Evidence Based
17

7 SAM-e Benefits + Side Effects, Dosage & Reviews

Written by Aleksa Ristic, MS (Pharmacy) | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Aleksa Ristic, MS (Pharmacy) | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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As millions of people are struggling with depression, joint pain, and liver disorders, scientists are on the hunt for effective remedies. SAM-e showed promising results, but it’s not for everyone. Read on for an ultimate breakdown of its benefits and side effects.

What is SAM-e?

SAM-e (S-Adenosyl-L-methionine or AdoMet) occurs naturally in the human body and enables a range of essential metabolic reactions.

It is classified as a supplement in the US and a prescription drug in some European countries. Some people take it for depression, joint and muscle disorders, liver diseases, and more [1, 2].

Snapshot

Proponents:

  • Helps with osteoarthritis
  • Protects the liver
  • May help with depression
  • May boost cognition
  • Potentially safe for pregnant women

Skeptics:

  • Harsh on the stomach
  • May trigger anxiety and mania
  • May interact with different medications

How it Works

As a supplier of a methyl group and organic sulfur, SAM-e drives complex metabolic reactions that control cell growth and lifecycle, inflammation, brain chemistry, and more [3, 4].

SAM-e prevents uncontrolled cell division, which is the main feature of cancer cells. It also inhibits MMP, an enzyme involved in cancer progression and inflammation [5].

The brain needs SAM-e to make serotonin, dopamine, and noradrenaline, which support mood, motivation, and overall mental health [6, 7, 8].

It combats oxidative stress and protects the cells by boosting the production of a master antioxidant, glutathione [9, 10, 11].

Role in Methylation

Methylation
Source: Forrest H. Nielsen and Susan L. Meacham, Journal of Evidence-Based Integrative Medicine

The body can produce SAM-e from a sulfur-containing amino acid, methionine. It does this well enough under optimal circumstances, but certain conditions — such as depression, liver disorders, and folate deficiency — may hinder this process [12, 13].

Along with folate and vitamin B12, S-adenosylmethionine participates in the one-carbon cycle (shown in the image above). Besides homocysteine metabolism, this cycle [14, 15, 16]:

  • Enables the production of red blood cells
  • Supplies energy
  • Supports the nervous system
  • Maintains mental health and cognition

SAM-e is key to proper methylation in the body.

It keeps the DNA methylated, which may prevent cell mutations. It also methylates amino acids and phospholipids and increases important neurotransmitters. This helps SAM-e achieve potential antidepressant and other effects we’ll outline throughout the post [17, 18].

Health Benefits

Likely Effective:

1) Osteoarthritis

Osteoarthritis (OA) attacks the cartilage of large joints, such as knee or hip. It causes joint pain and stiffness, which reduce patients’ quality of life [19].

A review of clinical studies with over 20,000 patients supports the use of SAM-e for osteoarthritis. It has the same effect as commonly-used NSAIDs with fewer side effects [20, 21].

In a Cochrane review of four trials with 656 patients, SAM-e moderately improved pain and joint function, compared with placebo. However, the authors pointed to certain flaws in study design discussed in “Limitations and Caveats” [22].

Given that long-term treatment with NSAIDs and other painkillers may cause stomach ulcers and other adverse effects, SAM-e could be a safer yet equally effective alternative [23].

Possibly Effective:

2) Depression

Depression rates keep growing, and standard treatment options sometimes fail to provide relief. Some people with depression have high homocysteine levels due to poor methylation [24].

Vitamin B12 and folate deficiencies can impair SAM-e production and, in turn, raise homocysteine and lower serotonin and noradrenaline [17].

SAM-e is one of the most studied complementary treatments for depression; extensive clinical reviews have documented its safety and efficacy. It acts faster than common antidepressants and yields similar results [25, 26, 27].

A large evidence-based database, Cochrane, reviewed eight clinical trials with over 900 depressed patients. They concluded that SAM-e works as well as antidepressant drugs and noted its excellent safety profile. However, neither of the treatment options was significantly better than placebo [28].

In a recent study of 60 patients with mild-to-moderate depression, a combination of SAM-e and vitamin B complex improved the symptoms while causing no side effects [29].

According to four studies with over 170 patients, SAM-e (800-1,600 mg daily) can even combat drug-resistant depression when added to standard treatment. It provided significant improvement in 35-60% of the patients [30, 31, 32, 33].

Please note that the health authorities advise against combining SAM-e with antidepressants, due to potential drug interactions (see “Drug Interactions” below for more details) [21].

The antidepressant effects of SAM-e may be more pronounced in men [34].

Besides improving the main symptoms of depression, SAM-e also enhanced cognition in these patients and reversed sexual dysfunction (caused by antidepressants) in some of these trials [35, 36].

SAM-e may help with mild-to-moderate depression, but its effectiveness is comparable to placebo. It acts faster and has fewer side effects than conventional antidepressants.

3) Liver Protection

As mentioned, S-adenosylmethionine boosts the master antioxidant, glutathione. Glutathione guards the liver against different chemicals, toxic metabolites, and oxidative stress [37, 38].

In a meta-analysis of 12 clinical trials (705 patients), SAM-e significantly reduced two markers of liver damage: bilirubin and AST. The researchers observed these effects in patients with [39]:

  • Liver scarring (cirrhosis)
  • Impaired bile flow (cholestasis)
  • Alcoholic liver disease
  • Liver cancer

That doesn’t necessarily mean that SAM-e can treat the above conditions.

Overall, SAM-e was safe and provided moderate benefits, but most patients responded even better to ursodeoxycholic acid (ursodiol).

SAM-e may also reverse cholesterol buildup in the liver and shield it against toxic drugs such as acetaminophen (Tylenol) and steroids [40, 41].

Bile Flow

Liver disease can lead to cholestasis or reduced bile flow. Bile acids and toxic metabolites build up and can further damage liver cells. This condition can also occur during pregnancy and may raise the risk of birth complications [42, 43].

According to two clinical reviews, SAM-e (1,600 mg daily) can improve markers of liver health in cholestasis and relieve symptoms such as skin itching, fatigue, and discomfort [44, 45].

Either alone or in combination with ursodeoxycholic acid, it improved the symptoms of cholestasis in another three clinical trials with over 150 pregnant women [46, 47, 48].

The same combination reduced birth complications from cholestasis in an analysis of 10 clinical trials (727 pregnant women). It lowered the rates of [49]:

  • Cesarean section, by 55%
  • Preterm birth, by 64%
  • Fetal suffocation, by 73%

The authors mentioned a few flaws in methodology as potential sources of bias in those trials.

A smaller study with 18 pregnant women found no significant benefits [50].

Alcoholic Liver Disease

Chronic alcohol consumption massively increases oxidative stress and wreaks havoc in the liver. Natural supplements such as SAM-e and silymarin have shown promising results in people with alcoholic liver disease [51, 52].

In 123 people, SAM-e (1,200 mg daily for 2 years) cut the risk of death and liver transplantation. It offered greater benefits in earlier stages of alcoholic liver disease [53].

SAM-e can boost antioxidant protection in the liver, stimulate bile flow, and reduce damage from alcohol and other toxins. Well-designed clinical trials should confirm these effects.

4) Fibromyalgia

Studies exploring complementary approaches to fibromyalgia are underway, and SAM-e is among them. According to a review of 70 clinical trials, SAM-e, magnesium, and L-carnitine showed the best results and the most potential for further research [54, 55].

In 44 patients with fibromyalgia, SAM-e (800 mg daily for 6 weeks) reduced [56]:

  • Muscle pain
  • Fatigue
  • Morning stiffness

It also relieved depression and increased pain tolerance in 17 fibromyalgia patients. In another trial of 34 patients, injected SAM-e had no influence on pain; it did, however, slightly improve fatigue, sleep quality, and stiffness [57, 58].

Insufficient Evidence:

No valid clinical evidence supports the use of SAM-e for any of the conditions in this section. Below is a summary of up-to-date animal studies, cell-based research, or low-quality clinical trials which should spark further investigation. However, you shouldn’t interpret them as supportive of any health benefit.

5) Cognition Enhancement

The beneficial effects of SAM-e on glutathione production may also shield the brain against oxidative damage caused by toxins or degenerative diseases [59, 11].

It reversed memory-related cognitive problems in 46 patients with drug-resistant depression [35].

In 12 healthy people, SAM-e supplementation (1,600 mg daily) supplied the brain with energy by boosting creatine production. This effect may underlie its ability to improve mood and cognition, but the lack of a placebo control prevents us from drawing conclusions [60].

In mice deficient in folate, SAM-e restored acetylcholine levels and enhanced cognitive performance. Interestingly enough, SAM-e also reduced the animals’ aggressiveness. It worked by increasing choline availability in the brain [61].

The risk of folate deficiency increases with aging and impairs cognition. Folate and SAM-e deficiencies may also contribute to cognitive problems in those with MTHFR mutations (677TT) [61, 62].

Alzheimer’s Disease

In people with Alzheimer’s disease, protein mutations and oxidative stress kill cholinergic neurons and cause a progressive cognitive decline. Brain levels of SAM-e also drop, thus lowering antioxidant protection [63, 64, 65].

A nutritional supplement with 400 mg of SAM-e improved the symptoms in 14 patients with early-stage Alzheimer’s disease. The other active ingredients were [66]:

This combination of active ingredients is likely synergistic, and we can’t determine how much SAM-e added to the overall benefit.

In 12 patients with moderate-to-late stage Alzheimer’s, the same formulation improved cognition, mood, and daily functioning by up to 30%. Both studies had tiny samples and lacked placebo controls, making the results questionable [67].

In vitamin B-deficient mice, SAM-e blocked the formation of inflammatory brain plaques, improved memory, and reversed disease progression [68].

Animal and Cellular Research (Lacking Evidence)

No clinical evidence supports the use of SAM-e for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

6) Anticancer effects

By supporting methylation, SAM-e may prevent the uncontrolled division of cancer cells and inhibit cancer-promoting enzymes [5].

In studies on mice, scientists observed inhibitory effects of SAM-e on [69, 70, 71, 72]:

  • Breast cancer
  • Liver cancer
  • Stomach cancer
  • Bone cancer

It even reduced the growth of some advanced forms of cancer with metastases.

Cell experiments voice the potential effects of SAMe on different types of cancer cells, but they can’t tell us anything about the actual effects of SAM-e on cancer in a living organism [73, 74, 5, 4].

Despite the promising preliminary research, SAM-e safety and efficacy is still unknown when it comes to cancer. Clinical trials are needed before we can draw any conclusions.

7) Weight Loss

Many supplements are promoted to stimulate weight loss, but none of them has yet been supported by strong clinical evidence and approved by the health authorities. A healthy, calorie-controlled diet and increased physical activity remain the only proven strategies for weight control.

A group of scientists noticed that SAM-e reduced insulin resistance and weight gain in obese rats with diabetes. It showed similar effects on insulin resistance in one study on fat cells [75, 76].

In theory, SAM may reduce appetite indirectly by improving mood, since depressed people are much more prone to binge eating [77].

Of course, the above findings don’t tell us anything about the actual weight loss effects. Rigorous clinical trials should put this to test.

Limitations and Caveats

Despite the promising effects of SAM-e on a range of conditions, there are some significant limitations to consider.

Some clinical trials for depression and liver diseases examined the effects of injected SAM-e, which may not occur during oral consumption [25, 45, 48].

Reviews for osteoarthritis and fibromyalgia noted the presence of many studies with small samples and design flaws such as uneven randomization [55, 22].

Studies with SAM-e for drug-resistant depression also had small samples, and they lacked placebo controls [33, 32, 78].

Despite the positive results for cholestasis in pregnancy, ursodeoxycholic acid (ursodiol) remains the first-choice treatment for this condition [47, 46, 43].

SAM-e For Dogs

This supplement is popular among pet owners, too. They mostly use it for dogs’ joint and liver disorders.

In different dog studies, SAM-e boosted glutathione and provided antioxidant liver support. It reversed the damaging effects of [79, 80, 81]:

  • Tylenol
  • Corticosteroids
  • Chemotherapy

Daily supplementation with 18 mg/kg of SAM-e was safe and effective for age-related cognitive decline in 36 dogs [82].

When it comes to osteoarthritis, a study with 33 dogs found no benefits of SAM-e [83].

Side Effects and Precautions

SAM-e was safe in most clinical trials. The most common side effects were nausea and other digestive issues, followed by anxiety [84, 85, 56, 20].

Despite some public concerns, SAM-e supplementation doesn’t increase the levels of homocysteine and the risk of heart disease [86, 87].

It may trigger mania in patients with bipolar disorder but also in vulnerable healthy individuals [25, 87].

Health experts suggest avoiding SAM-e for people with compromised immunity, due to an increased risk of some infections [21].

Drug Interactions

Drug interactions can be dangerous and, in rare cases, even life-threatening. Always consult your doctor before supplementing and let him know about all drugs and supplements you are using or considering.

SAM-e raises the levels of serotonin and could thus interact with antidepressants and increase the risk of serotonin syndrome. Even though some doctors safely combined it with different antidepressants in clinical trials, health experts advise against this combination [21, 27, 28, 30, 33].

Other drugs and supplements that can increase serotonin include [88, 89]:

SAM-e may also interact with a drug for Parkinson’s disease, L-DOPA. Excess amounts of SAM-e depleted dopamine and caused the symptoms of Parkinson’s disease in decades-old studies on mice. This combination should be avoided until new studies come out [90, 91, 92].

Use in Pregnancy and Children

SAM-e was safe in studies on pregnant women, but they should take it under strict medical supervision. Children should avoid it until we know more about its safety [49, 48].

SAM-e Dosage and Supplements

Despite the promising clinical and preclinical research, SAM-e has not been approved by the FDA for medical use. In general, regulatory bodies aren’t assuring the quality, safety, and efficacy of supplements. Speak with your doctor before supplementing.

The below doses used in clinical trials may not apply to you personally. If your doctor suggests using SAM-e, work with them to find the optimal dosage according to your health condition and other factors.

The following SAM-e dosage showed beneficial effects in clinical trials:

  • Depression: 800-1,600 mg daily, 6+ weeks [28, 85, 26]
  • Osteoarthritis: 1,200 mg daily, 1-4 months [93, 84, 94]
  • Liver disorders: 1,600 mg daily [45]
  • Cholestasis in pregnancy: 1,000 mg daily until delivery [46, 47]

Supplements

SAM-e comes in 200 mg or 400 mg pills, packed in blisters or bottles (see in “Additional Tips” below why this is important). It’s also a common ingredient in combined nutritional supplements for mood support.

User Reviews

The opinions expressed in this section are solely from the users who may or may not have medical background. Their reviews do not represent the opinions of SelfHacked. SelfHacked does not endorse any specific product, service, or treatment.

Do not consider user experiences as medical advice. Never delay or disregard seeking professional medical advice from your doctor or another qualified healthcare provider because of something you have read on SelfHacked.

Most users have reported positive experiences with SAM-e for depression. People also take it for joint pain and osteoarthritis and give them to dogs with these issues.

Some report the benefits of SAM-e for anxiety and its calming effect, which contradicts the data from clinical trials.

Plenty of users complain about digestive issues, which even demanded medical care in some cases. There are individual reports of worsened depressive symptoms, panic attacks, and irritability.

Additional Tips

SAM-e is unstable and requires optimal storage conditions. It can quickly change color and lose potency when exposed to air and moisture. For this reason, you may want to choose blister packs instead of bottles.

Those struggling with digestive side effects should take SAM-e with food and look for gastro-resistant pills, which are gentler on the stomach.

Takeaway

SAM-e boosts glutathione and supports methylation. People with depression, liver disorders, and folate deficiency make less SAM-e and may benefit from supplementing. SAM-e can also help with joint and muscle pain, while the evidence for cognitive benefits is insufficient.

Safe and effective doses range from 800-1600 mg for most conditions. Nausea, diarrhea, and other digestive issues are the most common side effects. SAM-e may also trigger anxiety and mania in vulnerable people.

Pregnant women should take SAM-e only under strict medical supervision, and everyone should consult a doctor before supplementing.

Where to Buy

Want Better Ways to Improve Your Mood?

If you’re interested in natural and targeted ways of improving your mood, we recommend checking out SelfDecode’s Mood DNA Wellness Report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your mood. The recommendations are personalized based on your genes.

SelfDecode is a sister company of SelfHacked. This section contains sponsored links, which means that we may receive a small percentage of profit from your purchase, while the price remains the same to you. The proceeds from your purchase support our research and work. Thank you for your support.

About the Author

Aleksa Ristic

Aleksa Ristic

MS (Pharmacy)
Aleksa received his MS in Pharmacy from the University of Belgrade, his master thesis focusing on protein sources in plant-based diets. 
Aleksa is passionate about herbal pharmacy, nutrition, and functional medicine. He found a way to merge his two biggest passions—writing and health—and use them for noble purposes. His mission is to bridge the gap between science and everyday life, helping readers improve their health and feel better.

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