SAMe: More than just Liver Support

SAMe (S-adenosylmethionine) is best known as a supplement for providing support for the liver.  However, SAMe is also used as a treatment for liver disease, depression, osteoarthritis, schizophrenia, as a safer alternative to NSAIDs for providing pain relief and has undergone clinical trials for many of these uses.  In fact, SAMe is the universal donor for over 100 different metabolic reactions throughout the body and is even able to transit the blood brain barrier to facilitate important and essential reactions within the brain itself.  Interest in SAMe in the medical community is intense.  Clinicaltrials.gov lists 61 clinical trials involving SAMe in various stages of completion for conditions including alcohol liver disease, Alzheimer’s disease, fibromyalgia, obesity, metabolic syndrome, oxidative stress, lymphoma, liver failure, sickle cell anemia, cognitive impairment, prostate cancer, HIV, depression and heart disease, among others.

What does the evidence say?  What are the main conditions SAMe can treat?

Liver support.  As it contains a key component necessary for carrying out many liver functions, it is often used as a liver support.  This is its most well-known use.

Depression.  More than 40 clinical trials have evaluated the use of SAMe in treating various kinds of depression.  A meta-analysis of 28 placebo-controlled randomized control trials found SAMe to be effective (as compared with placebo) in reducing depressive symptoms in a clinically significant way.  The same meta-analysis found SAMe to be as effective or superior to a range of pharmaceutical antidepressants, with fewer side effects.  A review article examining trials since the publication of that meta-analysis reached similar conclusions.

Liver Dysfunction and Cholestasis.  A study of 123 alcoholic patients with cirrhosis treated with 1,200 mg of oral SAMe per day found a 50% reduction in the overall combined measure of death or liver transplantation as compared with placebo.  Although that result was not statistically significant, when the most advanced liver disease patients were removed from the data, statistical significance was achieved (p=0.025) with a nearly three-fold improvement--29% of those in the placebo group died or received liver transplant vs only 12% in the SAMe group.  Another study (in women with a pregnancy-associated liver syndrome) found that after 10-20 days of 800 mg of intravenous SAMe treatment, there were statistically significant declines in serum conjugated bilirubin, serum total bile, alamine, and aspartate transaminase. 

Analgesic/Osteoarthritis.  A review article that considered studies from the 1980s concluded that patients taking 400-1,200 mg of oral SAMe per day showed significant improvement in both objective and subjective symptoms of osteoarthritis.  Moreover, after four weeks of treatment, the effectiveness was equivalent to that of NSAIDs (such as ibuprofen, naproxen, indomethacin and piroxicam).  However, more recent trials have generally not duplicated these results.  Thus, the evidence is mixed on whether SAMe is effective in treating osteoarthritis or as a substitute for NSAIDs.  Given its highly favorable safety profile as compared with NSAIDs, it may be the preferred treatment in milder cases or to reduce or complement NSAIDs.

Other conditions.  Other data (mostly from animal studies, small trials or anecdotes) suggest potential treatments for migraines, Parkinsons disease, Alzheimer disease, epilepsy, metabolic defects, HIV-related neurological conditions, and many others, as well as in protecting against gastrointestinal injury associated with alcohol.  Although promising, more research is needed to evaluate those potential uses. 

How does it work?

SAMe is the molecule that keeps giving.  Several steps in its metabolism produce valuable compounds.  The first step in this metabolism is to break off its methyl group.  This methyl group is then donated to combine with various nucleic acids, proteins and lipids, to facilitate more than 100 important reactions.  The liver in particular is a heavy user of these methyl groups, accounting for about 85% of these reactions.  (Further reading here.)  

After donating its methyl group to other receptors, the remaining compound splits into adenosine (a key regulator of heart rhythm and blood vessel dilation) and, eventually, glutathione (the main cell anti-oxidant).  Consequently, beyond its role as a methyl donor, SAMe also contributes to heart health and acts as an important antioxidant.  Other metabolites of SAMe are responsible for its demonstrated analgesic and anti-inflammatory properties.  (Further reading here.)

Is it safe?

It is highly safe, with few side effects even at very high dosages.  In fact, one safety study predicted it would take a dosage of 400,000 mg to be toxic in a 154 pound man.  One of the reasons it has been the subject of so many clinical trials is its favorable safety profile compared with various prescription drugs.  A list of potential side effects, interactions and warnings can be found here.

What is an enteric (or delayed release) coating and why is that important?

In its oral form, SAMe rapidly metabolizes, has low bioavailability, is chemically unstable and degrades quickly in the presence of moisture.  (Further reading here.)  Moreover, SAMe is expensive.  The enteric (or delayed release) coating protects the SAMe within it to ensure that it survives the stomach and can be absorbed in the intestines.  (“Enteric” means intestines.)  A rat study that compared portal blood SAMe concentration after injection of SAMe into the duodenum (beginning of the intestines) vs SAMe taken orally,  In that study, concentrations in the orally-administered rats barely moved, whereas duodenal injected rats saw sharp spikes in SAMe concentrations.  (See Figure 2 here.)  Thus, getting the SAMe to the intestines intact is key to its effectiveness.  The thicker enteric coating also serves as a better storage vessel for the unstable SAMe than uncoated or regular capsule coatings, thus improving shelf-life.  Thus, SAMe supplements that are not enterically coated or time delayed should be avoided.

Further stability is added by combining SAMe with a counterion such as tosylate.

What are some other considerations in supplementing with SAMe?

SAMe concentrations are significantly impacted by fasting.  In a dog study, SAMe concentrations in dogs rose sharply after administration of enteric-coated SAMe in fasting dogs but when those same dogs were administered the SAMe 30 minutes after a meal, the concentrations rose very slowly or not at all and never achieved the levels or the sharp increase as was seen in the fasting dogs.  (See Figure 3 here.)  After administration of SAMe after nighttime fasting, plasma SAMe levels in humans rise sharply during the first three hours after administration in women and during the third through the sixth hours in men.  (See Figure 4 here.)  Thus, the best time of day to take SAMe is after nighttime fasting and as much time as possible before breakfast.

Another factor in SAMe’s effectiveness is sex.  In general, females achieve higher concentrations and do so more quickly than males given the same doses of oral SAMe.  Thus, men may need to take higher doses than women to achieve the same results.

What dosage should I administer or take?

Whether to start a supplement and the dosing of that supplement are matters to discuss with your medical professional.  It is important to note that, although SAMe is very safe, there are both contraindications and known drug interactions with SAMe.  (Further reading here.)  Based on the relevant studies and clinical experience, Lignans for Life recommends the following dosages for dogs for liver support:

• For medium sized dogs 21 lbs to 40 lbs: give 1 (200 mg) tablet per day.
• For large dogs 41 lbs to 80 lbs: give 2 (200 mg) tablets per day.
• For very large dogs over 80 lbs: give 3-4 (200 mg) tablets per day.

In humans, dosing depends on the condition being treated, and is based on the doses studied for that particular condition.  These are the dosages suggested by rxlist.com:

• “For depression: Up to 1600 mg of SAMe daily in two divided doses for up to 8 weeks has been used alone or together with antidepressant medications. . . .
• “For osteoarthritis: 600-1200 mg of SAMe daily in up to three divided doses for up to 84 days has been used.
• “For cirrhosis: 600 mg of SAMe daily for one month has been used. A combination 30 mg of SAMe plus 100 mcg of vitamin B12 six times daily for 30 days has been used.
• “For fibromyalgia: 800 mg per of SAMe daily in two divided doses for 6 weeks has been used.
• “For conditions in which bile flow from the liver is slow or blocked (Intrahepatic cholestasis): 500 mg of SAMe taken twice daily until delivery or 1600 mg taken daily in two divided doses for 2 weeks has been used.
• “For sexual dysfunction: 400 mg of SAMe taken twice daily for 2 weeks, then increased to 800 mg twice daily for another 6 weeks, has been used.”