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. Or a high quality and bioactive Multi like my favorite, the Performance Lab® NutriGenesis Multi for men or women 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).
Or use a high quality Multi containing these bioactive B-Vitamins like my favorite, the Performance Lab® NutriGenesis Multi for men or women.
Join The Discussion - 367 comments
Valentin
September 12, 2023
Hello,
What do you think of these studies saying that sam-e might be toxic?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983724/
https://www.theguardian.com/society/2022/apr/10/biologists-warn-against-toxic-same-health-supplement
Thank you.
David Tomen
September 13, 2023
It is one opinion from the authors of that study. SAM-e works for some people and not for others. Each person needs to decide for themselves what will work for them and what will not work. My opinion is not to let someone else make decisions for me and my health unless I ask them. I suggest you do the same.
Andrei
September 2, 2023
Hi there,
One one of the Supplements that I have availbalbe in my country, Jarrow’s formula, one of the claims is:
– reducing DNA cell division errors by regulating the methylation process
A. Can you confirm this, with or without a study?
B. Will taking this everyday help prevend DNA cell division errors, or will it result in the same issue a lot of supplements result? Dependency, needing to create less GABA/Serotonin cuz it receives it, or in this case, less need to try to reduce DNA cell division errors, since it has an new supply of support?
Thank you David!
David Tomen
September 4, 2023
Andrei, scroll back up and read the section called “SAM-e benefits” for your DNA answer.
Some benefit from using SAM-e as a supplement and others make enough SAM-e naturally 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.
Andrei
September 5, 2023
Thank you! My worries were in regard to the second part of my questions.
You know how using 5htp or serotonin precursors only might affect dopamine ones? Or how there’s a debate that supplementing X supplements, maybe Gaba, everyday, or dopamine, or others, your body might feel the need to do less(like in the extreme case of steroids and their cause of side effects)
I was wondering if SAM-e won’t create a similar case, where it will do all it’s processes good with SAM-e, but if you were to suddnely stop it, it will be less efficient, at, let’s say – reducing DNA cell division errors by regulating the methylation process – than with continious use of it – because it got used to it
2 questions. Is this something that is happening with Sam-e? Can I supplement everyday without this happening? 2. Am I understanding that debate correctly, or am I under misconceptions caused by the internet?
Thank you!
David Tomen
September 6, 2023
Andrei, it does not work that way. SAM-e works for some people and not others. No one has said why but I think it is likely that those it does work for can not make SAM-e on their own for whatever reason. When they stop taking the supplement they are still SAM-e deficient. And without adequate SAM-e you can’t produce and breakdown the neurotransmitters acetylcholine, dopamine, serotonin, norepinephrine and melatonin in your brain.
On the other hand if it does not work for you your body is likely making enough on its own. You’ll find soon after you take SAM-e if it is going to work or not. If you take it a nothing happens the I suggest trying something else.
Emma
July 18, 2023
Hi David,
My Dr has prescribed me this product of sam e:
Orthoplex SAMe 400mg
You recommend sam e be in sealed gel packs, which these don’t seem to be. Do you think the tablet form of these will work being a prescription brand?
I’m worried about the “heart attack” warning but I’ll be including activated B complex with it so hopefully no issues.
Thanks
Emma
David Tomen
July 18, 2023
Emma, SAM-e in its natural form is unstable to use as a supplement and is sensitive to moisture and heat which is why it is sold in blister packs.
The manufacturer Gnosis by Lesaffre claims they have put their SAM-e in enteric coated tablets which once you take it travels to and is released in your small intestine. The same process is used for some probiotics to keep them stable and alive to be released where they do the most good.
Scroll back up to the section called “How things go bad” and read the part where it is says, “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.” That will increase homocysteine which can lead to hypertension and if left unchecked could cause a heart attack. As long as you you keep your B-Vitamin levels optimized you avoid this problem.
Emma
July 18, 2023
Thanks David.
So enteric coated tablets in blister packs would be a better choice, have I understood that correctly?
Can you recommend any brands?
David Tomen
July 19, 2023
Blister packs are used to keep SAM-e supplements fresh and stable until you take it out of the blister pack and swallow it which then gets to your small intestine in working order. This company figured out an alternative way to keep SAM-e fresh and stable and that was to put SAM-e into enteric coated tablets instead.
Petrus
July 17, 2023
Does SAM-e have any adverse interactions with any supplement or with any other substance?
What is the half-life of SAM-e?
David Tomen
July 17, 2023
Petrus, the half life of SAM-e is about 1.5 hours. Scroll back up to the Side Effects section of this review for potential adverse reactions.
Petrus
July 6, 2023
Hi David.
Is it safe to take L-tryptophan and SAM-e? Or Rhodiola Rosea and SAM-e?
David Tomen
July 8, 2023
Petrus, yes and yes. They are not contraindicated.
Joanna
July 3, 2023
Hi and thanks for this helpful website! Based on some reading I wanted to try sam-E again and have some fairly old boxes that I bought but never gave it a fair shot (I wanted to use those up if I could, since it is somewhat on the pricey side).
I saw that you said it has a short shelf life – what would the dangers be of taking my old stock? Thanks again! Joanna
David Tomen
July 8, 2023
Joana, best case you would get no benefit from using the expired supplement. The worst case is it could be toxic. I would not suggest using expired SAM-e.
Cari
June 6, 2023
Hello David,
What do you think of the warnings against SAM-E in this article?
https://www.theguardian.com/society/2022/apr/10/biologists-warn-against-toxic-same-health-supplement
David Tomen
June 9, 2023
Carl, I do not see a link to any clinical studies in that article. And the author contradicts herself by first saying that SAM-e is bad to use as a supplement. And then at the end she talks about recommended dosages. Do you sense a little confusion going on?
I highly recommend that if you are interested in SAM-e that you scroll back up to the very top of this review. And read it word by word all the way through to the end. Including clicking through and reading any peer-reviewed clinical studies I link to in the article.
SAM-e is difficult to produce as a supplement, the storage and delivery method must be exact, and it is not for everyone. Some can use SAM-e and get its benefits and others do you need it. This is one supplement I rarely recommend to my consultation clients because many do not need this supplement. But some do need it which is why this review was written.
Zanzara
May 7, 2023
Hi David,
I had been taking SAMe on and off for about 6 years with great results. However, I noticed that the benefits I had been experiencing were no longer effective, so I stopped taking it. I have two questions: First, does SAMe stop being effective with long term use? Secondly, is it safe to take it long term? I hope to use it again in the near future for the previous benefits.
Thanks kindly!
David Tomen
May 8, 2023
Zanzara, SAM-e is safe to use long-term IF your brain needs more than it can produce on its own. It could be you started using something else like a BioActive B-Complex or changed your diet, or … It could be any number of things.
But SAM-e is highly unstable so check expiration dates. And you should get tablets that are packed in sealed, gel-packs for freshness.
The dietary supplement industry has grown exponentially over the last few years. Which brings out the worst in some who end up selling either low quality, some other adulteration, or putting things in capsules or tablets which have no relationship with what is declared on the label. The best we can do is research the seller, buy directly from respected manufacturers, and hope the supplement is delivered in something other than a frozen or over-heated truck.
I hope that isn’t too much information. 🙂
Zanzara
May 13, 2023
That’s very helpful, thank you.