As millions of people are struggling with depression, joint pain, and liver disorders, a universal natural remedy for these conditions would be a lifesaver. Have we just found one? SAM-e offers impressive health benefits, but it’s no panacea and it’s not for everyone. Read on for an ultimate breakdown of its pros and cons.

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. People take it for depression, joint and muscle disorders, liver diseases, and more [1, 2].

Snapshot

PROs

  • Combats depression
  • Helps with osteoarthritis
  • Protects the liver
  • Boosts cognition
  • May help with cancer
  • Safe for pregnant women

CONs

  • Harsh on the stomach
  • May trigger anxiety and mania
  • May interact with 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].

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

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

Function and Role in Methylation

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

Your 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].

Theoretically, it was thought that SAM-e would raise homocysteine levels, however, it does not appear to do so [14]. Along with folate and vitamin B12, S-adenosylmethionine actually seems to participate in the break down of homocysteine in the one-carbon cycle (shown in the image above). Besides homocysteine metabolism, this cycle [15, 16, 17]:

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

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

It keeps the DNA methylated, protecting it from the hallmark of cancer – hypomethylation. It also methylates amino acids and phospholipids and increases important neurotransmitters. This helps SAM-e achieve antidepressant and other effects we’ll outline throughout the post [18, 19].

SAM-e Benefits

1) Combats Depression

Depression rates keep growing, and standard treatment options often fail to provide relief. Some people with depression have high homocysteine levels due to poor methylation [20].

Vitamin B12 and folate deficiencies can impair SAM-e production and, in turn, raise homocysteine and lower serotonin and noradrenaline [18].

SAM-e is one of the most studied natural remedies for depression; extensive clinical reviews have documented its safety and efficacy. It acts faster than common antidepressants and yields similar results [21, 22, 23].

A large evidence-based database, Cochrane, reviewed 8 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 [24].

In a recent study on 60 patients with mild-to-moderate depression, a combination of SAM-e and vitamin B complex improved the symptoms while causing no side effects [25].

According to 4 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 [26, 27, 28, 29].

The antidepressant effects of SAM-e may be more pronounced in men [30].

Besides improving the main symptoms of depression, SAM-e may also enhance cognition in these patients and reverse sexual dysfunction caused by antidepressants [31, 32].

Summary

S-adenosylmethionine may combat mild-to-moderate depression, both alone or added to standard treatment. It acts faster and causes fewer side effects than conventional antidepressants.

2) Helps With 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 [33].

A review of clinical studies with over 20K patients supports the use of SAM-e for osteoarthritis. It has the same effect as commonly-used NSAIDs with fewer side effects [34].

In a Cochrane review of 4 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 (see “Limitations and Caveats” below) [35].

SAM-e treatment (1,200 mg daily for 1-4 months) matched the effects of different NSAIDs in 3 clinical trials with over 220 patients. It relieved pain and stiffness in the knees and hips, which significantly improved the patients’ mobility [36, 37, 38].

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 [39].

3) Protects the Liver

As mentioned, S-adenosylmethionine boosts the master antioxidant, glutathione. Glutathione guards the liver against different chemicals, toxic metabolites, and oxidative stress [40, 41].

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 [42]:

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

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 [43, 44].

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 [45, 46].

According to two clinical reviews, SAM-e (1,600 mg daily) improves markers of liver health in cholestasis and relieves symptoms such as skin itching, fatigue, and discomfort [47, 48].

Either alone or in combination with ursodeoxycholic acid, it improved the symptoms of cholestasis in another 3 clinical trials with over 150 pregnant women [49, 50, 51].

The same combination reduced birth complications from cholestasis in an analysis of 10 clinical trials (727 pregnant women). It lowered the rates of [52]:

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

However, a smaller study with 18 pregnant women found no significant benefits [53].

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 [54, 55].

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 [56].

Summary

SAM-e can boost antioxidant protection in the liver, stimulate bile flow, and reduce damage from alcohol and other toxins.

4) Boosts Cognition

The beneficial effects of SAM-e on glutathione production may also shield the brain against oxidative damage caused by toxins or degenerative diseases [57, 11].

It reversed memory-related cognitive problems in 46 patients with drug-resistant depression [31].

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 [58].

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 [59].

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) [59, 60].

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 [61, 62, 63].

A nutritional supplement with 400 mg of SAM-e improved the symptoms in 106 patients with Alzheimer’s disease. The other active ingredients were [64]:

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

In a smaller trial (12 patients), the same formulation improved cognition, mood, and daily functioning by up to 30% [65].

SAM-e might also help with vitamin B deficiencies and high homocysteine – both of which may contribute to Alzheimer’s and cognitive decline. In vitamin B-deficient mice, SAM-e blocked the formation of inflammatory brain plaques, improved memory, and reversed disease progression [66].

5) Helps With Fibromyalgia

Studies exploring effective and safe dietary supplements for 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 [67, 68].

In 44 patients with fibromyalgia, SAM-e (800 mg daily for 6 weeks) reduced [69]:

  • Muscle pain
  • Fatigue
  • Morning stiffness

It also relieved depression and increased pain tolerance in 17 fibromyalgia patients. In another smaller trial of 34 patients, injected SAM-e had no influence on pain; it did, however, slightly improve fatigue, sleep quality, and stiffness [70, 71].

6) May Combat Cancer

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

In studies on mice, SAM-e was able to prevent the growth and spreading of [72, 73, 74, 75]:

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

It was even effective against the advanced forms of cancer with metastases.

Cell experiments voice the powerful effects of SAMe on different types of cancer. It may boost the effects of chemo while protecting the healthy cells [76, 77, 77, 5, 4].

However, the benefits and safety of SAM-e in people with cancer are unknown. Clinical trials are needed before we can draw any conclusions

7) May Support Weight Loss

SAM-e reduced insulin resistance and weight gain in obese rats with diabetes. It showed similar effects in one study on fat cells [78, 79].

It may also combat weight loss indirectly by improving mood, especially in depressed people who are prone to binge eating [80].

The initial results are promising, but we need stronger clinical evidence before adding SAM-e to the list of proven natural ways to lose weight.

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 [81, 82, 83]:

  • Tylenol
  • Corticosteroids
  • Chemotherapy

In the case of Tylenol poisoning, SAM-e treatment saved the dog’s life. He urgently received a loading dose (40 mg/kg), followed by a standard dose for liver protection: 20 mg/kg daily [81].

Daily supplementation with 18 mg/kg of SAM-e was safe and effective for age-related cognitive decline in 36 dogs [84].

When it comes to osteoarthritis, a study with 33 dogs found no benefits of SAM-e [85].

Limitations and Caveats

Despite the vast potential of SAM-e for 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 [21, 48, 51].

Reviews for osteoarthritis and fibromyalgia noted the presence of many studies with small samples and design flaws such as uneven randomization [68, 35].

Studies with SAM-e for drug-resistant depression also had small samples, and they lacked placebo controls [29, 28, 86].

Despite the positive results for cholestasis in pregnancy, ursodeoxycholic acid (ursodiol) remains the first-choice treatment for this condition [50, 49, 46].

Cognition-boosting, weight loss, and anticancer effects of SAM-e lack solid clinical evidence.

Side Effects and Precautions

SAM-e was safe in most clinical trials. The most common side effects are nausea and other digestive issues, followed by anxiety [37, 87, 69, 34].

Safety Concerns

Despite some public concerns, SAM-e supplementation doesn’t increase the levels of homocysteine and the risk of heart disease [88, 89].

It may trigger mania in patients with bipolar disorder but also in vulnerable healthy individuals [21, 89].

Drug Interactions

SAM-e raises the levels of serotonin and could, in theory, interact with antidepressants and increase the risk of serotonin syndrome. However, doctors safely combined it with different antidepressants in clinical trials [23, 24, 26, 29].

Other drugs and supplements that can increase serotonin include [90, 91]:

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 [92, 93, 94].

To stay on the safe side, make sure to consult with your doctor before taking SAM-e, especially if you’re using one of the above drugs or supplements.

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 [52, 51].

Dosage and Supplements

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

  • Depression: 800-1,600 mg daily, 6+ weeks [24, 87, 22]
  • Osteoarthritis: 1,200 mg daily, 1-4 months [38, 37, 36]
  • Liver disorders: 1,600 mg daily [48]
  • Cholestasis in pregnancy: 1,000 mg daily until delivery [49, 50]
  • Alzheimer’s disease: 400 mg daily, 3+ months (with other nutrients) [65, 64]

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.

Reviews

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.

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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.

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 and cognitive impairment.

Safe and effective doses range from 800-1,600 mg for most conditions, and they are suitable for long-term supplementation.

Nausea, diarrhea, and other digestive issues are the most common side effects. SAM-e may also trigger anxiety and mania in vulnerable people. Due to potential drug interactions, make sure to consult your doctor before supplementing.

About the Author

Aleksa Ristic, MSc (Pharmacy)

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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