluded that looking at total homocysteine levels could be a measure of depression. When it is caused by a folate deficiency, impaired methylation (SAM-e), and poor neurotransmitter metabolism (SAM-e). And a potential benefit to simply using vitamin replacement to treat severe depression.[xi]
Or supplementing with SAM-e to treat depressive symptoms.
SAM-e for ADHD in Adults
Ritalin and Adderall are thought to be the most effective treatment in children and adults with ADHD. These stimulants work by potentiating both dopamine and norepinephrine at the synaptic cleft. But stimulant meds for ADHD come with side effects.
SAM-e acts as a methyl donor and is involved in many metabolic pathways. It has both adrenergic and dopamine receptor agonist activity.
A research team at the University of California used SAM-e with subjects diagnosed with Adult ADHD in a 9-week double-blind, placebo-controlled trial.
The research team found that 75% of the patients had a significant improvement in ADHD symptoms while using SAM-e. And the 25% who did not respond to SAM-e, did not respond to Ritalin either.[xii]
SAM-e Treats Depression
Scientists at the US Department of Health and Human Services conducted an analysis of 102 individual studies in 25 databases on SAM-e and depression in 2002. The report distilled data gleaned from published studies conducted around the world up to 2002.
This comprehensive report is called, “S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease.” The researchers found that SAM-e is just as effective as standard antidepressant drugs at treating depression.
The agency concluded, “Treatment with SAM-e was equivalent to standard therapy for depression”.[xiii]
SAM-e Recommended Dosage
Recommended dosage of SAM-e for nootropic benefit is 400 mg per day.
SAM-e for depression: 400 – 1600 mg daily in divided doses
SAM-e for bone and joint health: 200 – 1200 mg daily in divided doses
SAM-e for liver function issues: 1600 mg daily in divided doses
SAM-e for alcoholic liver disease: 600 – 1200 mg daily in divided doses
Some research and many user reports suggest that once positive effects are achieved, SAM-e doses can be reduced. Some report benefit with as little as 100 mg of SAM-e daily.
Studies show that SAM-e should be consumed with B-Vitamins. When SAM-e donates its methyl group, it breaks down into homocysteine. Elevated homocysteine levels are associated with increased heart disease, birth defects and depression.
Choose a bioactive B-Complex to use with SAM-e. Like the high quality B-Complex like Performance Lab® B-Complex which contains therapeutic amounts of each of the B-Vitamins you need while using SAM-e.
In order to prevent homocysteine accumulating, logic tells us based on its mechanism of action that sufficient levels of B-Vitamins must be present to convert homocysteine into the potent antioxidant glutathione.
Take SAM-e on an empty stomach and an hour before eating any food. SAM-e is best digested in your intestines and not your stomach. Not letting SAM-e settle into your digestive tract could cause stomach upset.
SAM-e Side Effects
SAM-e is produced naturally in your body. So is considered well-tolerated and safe.
If you have bipolar disorder, you could develop mania when supplementing with SAM-e. So check with your doctor before using SAM-e.
If you’re on antidepressant medication, you should check with your doctor before supplementing with SAM-e.
High doses of SAM-e can cause gas, upset stomach, diarrhea, constipation, dry mouth, headache, dizziness, anxiety or skin rashes. SAM-e may also trigger an allergic reaction in some people.
Type of SAM-e to buy
SAM-e is available in 200 and 400 mg tablets.
For optimal effects with SAM-e, stable, enteric-coated tablets are recommended. SAM-e should be taken on an empty stomach, either one hour before or two hours after meals.
SAM-e is highly unstable so check expiration dates. And you should get tablets that are packed in sealed, gel-packs for freshness.
Avoid SAM-e in powder form as you’ll likely be unsatisfied with the results.
Nootropics Expert Recommendation
SAM-e 400 mg per day
I recommend using SAM-e as a nootropic supplement.
Your body does make some SAM-e on its own. But SAM-e levels decrease as we age. And you cannot get SAM-e from food.
SAM-e is critical for the methylation process needed for making important neurotransmitters including acetylcholine, dopamine, serotonin, norepinephrine and melatonin.
SAM-e is also involved in the cycle which produces the critical antioxidant glutathione. And it’s involved in maintaining brain cell membrane integrity and fluidity.
SAM-e increases muscarinic receptors in your hippocampus which boosts the activity of acetylcholine and other critical neurotransmitters in your brain. Leading to improved learning, memory and mood.
SAM-e is especially helpful if you’re dealing with depression. Or having difficulty coping with any kind of stress.
We suggest a dose of 400 mg daily. It may take a while for SAM-e to build up in your system. So be patient. Once you’re achieving the affects you want from SAM-e, you can eventually try scaling back your dose to 100 or 200 mg.
SAM-e needs Vitamins B6 & B12 and folate to work. Or SAM-e may not provide the benefit you are looking for. Most integrative medicine doctors and naturopaths recommend stacking a high quality B-Complex when using SAM-e. So make sure you stack SAM-e with the B-Vitamins listed above, or a good Vitamin B Complex formula that uses methylfolate (NOT folic acid).
A high quality B-Complex containing these bioactive B-Vitamins like the Performance Lab® B-Complex .
Join The Discussion - 390 comments
Andrew
October 20, 2022
I was thinking of trying Sam-E for a while
I’m already on
Astaxanthin
taurine
b-complex
Vit D
omega
NAC
L-theanine
would be safe to add this in at 200MG
David Tomen
October 22, 2022
Andrew, it is safe to try.
Sandra
September 24, 2022
Hi David!
I have homocysteine BELOW reference. How is that possible? I take Life extension bioactive B complex for 2 years now.
I also had brain white matter lesions due to gluten ataxia so maybe homocysteine could be lowered due to excessive use of glutathione?
Shoul SAM-e work to raise it? What should I do?
Thank you!
David Tomen
September 24, 2022
Sandra, you are likely low in Glutathione. Because homocysteine product requires adequate levels of Glutathione. Try a Reduced Glutathione supplement and see what happens.
Anne
September 17, 2022
Hi David – I’ve read elsewhere on the internet that taking Sam-E and l-methylfolate together can result in “over methylation.” What is your take on that? What, if any, mg of l-methylfolate should someone with a partial MTHFR deficiency take along with Sam-E?
We all appreciate you!
David Tomen
September 20, 2022
Anne, that is not entirely true because it depends on your system. You need the B-Vitamins to ensure homocysteine is not elevated to dangerous levels. And that the homocysteine that is created is able to help produce glutathione.
It’s a delicate balancing act going on when you are dealing with a MTHFR mutation. Best to find and work with a doctor who understands methylation on a deep level. Do a search for “methylation doctor near me” and see who turns up. Then read the user reviews before you call anyone to make an appointment.
Gloria
September 25, 2023
Hey there, just wanted to comment on what Anne said about taking the B vitamins along with the Sam E. I’ve tried many things over the years and I have tried Sam E by itself which was a big mistake. It raise my homocystine levels tremendously. It is a trial and error and finding out what works for you. I now have been taking 400 mg of Sam E along with a methylated multi B vitamin twice a day now. I am 76 yrs old and have been depressed ever since I was a kid. I have worked very hard trying different things over the years. Withthe new research and gene research, I and others are able to find solutions on our own. Wishing you well, God bless
David Tomen
September 26, 2023
Gloria, that is great advice especially if a person is dealing with methylation problems.
Jatin
September 3, 2022
Hi David,
What noots to look for if someone is involved with a job like coding / software programming? I tend to feel mentally exhausted after about 1 hour into it.
Thanks.
David Tomen
September 3, 2022
Jatin, a good basic stack for what you are trying to do can be found in my article on nootropics for studying:https://nootropicsexpert.com/best-nootropics-for-studying/. Those are the fundamentals that IF you follow dosage recommendations should get you back on track within a week or so. And long-term, daily use will prevent the type of mental fatigue you describe.
Jatin
September 6, 2022
Thanks. Just wanted to say if you haven’t please do read “Nutrient Power” by William J Walsh. I have just started it and it has some very interesting findings on ADHD.
David Tomen
September 7, 2022
Jatin, thanks for the tip. Nutrient Power (https://geni.us/mz3b) looks like what I’ve been writing and talking about since I started Nootropic Expert.
Jatin
September 8, 2022
Indeed. I particularly liked the ‘undermethylation’ information on adhd. I’m about to try some SAM e. Let’s hope for the best.
Rob
September 2, 2022
Dear David,
I suspect I have an MTHFR mutation,and accordingly I have been taking a b complex with L-methylFolate. It helps a lot,but something was still quite missing.
I did some research and tried SAMe 400mg a week back.its a good enteric coated tablet,and was blown away with the effect,I actually felt happy, could focus,was calm. I thought I hit the damn jackpot,felt my life had changed.
Unfortunately it only lasted for 2 days,after then,back to normal again.
I have been taking the tablets properly,on an empty stomach,1 hr before a meal . And after about 4 hours,I could literally feel it kicking in.it was surreal how profound an effect it was having .
My question is, since SAMe worked so well for 2 days,it was definitely providing something my body needed,and I felt normal, so why did it suddenly stop working after 2 days?
David Tomen
September 3, 2022
Rob, if it worked that well for you but it was temporary the only thing that could have caused that is the dose was too high.
I realize it is difficult to reduce the dose with an enteric coated tablet. The only other option is to use SAM-e once every 2nd or 3rd day and see if that helps.
Rob
September 4, 2022
Thanks,I’ll try 200mg tablets
Gabi
August 31, 2022
Hey David,
I wanted to reach out to see if you would be able to provide any insight. I took SAM-E for about 2 weeks. All was well until I experienced a severe dissociation/panic attack. I blamed it on the SAM-E so I stopped cold turkey. Since then, I’ve been experiencing what seems like withdrawal symptoms. It’s been about 3 months now and I still experience symptoms (it’s gotten better but still there). I don’t see many people talking about it so I am assuming I am more of a rare case but wondering if maybe this messed up my methylation cycle or something. Have you seen these cases before and do you have any advice?
David Tomen
September 1, 2022
Gabi, you could have undiagnosed bipolar disorder which is the only reason I can think of that would cause that type of effect. And if that is the case it has been my experience that some type of unusual ‘event’ can trigger something that was previously dormant.
If that is the case I highly recommend finding a psychiatrist who is willing to work with you. Explain what happened and ask if they can test you somehow to verify it. Messing up your methylation cycle would be temporary. It wouldn’t hang around for 3 months.
Alexis
August 30, 2022
Dear David,
I am an undermethylator, so am taking 800 mg daily S-ame for that for the past 5 months. I know it can take up to a year to truly work for some. Because of being an undermethylator, my doctor says I cannot take folate. My blood shows normal ranges that I assume are from eating my vegetables. I do take a B Complex 3 times a day with extra B1 and B5 at night. I still feel like I am missing something. Still anxious with high cortisol levels for the past 9 months. Should I increase my S-ame to 1200 mg a day? Add more Bs? Any suggestions for lowering cortisol? I take ashwagandha, holy basil, PS100? Any suggestions for relief would be appreciated!
Thank you!
David Tomen
August 31, 2022
Alexis, you can safely increase your SAM-e dose to 1200 mg per day. Try it and see if that helps.
You can also lower cortisol with L-Theanine and magnesium (Bisglycinate, Taurate, or L-Threonate).
Enoch Satyananda
August 28, 2022
I finally caved (always thought was too $$$) and picked up a bottle at Kroger (Simple Truth brand even) 30x 400mg for about $18… And WOW. Been taking it when I get up in the morning and it makes me feel like a kid again. Not sure how else to explain it/hard to put finger on but it’s as if the weight on my shoulders has been lifted or at least lightened to a noticeable degree!
It’s mildly energizing, slightly euphoric and even has me making funny noises and singing silly songs occasionally. I have not noticed any negative side effects and so far don’t feel I need to take more than one. (Though I might try 200mg x2 if I can get my hands on some)
Also seems to have some type of relaxing effect on my joints and my neck has been popping (in what feels like a good way) more often. (it rarely does)
Worth noting that (after a little research) I am also taking with Alpha GPC 300mg caps which seem to work best double stacked. (i.e. 600 GPC 400 Sam-e) Noticed that drinking alcohol isn’t giving me a gross feeling either.
David Tomen
August 31, 2022
Enoch, SAM-e can be life changing for some people while others receive no benefit. You are fortunate to find something that works for you so quickly. But do NOT take more if you are already getting the benefits from SAM-e. More is never better in this business.