SAM-e: A Natural Alternative to Antidepressants

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Antidepressant medications are one of the most common treatment options for those suffering from depression. Though typically effective, antidepressants can cause several side effects. 

There are a number of natural treatment options for depression ranging from lifestyle changes to dietary supplements, to ketamine infusions. SAM-e has been garnering attention recently as an effective alternative to traditional antidepressants.

Though it only hit the U.S. market in 1999, it has been studied in Europe since the 1970’s. When researchers found abnormal levels in patients with liver disease and depression, they began clinical studies focused on SAM-e supplementation. Not only has SAM-e shown promise in aiding symptoms of depression, but also osteoarthritis and liver function. 

What is SAM-e?

SAM-e (S-adenosyl-L-methionine) is a compound produced naturally in the body. It also goes by the name, adenoethionine. It is composed of the molecule adenosine triphosphate (ATP), and the amino acid methionine.

It is a methyl donor, meaning it contributes methyl groups to substances that need them. In this way, it helps to:

  • Maintain cell membranes
  • Synthesize proteins & enzymes
  • Build neurotransmitters like serotonin, dopamine, and adrenaline

It has been used to treat osteoarthritis, a condition in which the protective cartilage in the hands, knees, hips, and spine begin to wear down and cause pain and stiffness. One double-blind study found that it was as effective as a nonsteroidal anti-inflammatory drug (NSAID) for symptom management.

It has been used to treat liver disease for years. One review found SAM-e effective in treating cholestasis (when the flow of bile becomes blocked) associated with hepatic diseases. SAM-e also shows promise for those suffering from alcoholic liver cirrhosis.

Other uses include enhancing cognitive function for those with Alzheimer’s Disease and alleviating symptoms of fibromyalgia.

Does it work for depression?

It is a safe and effective treatment for depression.

Though researchers are not entirely certain of how it combats depression, evidence implies that it raises serotonin levels. However, it works slightly differently than traditional prescription antidepressants. 

Does SAM-e increase serotonin? Yes, SAM-e can increase serotonin levels in the body.

It’s worth noting that many studies of SAM-e use injectable forms as opposed to oral SAM-e. The effects of oral SAM-e have been examined more recently. One study was conducted with postmenopausal women experiencing depression. Another study gave SAM-e to 15 patients with major depressive disorder. Both studies yielded positive results.

SAM-e vs. Antidepressants

What is the difference between SAM-e and SSRI’s? SAM-e aids with the synthesis of serotonin, while selective serotonin reuptake inhibitors (SSRIs) block the reabsorption of serotonin, leaving more available for signaling purposes. Here are some other key differences.

Side Effects

It doesn’t cause the side effects commonly associated with antidepressants — weight gain, sexual dysfuction, sedation, etc. It can be a good treatment option for those who don’t respond to SSRIs.


Antidepressants tend to have a 4-6 week delay before mood improvement becomes noticeable. It can prove effective in as little as a week’s time. Also, it tends to have milder side effects overall than prescription drugs.

 How long does it take for SAM-e to start working? It typically takes about 2 weeks to notice the effects of it.

Drug Interactions

Compared to other antidepressants, the list of drug interactions with it is minimal. 

How to Take SAM-e

Though it has been prescribed in other forms in Europe for decades, it has not yet been approved by the Food and Drug Administration (FDA) for medicinal use. In the U.S. It is only available as a synthesized oral supplement. 

It is best taken on an empty stomach, before meals. Look for enteric-coated tablets that allow it to pass through the stomach intact.

While there’s no dosage of it set in stone for treating depression, the typical recommended range is 400-800 mg twice daily. 

It also works well alongside vitamin B12 and folate. Deficiency in vitamin B12 or folate can decrease levels of it. So, be sure to eat plenty of meat (for vitamin B12) and leafy greens (for folate) to maintain your natural SAM-e. 

Can you get it from foods? Unfortunately, you cannot get it from food. You can, however get the amino acid methionine from food, which makes it.

Safety & Potential Interactions

While it is typically safe, high doses of SAM-e supplementation include:

  • Anxiety
  • Constipation
  • Diarrhea
  • Dizziness
  • Headaches
  • Nausea

SAM-e could have interactions with the following:

  • Amphetamines: Combining amphetamines and SAM-e could increase the risk of serotonin syndrome.
  • Antidepressants: Because antidepressants have similar effects to SAM-e, combining them could compound serotonin levels, leading to serotonin syndrome.
  • Levodopa: This medication is used to alleviate symptoms in Parkinson’s patients. Taking SAM-e in combination with Levodopa could weaken the effects of the Parkinson’s disease medication.
  • St. John’s Wort: This supplement is taken to help with mood. Taking it with SAM-e could cause serotonin syndrome.

Those with health conditions such as bipolar disorder, Parkinson’s disease, or a weakened immune system should not take SAM-e. Also, be cautious of taking SAM-e if you’re pregnant or breastfeeding. 

Because SAM-e can affect blood vessels, be sure to stop taking it at least 2 weeks before a surgery is performed.

The Benefits of an Antidepressant — Without the Side Effects

SAM-e is a great option for anyone who either doesn’t respond to SSRI’s or just doesn’t want to risk the side effects of traditional antidepressants. 

While SAM-e is a promising alternative to prescription drugs, it’s still important to discuss any changes in medication with your healthcare provider. 

Prime Health is more than happy to help you explore holistic treatment options for any conditions you’re concerned about. Contact us to schedule a free consultation. Follow us on Instagram for the latest in holistic health topics.


  1. Institute for Quality and Efficiency in Health Care. (2015). Depression: How effective are antidepressants.
  2. Knowlton, L. (2001). Investigating SAM-e for Depression. Psychiatric Times. May, 18(5).
  3. Najm, W. I., Reinsch, S., Hoehler, F., Tobis, J. S., & Harvey, P. W. (2004). S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial.[ISRCTN36233495]. BMC musculoskeletal disorders, 5(1), 1-15. 
  4. Guo, T., Chang, L., Xiao, Y., & Liu, Q. (2015). S-adenosyl-L-methionine for the treatment of chronic liver disease: a systematic review and meta-analysis. PloS one, 10(3), e0122124.
  5. Jacobsen, S., Danneskiold-Samsøe, B., & Andersen, R. B. (1991). Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scandinavian journal of rheumatology, 20(4), 294-302. 
  6. Almasio, P., Bortolini, M., Pagliaro, L., & Coltorti, M. (1990). Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. Drugs, 40(3), 111-123.
  7. Mato, J. M., Cámara, J., De Paz, J. F., Caballería, L., Coll, S., Caballero, A., … & Rodés, J. (1999). S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. Journal of hepatology, 30(6), 1081-1089. 
  8. Montgomery, S. E., Sepehry, A. A., Wangsgaard, J. D., & Koenig, J. E. (2014). The effect of S-adenosylmethionine on cognitive performance in mice: an animal model meta-analysis. PLoS One, 9(10), e107756.
  9. Cuomo, A., Beccarini Crescenzi, B., Bolognesi, S., Goracci, A., Koukouna, D., Rossi, R., & Fagiolini, A. (2020). S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): a clinician-oriented systematic review. Annals of general psychiatry, 19(1), 1-7.
  10. Salmaggi, P., Bressa, G. M., Nicchia, G., Coniglio, M., La Greca, P., & Le Grazie, C. (1993). Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychotherapy and psychosomatics, 59(1), 34-40. 
  11. Kagan, B. L., Sultzer, D. L., Rosenlicht, N., & Gerner, R. H. (1990). Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. The American journal of psychiatry
  12. Papakostas, G. I., Mischoulon, D., Shyu, I., Alpert, J. E., & Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. American Journal of Psychiatry, 167(8), 942-948.
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