S-adenosyl-methionine, or SAMe, is the universal methyl donor for the methylation of DNA, RNA, histones, phospholipids, catecholamines (especially dopamine), and proteins. SAMe is the only supplement I have ever tried that has had a clear-cut effect on my energy and mood – at least temporarily.
Personal experience
I have gone on and off SAMe multiple times over the past couple of years. Every time about 24-36 hours or so after starting/increasing SAMe, for one to two days or so I feel on top of the world: motivated, emotional, and euphoric. The delay in effect likely represents the time it takes for SAM-e to increase dopamine levels (discussed shortly). About three or four of my friends have also tried taking it and they all had a similar experience.
Conversely, whenever I stopped taking SAMe, about 24-36 hours or so after I feel a significant drop in motivation, anhedonia, and some symptoms resembling biological depression. This state generally lasts for about 2-4 days and thereafter things tended to gradually get back to normal over the course of one to two weeks or so.
Whether SAMe alters my baseline sustainably is hard to say but it surely does so for the first couple of weeks. Also, I have suffered from sleep paralysis a couple of times in my life. Interestingly, every single time was related to starting or increasing SAMe.
Because I am a carrier of some adverse SNPs in the MTHFR pathway, I suppose that SAMe supplementation is more powerful for me than for people with a more “normal” folate pathway. Whenever I take SAMe, I take it with L-methyl folate and TMG to prevent the potential rise in homocysteine, which may have adverse effects on cardiovascular health.
SAMe is a hit-or-miss and it seems that some people do not respond to it at all, others respond to it in an exaggerated manner, and others get insomnia and irritability. For the friends who had tried it, everyone independently reported a considerable increase in energy & mood during the first week or so. Two friends also reported restlessness and irritability.
In sum, SAMe is a viable alternative to prescription antidepressants – particularly useful for getting out of a light funk.
How it works
SAMe is a molecule that serves as a methyl donor in several biochemical reactions. Methylation is a process that involves the transfer of a methyl group (CH3) from one to other molecules, such as DNA, RNA, proteins, and certain neurotransmitters.
These methylation reactions are crucial for the regulation of gene expression, the synthesis of some neurotransmitters and hormones, and the maintenance of cellular structure and function. Because SAMe is one of the major cellular methyl donors, it has been used as a dietary supplement for the treatment of depression, liver disease, and osteoarthritis. In some countries, SAMe is only available on prescription.
I want to specifically mention the effect of SAMe supplementation on monoamine neurotransmitters (dopamine, serotonin, noradrenaline). SAMe is most useful in increasing dopamine levels with moderate effects on noradrenaline and only negligible effects on serotonin.
Because it increases dopamine synthesis, at least temporarily, it is useful for improving the commonly inadequately treated symptoms of lack of motivation and anhedonia, which may be (in part) due to deficient dopamine signaling. I share my thoughts on this barbaric neglect of dopamine in the treatment of depression in more detail here.
Unfortunately, SAMe is not patentable and so little money can be made from it, which makes it an almost forgotten agent in psychiatry. Most psychiatrists I have talked to have never even heard of it.
Warnings & risks
- SAMe should not be used by people with bipolar disorder (or a family history of bipolar disorder) as it carries a significant risk of inducing a manic switch, possibly more so than most prescription antidepressants. High doses of SAMe (1200mg) are known to trigger temporary hypomania even in healthy people.
- Likewise, it should not be used by people with a history or a family history of psychosis, as the elevation of dopamine brought about by SAMe can nudge someone with a genetic predisposition towards and into psychosis.
- Because SAMe potently increases dopamine synthesis, a high dose of SAMe supplementation for many years may (in theory) increase the risk and/or hasten the onset of developing Parkinson’s disease later in life. PD is in part caused by the generation of toxic dopamine metabolites.
- There is experimental evidence that excessive SAMe levels may be (epi)genotoxic. SAMe breaks down into adenine and methylthioadenosine, having potentially adverse effects on DNA methylation. This is also evidenced by the fact that SAMe is effective in stopping some cancerous cells from dividing because it induces widespread epigenetic methylation and thus cellular differentiation.
I do not know (and I suppose nobody does) whether these risks are of practical relevance for common SAMe dosages below 800mg per day, but my gut feeling is that supplementing with SAMe for many years is not safe.
SAMe is a methyl-group donor involved in thousands of reactions throughout the body. While great for neurotransmitter synthesis (the only thing I “feel”) supplementing with SAMe may have potentially dangerous effects on a number of physiological processes (the effects of which I do not “feel”).
I am particularly concerned about the (potential) epigenotoxicity. Even though it is unclear whether this applies to humans (it does to in vitro cultured human cells), this was enough for me to stop taking SAMe. I phased it out and after a rough couple of days, I was mostly back to normal.
In sum, SAM-e is not a benign supplement. It has potent neurobiochemical effects with potentially far-reaching effects.
Other experience reports
For a discussion of the molecular correlates of well-being, and links to accounts of various related molecules I have experimented with, read here.
For a full list of experience reports click here.
Sources & further information
- Scientific review: S-Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders
- Scientific review: S‐adenosyl methionine (SAMe) for depression in adults
- Website: Wikipedia – S-adenosyl-methionine
Disclaimer
The content available on this website is based on the author’s individual research, opinions, and personal experiences. It is intended solely for informational and entertainment purposes and does not constitute medical advice. The author does not endorse the use of supplements, pharmaceutical drugs, or hormones without the direct oversight of a qualified physician. People should never disregard professional medical advice or delay in seeking it because of something they have read on the internet.