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.
- 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.
Table of Contents
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 liver disease.
SAM-e is sold as an OTC 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, cytokine, 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, folic acid, 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
↓ Folic acid, 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, and dementia.
But even if you’re not concerned with genetic defects, a lack of B-Vitamins, or the effects of aging, SAM-e can help.
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 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 folate (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 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. Caused by folate deficiency, impaired methylation (SAM-e), and 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 to Treat Adult ADHD
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 problems: 1600 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 folate (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.
[i] Kagan B.L., Sultzer D.L., Rosenlicht N., Gerner R.H. “Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial.” American Journal of Psychiatry. 1990 May;147(5):591-5. (source)
[ii] Muccioli G., Scordamaglia A., Bertacco S., Di Carlo R. “Effect of S-adenosyl-L-methionine on brain muscarinic receptors of aged rats.”European Journal of Pharmacology. 1992 Nov 2;227(3):293-9. (source)
[iii] Park L.K., Friso S., Choi S.W. “Nutritional influences on epigenetics and age-related disease.” Proceedings of the Nutrition Society. 2012 Feb;71(1):75-83. (source)
[iv] Ray J.G., Cole D.E., Boss S.C. “An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise?” Clinical Biochemistry. 2000 Jul;33(5):337-43. (source)
[v] Saunderson E.A., Spiers H., Mifsud K.R., Gutierrez-Mecinas M., Trollope A.F., Shaikh A., Mill J., Reul J.M. “Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus.” Proceedings of the National Academy of Sciences U S A. 2016 Apr 26;113(17):4830-5 (source)
[vi] Williams A.L., Girard C., Jui D., Sabina A., Katz D.L. “S-adenosylmethionine (SAMe) as treatment for depression: a systematic review.” Clinical and Investigative Medicine. 2005 Jun;28(3):132-9. (source)
[vii] Najm W.I., Reinsch S., Hoehler F., Tobis J.S., Harvey P.W. “S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial.” BMC Musculoskeletal Disorders. 2004 Feb 26;5:6. (source)
[viii] Tavoni A., Vitali C., Bombardieri S., Pasero G. “Evaluation of S-adenosylmethionine in primary fibromyalgia.” A double-blind crossover study. American Journal of Medicine. 1987 Nov 20;83(5A):107-10. (source)
[ix] “Major Depression Among Adults” National Institute of Mental Health nimh.nih.org Retrieved July 25, 2016 (source)
[x] Rabin R.C. “A Glut of Antidepressants” The New York Times blogblogs.nytimes.com Retrieved July 25, 2016 (source)
[xi] Bottiglieri T., Laundy M., Crellin R., Toone B.K., Carney M.W., Reynolds E.H. “Homocysteine, folate, methylation, and monoamine metabolism in depression.” Journal of Neurology, Neurosurgery and Psychiatry. 2000 Aug;69(2):228-32. (source)
[xii] Shekim W.O., Antun F., Hanna G.L., McCracken J.T., Hess E.B. “S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: preliminary results from an open trial.” Psychopharmacology Bulletin. 1990;26(2):249-53. (source)
[xiii] “S-Adenosyl-L-Methionine (SAMe) for Depression, Osteoarthritis, and Liver Disease” US Department for Health and Human Servicesarchive.ahrq.gov Retrieved July 25, 2016 (source)
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Hi! Is it okay to take SAM-e with 5htp, complex b vitamins, l tyrosine, GABA, and L-theanine?
David Tomen says
Kristy, as long as it works for you it’s OK.
Hi David, I’ve had good success with SAM-e (400-600mg, split dose across the day) – I’ve been diagnosed as an undermethylator (effectively under produce neurotransmitters) plus an out of whack zinc/copper ratio and currently on a nutrient/nootropic plan to fix. I’m also COMT met/met so SAM-e helps in the degradation of catecholamines too.
Do you have any thoughts on supporting methylation or all-rounder type nootropics that can help?
I have a stack including SAMe, ML Pro (2x tabs), Tryptophan, Omega 3, Multivit, VitD, Magnesium, CoQ10 etc all at the right levels so got most of the bases covered.
I suffer from stress-induced anxiety and depression with a bit of ADD and OCD tendencies mixed in.
Any tips would be awesome.
Just to clarify, when I say all-rounder I mean like SAM-e that underpins the ‘system’ is helpful and wondering what else can help bump up all the levels if they are depleted. I’ve got a list of things to try and trying to do it with ones that cover more areas then say targeting one particular pathway (which I know you would recommend for anyone starting out). Thanks
David Tomen says
Phil, the advantage to targeting one neurotransmitter pathway at a time is it’s the only way to know which you are deficient in. For example, L-Tyrosine increases dopamine. L-Tryptophan increase serotonin. Alpha GPC or CDP-Choline increases acetylcholine. Each of these precursors require specific cofactors as well.
But there is no “all-rounder” like SAM-e. And SAM-e contributes to the synthesis and removal of these neurotransmitters. But it cannot do it on its own if you do not have enough L-Tyrosine present to produce dopamine as one example.
Phil Muggeridge says
Thanks David, I thought as much.
I’m on a plan with tryptophan and MLP currently. Will see how that goes.
Just wondering if SAM-e would be ok to take on the same day as dextroamphetamine. Pills I’ve got are 200mg and 15mg respectively. I followed everything you said about grabbing the right kind to make sure they actually work too.
Just wanted to know if there’d be any potential risk of SS or mania or anything with this combo. Dex and ginkgo was definitely a bad one, and a few others definitely have not been good too, so, I’d like to know before moving forward with this if this will be ok or if it’s something I should be concerned about/avoid.
David Tomen says
Shaan, there are no contraindications to using both but you already mentioned your negative experience with Ginkgo Biloba so I wish I could give you a definitive answer. But they only way to find out is to try it to see how it affects you. Just make sure you haven’t anything to do that’s important for the next few hours. 🙂
Many thanks for your quick response :).
Yes I found ginkgo made it quite panicky and anxiogenic. May have been a one-time thing though; I ought to give the combo another shot some day but as of right now I’m a little worried/sketched out from the last time I did it. Seemed to do what caffeine does to me – made me hypomanic. I don’t think ginkgo’s done that before, but it’s been a while since I’ve last done it (quite a few years). And come to think of it, I don’t think it ever really for along with me anyway, so I’ll probably just end up leaving it.
Anyway sounds good!! I’ll give it a try and see what happens. Seems to be the standard protocol for most of these eh? :P. I’ll come back and let you know what happens after I’ve done it, which should be relatively soon.
Cheers again David,
I wanted to add my thoughts here, as I have now tried this combo a couple of times, taking an activated form of a vitamin B complex alongside it to ensure that the sam-e was potentiated, and most recently it made me quite ill. I took sam-e for the purpose of modulating my dextroamphetamine prescription, to smooth out some of the jittery side effects and come-down. About 45 minutes following ingestion of both compounds at the same time; I experienced a racing heartbeat, increased blood pressure, and distinct nausea. Although there are many anecdotal reports indicating that the two should not interact with one another, I had a different experience. Here is some additional color on this:
As dextroamphetamine also markedly increases dopamine and to a lesser extent norepinephrine, I do not recommend this combination.
Anyone with more knowledge and experience, please feel free to correct me, or add your thoughts.
All the best
PS: for purposes of clarity, I wanted to add that I had taken 400 mg of S-Adenosyl methionine together with 10 mg of dextroamphetamine as a fast-acting tab, alongside a vitamin b compound which contained 45 mg of b6 as p5p. While vomiting helped reduce the nausea, the experience was unpleasant. In the past, taking the sam-e a few hours apart from the dextroamphetamine did not seem to have this effect.
Is Sam-e a substance that I can take daily? Does one develop a tolerance to it over time? Is it difficult to stop taking if you have been taking for a long period of time?
David Tomen says
Mark, you can use SAM-e daily, you cannot grow tolerant to it, and if it works for you it’s safe to use long-term.
Phil Muggeridge says
Hi David, thank you for all the information on the site. I have been taking SAM-e about a week, I read a lot about it after being both MTHFR and COMT homozygous. Then read more when looking at the Walsh approach as being methylation tested at the moment.
I am taking 400mg AM and lunchtime, its a Now Foods product that says its stabilized – NOW Foods – SAM-e 400 mg – it has shown some promise so far, it had some initial uplift.
I am taking this multi with it and was interested by your view – think it covers all the bases – Inessa Wellness Advanced Daily Multivitamin
Lastly, the Walsh book ‘Nutrient Power’ talks about Vitamin B5 as actually lowering production of serotonin and dopamine. Seeing a practitioner next week as being tested for methylation.
Any comments would be awesome.
David Tomen says
Phil, I normally like NOW Foods supplements as long as they don’t include toxic “other ingredients”. But in this case they claim that this SAM-e supplement is stabilized but they don’t say how. And the tablet is not enteric coated. Some I am a little wary about this without further investigation which I suggest you do and find out exactly how they stabilized it.
The multivitamin you are using contains bioactive vitamins which is good. But it is missing some critical minerals. Please compare their label to this one: https://bit.ly/347dm5M which is the Multi I use and recommend.
And does Walsh explain why she thinks Vitamin B5 depletes serotonin and dopamine? Because it doesn’t make any sense. B5 is needed for the synthesis of Coenzyme-A which is needed to produce serotonin.
Phil Muggeridge says
Thanks David, the b5 comment is in a table in the book. I see someone Tuesday so can report back.
As for the multi, from what I can see it doesn’t have iron (my iron is high), copper (quite high) and Vanadium – not heard of.
Magnesium I take at a proper dose separately.
As for the SAM-e I’ve got Doctors Best in blisters in the cupboard so taking 200+200 today.
The NOW foods one says to refrigerate after opening, I’ll drop them a message.
David Tomen says
Phil, these are the minerals that should be in your multivitamin and why you want them there: https://nootropicsexpert.com/13-minerals-essential-for-the-optimized-brain/. Not enough Molybdenum and see what goes wrong. It’s this type of thing that is easy to miss but so critical.
Thanks, good to review re Boron (& SAM-e) and Potassium (which I’ve tried to up before).
By the way had a response from Now Foods on the tablet in their form:
“In early 2021 we introduced an improved 400mg tablet. Our world-renowned SAMe supplier has done a lot of research on developing a superior product as well as an extended release tablet coating which does an excellent job in protecting the stability and bioavailability, especially when refrigerated after opening*. See more below. We can offer a better value with equal stability compared to blister packaging at increased cost.
*Store in a cool and dry environment in tightly sealed original packaging at refrigerated conditions 2-8°C (36-46°F)at less than 50% relative humidity.”
David Tomen says
Phil, what they are saying is likely true because it’s not hard to imagine that an “extended release tablet coating” should protect the ingredient inside that coating.
Can you recommend a Sam-e supplement product? Can this be taken with NAC/ inositol / ashwagandha and Maca?
David Tomen says
Tom, you can get SAM-e from several good supplement companies like this one: https://amzn.to/3DbsJJf. The tablet must be enteric coated, sealed in bubble packs, and be fresh. This last one is important because SAM-e is very unstable and you can get spoiled supplements even from the most trustworthy companies. So inspect it once it arrives to make sure it’s useable.
And SAM-e is not contraindicated with any of the the supplements you mentioned.
Would be safe to use Sam-e and l-tryptophan to help with serotonin production?
Preferably sam-e in the morning and l-tryptophan (250mg)before bed.
David Tomen says
Dan, SAM-e is a methyl donor required for the synthesis of serotonin and works with Tryptophan to do that. The half-life of SAM-e when consumed in an enteric coated tablet is 100 minutes. So I suggest using them together. Possibly SAM-3 a couple of hours before taking Tryptophan.
Can I use SAM-e with below stack?
Performance Lab Sleep
Performance Lab Energy
David Tomen says
Yazan, you should be able to use SAM-e with that stack. But make sure you also follow dosing suggestions including a bioactive B-Complex supplement.
And when using the racetams you will get better results by including 300 mg Alpha GPC or CDP-Choline.
Samaiyah Henderson says
Hello Dr. Tomen,
I have a question for you, I hope this comment finds you well. What would you recommended for a child suffering with liver problems? I know the recommended dosage for adults liver conditions is 800 mg twice a day, usually child dosages are half. So would you recommended 400 mg twice a day? Please advise. Also, if someone has the MTHFR gene, can they add methyl-folate to folic acid and it be sufficient?
David Tomen says
Samaiyah, I cannot offer dosage recommendations for children because my area of expertise is with adults. I suggest checking with your child’s doctor to confirm the best dosage. This is important because depending on the child’s age it could be 1/2 or even 1/3 of the adult dosage.
And for someone with a MTHFR gene mutation it is best to avoid folic acid altogether because it cannot be converted into a form of this vitamin that can be used by the body. It ends up attaching to receptors unused and prevented methyl-folate from attaching. This goes or any age of human with a faulty MTHFR gene. Only methyl-folate and methylcobalamin should be used.
Hi. Great information. I’ve been taking Sam-e with success for depression almost 2 months. I began 400mg then switched to 200mg (with a b-complex). While I feel 85% better i’m hesitant to stop due to some recent stressors & life changes but also feel the 200mg too activating and actually causing elevated anxiety and sleep disturbance. I cannot find 100 mg anywhere. I was considering 200 mg every other day but can’t find any literature on this. Any thoughts?
Thank you! Amy
David Tomen says
Amy, are you using your SAM-e with a high quality B-Complex supplement? Because if you are not chances are you are increasing homocysteine which is not only dangerous but could be contributing to your symptoms.
If you are using a B-Complex and cannot find a 100 mg SAM-e supplement then try using it every 2nd day and see if that helps.
how many vitamin b should i take while taking 200mg of sam e a day for 12 days?
David Tomen says
Oscar, all you need is a high-quality, bioactive B-Complex like this one: https://amzn.to/3BhEixs
after i stop taking sam e there is no need to take vitamin b no more?
David Tomen says
Oscar, most are deficient in at least some of the B-Vitamins so I think everyone should be using a high quality B-Complex. Because the B-Vitamins are involved in nearly everything going on in your brain.
Gary Simone says
Can I use sam-e and saffron together as I ween off valium 4mg
David Tomen says
Gary, you should be able to use them together.
I want to take SAM-E for occaisonal depression, fibromyalgia and joint pain. I started with a low does of 200mg first thing in the morning on an empty stomach. After 2 days, I had horrible insomnia and I had to stop. I had noticed that my joint pain had gotten better in 2 days, but of course when I stopped it came back. I really want to take this because I believe it can help, but I can’t sleep by the 2nd day. Do you have any idea on what can help with insomnia. I took over the counter sleep aids and nothing worked. Also, I am going to add the Vitamin b12,b6 and folate. I doubt this will help with insomnia. Any suggestions are greatly appreciated. I know I was able to take this 15 years ago without insomnia. Also, I think 200 mg is the lowest dose. I was thinking of taking it for 2 days and stop 1 day and then 2 days and try to build up.
David Tomen says
Nancy, SAM-e needs some of the B-Vitamins to work properly. The other thing is that as a methyl donor, SAM-e is involved in the production and recycling of hormones, cytokines, and the neurotransmitters acetylcholine, dopamine, norepinephrine, and serotonin.
Your hormones 15 years ago are likely very different than your hormones now which may have something to do with it.
Malik G says
How does this stack sound for alievating depression , anxiety brain fog , lack of motivation, and just the feeling that everything is pointless , I know I’ve had gut issues that I’m currently working on healing that have led to this , but would stack help me in the short term
1000 mg of NALT IN THE AM
200 mg of SAM-E In the AM
B complex AM 1 of 2 capsules
1000 MG of NALT
200 MG of SAM-E
B complex AM 2 of 2 capsules
5htp 100 MG
David Tomen says
Malik, your stack will only alleviate anxiety, depression, and brain fog if you are low in dopamine. Because that is what you are primarily working on by using NALT. And SAM-e is a methyl donor that contributes to the synthesis of dopamine.
You need to activate AMPA receptors to boost motivation. See this article: https://nootropicsexpert.com/hacking-motivation-with-nootropics/
If that stack does not provide the benefit you are looking for then I suggest testing each of the other neurotransmitters to see which one is dysfunctional. This article tells you how: https://nootropicsexpert.com/best-nootropics-for-anxiety/
Malik Gilmore says
Ok so after reading that article I assume this stack could also work then since it’s covering all basis
Rhodiola rosea 120 MG
Alpha GPC 600 MG
NALT 500 MG
Aniracetam 750 MG
Does that cover all my basis in terms of neurotransmitters? Also I planned on another dose of these in the afternoon around 4 , the first round would be around 9 AM
Malik Gilmore says
I also forgot to add that I’ll be taking 5G of L glutamine a day as well
David Tomen says
Malik, I think you missed the message I was trying to convey in the Anxiety article. That article explains trying each precursor one-at-a-time to test each neurotransmitter. And see if you can isolate which one is giving you problems. You’ll find that in this section called “How to Find the Root Cause” in my anxiety article. That applies to depression as well if depression is caused by a neurotransmitter dysfunction.
The intention is not to “cover all the bases”. It should be in my opinion to find which one is causing problems. And one you find it then find other nootropics that support that neurotransmitter.
Also I forgot to mention more than anything at all, my biggest thing I want to rid myself of is the anxiety that I’m experiencing, as I’ve stated before I know it’s due to nutritional imbalances due to stomach issues I’ve been happening , I just wanted to make sure with that particular stack I was covering all my basis in regards to neurotransmitters, I have a very taxing job and my performance has been lackluster , and needed a stack that could pick me up in the meantime
Is it safe taking SAM-e with St John’s Wort?
David Tomen says
Tas, it depends on the person and how you react. Because SAM-e will potentially potentiate the effects of St. John’s wort.
Hi David, you might want to include the following systematic reviews of the antidepressant properties of SAM-e:
These are from 2016 and 2020 respectively, so presumably they’re more reliable than the 2005 review you’ve linked as a source for the antidepressant claims here. The former also seems to suggest relatively little effect, although the latter seems more positive again.
Hope this is helpful, and thanks for all the effort you’ve put into this site!
David Tomen says
Patrick the second study you linked to was published in 2005 and favorable to concluding SAM-e could be used for depression.
But I suggest you take a look at the author “Declarations of interest” in the first meta-analysis. I think it’s clear that once you learn who paid these guys why they would conclude “more study” was necessary before declaring SAM-e useful for depression.
Sorry, I must have accidentally pasted the wrong link, here’s the 2020 review:
While I agree that one should be skeptical of ties between researchers and pharmaceutical companies, as far as I can tell the 2016 analysis was publicly funded, and what potential conflicts of interests are listed mainly seem problematic for three of its authors: Lam, Yatham and Young. The former two are listed as having “commented on the protocol and on the final draft”, while Young “commented on the protocol and on the final draft, performed assessment of risk of bias, and was a third author to resolve any disputes on study inclusion, study quality and data extraction”.
Considering the relatively minor roles apparently played by these potentially unreliable researchers, compared to the lack of potential conflicts of interests among the majority, including the leader and central contributors, it appears to me a bit hasty to dismiss the results as biased.
The 2020 analysis is funded by a pharmaceutical company, so it might be tempting to similarly dismiss that too, although it does include several studies showing significant effect, and concludes that SAM-e treatment for MDD seems promising.
However, in both these cases, these are reviews of existing literature, not original research. While there is still the possibility of tweaking the inclusion criteria to include or exclude certain studies, or interpreting results in ways amenable to certain views, a cursory scan by a layman at least gives the impression that their methodology is sound, and one can always check the studies they’re examining to judge whether or not they’re accurately represented.
And on the topic of bias, should we dismiss your selection of scientific sources due to your ties with Performance Lab? You’re upfront about the fact that you have a financial interest in recommending substances included in their products, after all. I’m not saying I will, and trust you to at least try to stay neutral and follow the science, but I’m not convinced there’s a substantial difference between your site and the 2016 review you’re dismissing…
David Tomen says
Patrick, well said and a good analysis. I stand by my comment about conflicts of interest. But it may not be as important in this case because this is just a review of several SAM-e clinical studies. I like your attitude in the way you look at this information. While I’m a skeptic a heart the science speaks for itself.
It’s best to educate ourselves and keep an open mind when it comes to biohacking. The bottom line of course is “does it work”.
So glad i came across this article.
I stopped taking Zoloft almost 8 months ago after being on it for 13yrs.
I’ve been taking 5htp 100mg x 2 a day, tyrosine, B-complex, vitamin D, fish oil. L-theanine, probiotics, magnesium glycinate, glycine BUT i can’t seem to shake these intrusive and ruminating thoughts ive been having the past 3.5 months. Do you think SAM-e will help?, I just don’t know what to do anymore.
Thanking you in advance
*I forgot to mention i am also taking NAC and Ashwagandha
David Tomen says
Anastasia, ruminating thoughts can be caused by low GABA or L-Glutamine levels. You can try SAM-e and see if it helps. I also suggest trying GABA (PharmaGABA), L-Glutamine, and Lemon Balm extract.
Thank you for the quick response. What dosage do you recommend?
David Tomen says
Anastasia, dosage for which supplement?
I include dosage recommendations for each of the supplements mentioned here. You can easily find them by scrolling down this list (https://nootropicsexpert.com/nootropics-list/) and clicking through to each supplement.
I’m suspecting I have some form of undermethylation, since I have anxiety, repetitive behaviors, perfectionism, sleep issues, hay fever, high histamine, high salivation.
I’ve read that SAMe could help. Is it true that SAMe raises homocysteine levels?
If this is the case, would TMG be a better option?
What about inositol, do you think it is good for undermethylation and my other issues?
Thanks A LOT for.your help!
David Tomen says
Jack, studies show that SAM-e should be consumed with B-Vitamins because When SAM-e donates its methyl group, it breaks down into homocysteine. Increasing your B-Vitamins will counter this rise in homocysteine. Use it with a B-Complex like this one: https://amzn.to/3xk3SQT
First, I want to thank you for the wealth of information you provide on this site–it has been a huge help to me.
I have been taking SAM-e since last June for depression (Nature’s Way, along with a quality B-Complex) and it has worked quite well for me until recently. It seemed to just stop working, even with an increased (1600) dose. So I have a couple of questions: Is this a common problem and do you know why this could be? I also had seen reference somewhere that possibly a break should be build in, such as skipping a day each week. Do you agree with this? Could simply taking a break from it for a time and resuming cause it to start being effective again?
Thank you so much for your help!
David Tomen says
Gayla, a couple of thing come to mind. First, has anything changed in your life that coincides with SAM-e no longer working? A change in diet, living environment, etc.
Second, is it possible your last bottle of SAM-e is defective? As a supplement, SAM-e is highly unstable and unless it is packaged and stored properly it can go bad quickly.
We have had major supply disruptions in the last year because of COVID-19. Maybe you just got a bad supplement?
David, thanks so much for your reply and suggestions. I think the supply should be pretty reliable. I notice now I said Nature’s Way in my comment and I actually meant Nature Made, which is in blister packs and, at least as far as I know, is a dependable supplier of SAM-e. The time span it has been lacking efficacy for me has covered more than one box.
As far as anything changing in my life, nothing recently, really. Perhaps I have allowed the weight of what has gone on over the past year and the continuing political strife in this country to just finally overwhelm my system beyond what SAM-e can help.
Unless you know of something simple I could add or try, maybe I will just give it more time and hope it starts working again. I love to read about the various supplements, but my mind starts whirling when I try to comprehend the complex combinations and how they all work together. I am finding I need to keep things as simple as I can right now. ha!
Thanks so much for your help!
P.S. I probably should have added that I also take ashwagandha. I originally started taking it simply for general health and don’t think I really considered the depression/anxiety aspect when I started taking SAM-e. I was just reading up on it again and guess I need to take that into consideration as well. (Other than that, I take fish oil, turmeric, multi-vitamin, and vitamin D.)
David Tomen says
Gayla, it could be so many things that even with trial and error you may never figure out the cause of why SAM-e is now working as before.
SAM-e is involved in the synthesis of all the major neurotransmitters. So you could try testing each one by using a precursor to make dopamine, acetylcholine, serotonin, etc. And see if any of those help you. This article explains how to do that: https://nootropicsexpert.com/best-nootropics-for-anxiety/
Thank you so much, David–I will start there. I appreciate immensely your taking the time to help me, as well as the expertise you share with all of us via your website. I trust that all the good you do will come back to you in spades.
Mike Carson says
I haven’t seen any indication that my last two replies were successful, so this is one more attempt to get you the information you asked for regarding SAM-e and compromised immune systems.
You are immunocompromised: There is a theoretical risk that SAM-e could enhance the growth of a microorganism called Pneumocystis carinii.
If you have a compromised immune system, talk to your doctor before taking SAMe. People who have a weakened immune system may be at increased risk of an infection caused by bacteria known as pneumocystis. SAMe may boost this microorganism’s growth.
There’s theoretical reason to believe that taking SAMe may promote Pneumocystis infection in people who are immunocompromised, such as those who are HIV-positive.
Most people who get PCP have a medical condition that weakens their immune system, like HIV/AIDS, or take medicines (such as corticosteroids) that lower the body’s ability to fight germs and sickness. PCP is extremely rare in healthy people, but the fungus that causes this disease can live in their lungs without causing symptoms. In fact, up to 20% of adults might carry this fungus at any given time, and the immune system removes the fungus after several months.
Most people who get PCP have weakened immune systems, meaning that their bodies don’t fight infections well. About 30-40% of people who get PCP have HIV/AIDS. 7,9 The other people who get PCP are usually taking medicine (such as corticosteroids) that lowers the body’s ability to fight germs or sickness or have other medical conditions, such as:
• Chronic lung diseases
• Inflammatory diseases or autoimmune diseases (for example, lupus or rheumatoid arthritis)
• Solid organ or stem cell transplant
David Tomen says
Mike, I’m behind on participating in the comments section so my apologies.
I saw what you posted earlier and checked it out. And my response is the same. These sites mention a “theoretical risk” of using SAM-e in someone who is immune compromised. But so far I have not seen any proof.
And by proof I mean at least one peer-reviewed clinical study in a respected medical journal telling us that if you are immune compromised you should not be supplementing with SAM-e. And why.
You will notice that when someone makes a statement like this it is copy and pasted to other sites. Over and over again with no one taking the initiative to back up what they are saying.
Unless I’m missing something. Am it?