SAMe is a compound best known for its antidepressant action. In this article, we seek to touch on the significant body of evidence that supports SAMe in the treatment of depressive disorders and also highlight other primary clinical uses:^3,16

• Liver disorders
• Osteoarthritis
• Fibromyalgia

The universal methyl donor 

S-adenosyl-L-methionine (SAMe) is a naturally occurring molecule found within every cell of our body. It is the active form of the amino acid methionine, derived from L-methionine and the nucleic acid adenosine triphosphate (ATP), catalysed by S-adenosylmethionine synthetase.^3,6,10

Our body’s ability to synthesise SAMe can become compromised by a deficiency of methionine, folic acid and vitamin B12. Levels of SAMe are typically lower in men and the elderly.^11,16

Often referred to as the “universal methyl donor” SAMe functions in cellular transmethylation reactions. It is significantly more efficient at transferring methyl groups than other methyl donors. SAMe functions in crucial metabolic pathways, including methylation of DNA bases, phospholipids, catecholamines and neurotransmitters.^1,2,8,16

SAMe is also necessary for synthesising vital sulphur-containing compounds in our body, such as the antioxidant glutathione (GSH), which protects cells from toxic injury through biotransformation of xenobiotics and in the components that form cartilage.^2,16

The liver is the hub of SAMe metabolism. SAMe plays an essential role in hepatocyte proliferation, differentiation, and death. 85% of all transmethylation reactions take place in this organ. Damage to the liver can compromise SAMe bioavailability resulting in wide-ranging pathological effects.^6,15

SAMe: A well-established therapy for depressive disorders

In European countries, SAMe has been used for over 30 years to treat depressive disorders. 

SAMe plays a primary role in the central nervous system (CNS) methylation throughout the lifespan, from brain development in utero to cognitive decline in old age. Disruption to CNS methylation processes is involved in the pathogenesis of disorders such as depression and dementia.^4,6,8 

Research suggests several mechanisms through which SAMe exerts an antidepressant activity:^2,4,8 

1. Maintaining the health of the neuronal membrane via methylation of plasma phospholipids. Enhancing membrane fluidity and promoting optimal function of proteins within the membrane, such as monoamine receptors and transporters. 

2.  Enhancing metabolism and synthesis of various neurotransmitters, including dopamine, serotonin and noradrenaline.

3. Reduction of oxidative stress through anti-inflammatory effects such as modulation of inflammatory genes and inhibiting pro-inflammatory mediators. 

SAMe is generally considered safe with relatively rapid onset. Effective as both a monotherapy and adjunct to antidepressants, research suggests it may have a synergistic effect with SSRIs. Use caution in patients with depression on the bipolar spectrum as it can promote mania and hypomania.^4,5,8,16

Liver Disorders 

SAMe levels are regulated primarily in the liver, where it is synthesised and broken down. It also participates in hepatocyte proliferation, death and differentiation.⁶ 

SAMe has a hepatoprotective function, which is crucial in preventing oxidative stress. It also plays a role in detoxifying bile acid metabolism, synthesising and secretion of bile acid, and alleviating cholestasis.^10,16 

Liver disease depresses the biosynthesis of endogenous SAMe.^2,15 Supplemental SAMe has been shown in preclinical and clinical trials to improve liver function and symptoms associated with:^2,7,15,16 

• Cholestasis 
• Chronic hepatitis
• Non-alcoholic fatty liver disease
• Pregnancy-induced liver injury
• Alcoholic hepatitis
• Oestrogen excess | oral contraceptive-induced liver injury
• Paracetamol-induced liver injury
• Chemotherapy-induced liver injury
• Gilbert syndrome

The hepatoprotective effect of SAMe is achieved through three main mechanisms:^2,7,15 

1. Stabilising and enhancing the function of hepatocyte cell membranes by acting as a donor of methyl groups for transmethylation of phospholipids. 

2. Modulating cytokine production inhibits the pro-inflammatory cytokines such as TNF-ɑ and assists in regulating anti-inflammatory cytokine IL-10.

3. As a precursor for synthesising, restoring and regulating intracellular glutathione (GSH) via glutathione reductase in the hepatocytes. GSH is the most important endogenous hepatoprotective agent.

Osteoarthritis

In vitro studies show that SAMe enhances chondroproliferation and proteoglycan synthesis within the joint’s lining, suggesting SAMe supplementation may influence cartilage metabolism homeostasis allowing for chondroprotection and regeneration.^11,16 

Although the mechanisms are not fully understood, evidence suggests SAMe plays a role in protecting synovial cells by:^11,16 

1. Preserving GSH within the cell enhances the antioxidant enzyme glutathione peroxidase, decreasing oxidative stress.

2. Blocking enzymes that play a role in cartilage degradation.

3. Supporting the integrity of cartilage proteins and proteoglycans

According to several randomised clinical trials, including more than 22,000 patients, SAMe was demonstrated to be as effective as non-steroidal anti-inflammatory drugs (NSAIDs) for relieving osteoarthritic pain.^11,16,17   

Used as a monotherapy or adjunct to NSAIDs, SAMe is well tolerated. It may eliminate or counterbalance the toxicity and side effects of NSAIDs while also improving clinical symptoms. Benefits are usually seen after 4-5 weeks.^3,11,16 

Fibromyalgia

It is not surprising that the antidepressant, anti-inflammatory and analgesic actions of SAMe have shown an effect on the symptoms of fibromyalgia. Especially considering one-third of patients with fibromyalgia report suffering from depression.^3,17 

Several small clinical studies have used SAMe as a treatment for fibromyalgia. Significant improvements in pain, reduced number of trigger points, fatigue and mood compared to placebo have generally been reported. Benefits can take up to 6 weeks to establish.^3,12,18 

Conclusion 

SAMe provides a unique combination of antidepressant, anti-inflammatory, analgesic and hepatoprotective effects. In addition to treating depressive disorders, it is effective in liver disorders, osteoarthritis and fibromyalgia. Often a combination of these conditions presents together, making SAMe a versatile therapeutic agent.