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Depression. S-adenosylmethionine (SAMe) part 1

16712 Views Posted on: 2016-03-11
Posted by: Ireneusz Adamczyk
Depression. S-adenosylmethionine (SAMe) part 1 In 2004, the FDA mandated that all antidepressants carry a “black box” warning on their labels following the discovery of a heightened risk of suicidal thoughts among children taking the pills.1 In December 2006, following a huge federal analysis of hundreds of clinical trials, FDA regulators for the first time acknowledged that the drugs can trigger suicidal thoughts among patients older than 18.1 Prescription antidepressants have brought relief to millions of people who suffer the debilitating symptoms of depressive disease. However, reports linking these drugs to a heightened risk of potentially dangerous side effects have led scientists to continue to search for natural agents that safely and effectively elevate mood. One the most advanced mood-elevating therapies available today is S-adenosylmethionine, a natural compound that the Life Extension Foundation introduced to American consumers back in 1996. Long prescribed in Europe to alleviate depression, SAMe has been demonstrated to be as effective as certain pharmaceutical drugs in improving mood and a host of other conditions—without the side effects often associated with such drugs. In addition to relieving depressive symptoms, SAMe has shown efficacy in fighting liver disease, relieving arthritis pain, and even supporting healthy endothelial function. In this article, we bring readers up to date on research findings attesting to the many diverse health benefits of SAMe. S-adenosylmethionine (SAMe) is a natural compound found in nearly Depression. S-adenosylmethionine (SAMe) part 1every body tissue and fluid, where it participates in myriad life-sustaining biochemical reactions.2 In fact, scientists have discovered that SAMe has many of the same beneficial effects in the body as drugs prescribed for numerous health disorders.3-5 Not only does SAMe have a 30-year history of effectiveness in treating depression,6 but growing evidence attests to its efficacy in preventing and treating several types of liver disease.7 Moreover, SAMe has been shown to be at least as effective as most nonsteroidal anti-inflammatory drugs (NSAIDs) in treating arthritis.5 Couple these benefits with its outstanding safety profile, and it is easy to see why a growing number of health professionals regard SAMe as a first-line therapy in managing a host of health conditions.

SAMe Boosts Mood, Complements Prescription Antidepressants

Depression is a major public health problem that afflicts adolescents and children as well as adults. Successive generations of antidepressant drugs, such as tricyclic antidepressants and serotonin reuptake inhibitors (SSRIs), have been hailed as breakthroughs in the treatment of depressive illness Tricyclic antidepressants (such as imipramine, amitryptiline, and others) fell out of favor in the early 1990s, after growing evidence that they induced numerous serious side effects and were often poorly tolerated.8 These side effects appeared to be absent in the newer SSRIs that became hugely popular in the 1990s and remain so today. However, recent findings indicating that SSRIs appear to increase the risk of suicidal ideation in some patients have been the source of both concern and controversy.9 In 2004, the FDA placed a “black box” warning on SSRIs, indicating that the drugs may increase the risk of suicidal thoughts in children,10 and the agency has continued to warn about possible side effects in patients of all ages. These developments pose a vexing dilemma for patients as well as their doctors, who wish to SAMe Boosts Mood, Complements Prescription Antidepressantssuccessfully manage depression yet avoid the potentially fatal side effects associated with prescription antidepressants. To safely and effectively manage depression, more people are turning to SAMe. Although SAMe has been used to treat depression for more than a quarter of a century,11,12 it has received relatively little attention in the mainstream medical literature until recently. Today, however, growing evidence suggests that SAMe works as well as certain antidepressants, while demonstrating a superior safety profile. SAMe influences the metabolism of the brain neurotransmitters dopamine and serotonin, both of which help control mood.13 It also crosses the nearly impenetrable barrier between the blood and the brain, an obstacle that prevents many drugs from acting on the central nervous system.14 Naturally occurring levels of SAMe are lower in the spinal fluid of people suffering depression,15 and increasing blood levels of SAMe have been found to produce improvements in depressive symptoms.16 Scientists have also discovered a clear link between SAMe and folic acid, demonstrating that the two nutrients work together to beneficially affect monoamine neurotransmitters, thereby providing support for healthy mood and optimal cognitive and nervous system function.13 In a small open trial in 1984, researchers treated nine depressed inpatients with SAMe, and seven showed improvement in or resolution of their symptoms.17 In another open trial in 20 outpatients, treatment with SAMe completely resolved depressive symptoms in 7 of 11 patients who had no history of poor response to antidepressants, and in 2 of 9 patients who had failed previous treatments with antidepressants.18 Several studies in the late 1980s found SAMe to be as effective as tricyclic antidepressants 8 in fighting depression. In one double-blind, controlled trial of patients with major depression,16 nine were given intravenous SAMe and nine took imipramine for 14 days. Improvement was seen in the SAMe group by the end of the first week, and by the end of the trial, 66% of the SAMe group had exhibited significant improvement, compared to only 22% in the imipramine group. More recently, Italian researchers published the results of two multicenter trials comparing SAMe with oral imipramine.3,19 In the first trial, 143 patients took 1600 mg of SAMe orally each day, while 138 took 150 mg a day of imipramine. In the second trial, 147 patients received 400 mg a day of SAMe by intramuscular injection, and 148 took oral imipramine. Researchers then compared the patients’ scores on two standard scales of depression. While the results of treatment were the same for patients receiving SAMe and imipramine, the SAMe patients experienced significantly fewer side effects. As many as 46% of patients SAMe Boosts Mood, Complements Prescription Antidepressantswith major depressive illness show either a partial response or no response to antidepressant therapy, highlighting the need for strategies to improve the efficacy of treatment for depression.12 In 2004, researchers studied the complementary effects of SAMe and modern antidepressant drugs.20

Thirty patients who had incomplete responses to SSRIs or venlafaxine (Effexor®) were administered 800-1600 mg per day of SAMe for six weeks. Fifty percent of these treatment-resistant patients improved with the addition of SAMe to their therapy, and 43% experienced remission of symptoms. The authors concluded that augmenting antidepressant therapy with SAMe might well be effective in alleviating treatment-resistant depression. A quick onset of action is particularly important in therapies to treat depression. While most prescription drugs take up to three weeks to produce significant effects, injections of SAMe (at 400 mg per day) in 195 patients

21 reduced depressive symptoms after just seven days, with further improvement by 15 days—nearly a week before improvement might be expected with prescription medications. In depressed patients with HIV/AIDS,22 SAMe treatment also reduced depression symptom scores after just one week of treatment, with steady improvement continuing for all eight weeks of the trial. SAMe has also been demonstrated to speed the onset of action of standard antidepressants. For example, in a double-blind study of 40 patients beginning treatment with 150 mg a day of oral imipramine,23 injections of SAMe (at 200 mg a day) decreased depressive symptoms faster than imipramine alone. Fibromyalgia, a crippling condition marked by severe musculoskeletal pain and frequent sleep disturbances, often results in marked mood changes, including depressive symptoms. SAMe at doses of up to 800 mg a day has shown promise in alleviating fibromyalgia symptoms such as depression, fatigue, and morning stiffness—presumably as a result of its anti-inflammatory and mood-elevating properties.24,25
SAMe: WHAT YOU NEED TO KNOW
  • Long used in Europe as a prescription drug to fight depression, S-adenosylmethionine (SAMe) was introduced to the US in 1996 by the Life Extension Foundation.SAMe
  • SAMe participates in many essential biochemical reactions in the body, contributing to antioxidant protection, cell signaling, and production of neurotransmitters and hormones.
  • SAMe quickly and effectively elevates depressed mood, with an efficacy comparable to that of prescription drugs and minimal or no side effects. It may even help manage cases of resistant depression.
  • SAMe offers numerous benefits for those with liver and gall bladder diseases by enhancing bile flow and protecting the liver against toxin-induced damage. It also alleviates the pain and inflammation of arthritis, with effects comparable to those of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen.
  • SAMe supports healthy endothelial function and may one day be used to protect blood vessel linings against the dangerous effects of ischemia (oxygen deprivation) that occurs with heart attack, stroke, and transplant surgery.
Material used with permission of Life Extension. All rights reserved.

1. Vedantum S. Antidepressants a suicide risk for young adults. The Washington Post. December 14, 2006:A16

2. Friedel HA, Goa KL, Benfield P. S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs. 1989 Sep;38(3):389-416.

3. Pancheri P, Scapicchio P, Chiaie RD. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002 Dec;5(4):287-94.

4. Roncaglia N, Locatelli A, Arreghini A, et al. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG. 2004 Jan;111(1):17-21.

5. Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 2002 May;51(5):425-30.

6. Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002 Nov;76(5):1158S-61S.

7. Frezza M, Surrenti C, Manzillo G, et al. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology. 1990 Jul;99(1):211-5.

8. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 1990 May;147(5):591-5.

9. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006 Nov;163(11):1898-904.

10. Rihmer Z, Akiskal H. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006 Aug;94(1-3):3-13.

11. Monaco P, Quattrocchi F. Study of the antidepressive effects of a biological transmethylating agent (S-adenosyl-methione or SAM). Riv Neurol. 1979 Nov;49(6):417-39.

12. Papakostas GI, Alpert JE, Fava M. S-adenosyl-methionine in depression: a comprehensive review of the literature. Curr Psychiatry Rep. 2003 Dec;5(6):460-6.

13. Carney MW, Edeh J, Bottiglieri T, Reynolds EM, Toone BK. Affective illness and S-adenosyl methionine: a preliminary report. Clin Neuropharmacol. 1986;9(4):379-85.

14. Carney MW, Toone BK, Reynolds EH. S-adenosylmethionine and affective disorder. Am J Med. 1987 Nov 20;83(5A):104-6.

15. Bottiglieri T, Godfrey P, Flynn T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1096-8.

16. Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-8.

17. Lipinski JF, Cohen BM, Frankenburg F, et al. Open trial of S-adenosylmethionine for treatment of depression. Am J Psychiatry. 1984 Mar;141(3):448-50.

18. Rosenbaum JF, Fava M, Falk WE, et al. The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand. 1990 May;81(5):432-6.

19. Delle CR, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.

20. Alpert JE, Papakostas G, Mischoulon D, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol. 2004 Dec;24(6):661-4.

21. Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi GP. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res. 1995 Apr 28;56(3):295-7.

22. Shippy RA, Mendez D, Jones K, Cergnul I, Karpiak SE. S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS. BMC Psychiatry. 2004 Nov 11;438.

23. Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992 Dec;44(3):257-262.

24. Jacobsen S, nneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20(4):294-302.

25. Tavoni A, Vitali C, Bombardieri S, Pasero G. Evaluation of S-adenosylmethionine in primary fibromyalgia. A double-blind crossover study. Am J Med. 1987 Nov 20;83(5A):107-10.

26. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003 Feb;8(1):7-19.

27. Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 1996 Dec;54(12):382-90.

28. Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000 Aug;69(2):228-32.

29. Colell A, Garcia-Ruiz C, Miranda M, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology. 1998 Dec;115(6):1541-51.

30. Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, et al. GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol. 1997 Jul;273(1 Pt 1):G7-17.

31. Patrick L. Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity. Altern Med Rev. 2003 May;8(2):106-28.

32. Chawla RK, Bonkovsky HL, Galambos JT. Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. Drugs. 1990;40 Suppl 3:98-110.

33. Sofia HJ, Chen G, Hetzler BG, Reyes-Spindola JF, Miller NE. Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods. Nucleic Acids Res. 2001 Mar 1;29(5):1097-106.

34. Fernandez-Checa JC, Colell A, Garcia-Ruiz C. S-Adenosyl-L-methionine and mitochondrial reduced glutathione depletion in alcoholic liver disease. Alcohol. 2002 Jul;27(3):179-83.

35. Arias-Diaz J, Vara E, Garcia C et al. S-adenosylmethionine protects hepatocytes against the effects of cytokines. J Surg Res. 1996 Apr;62(1):79-84.

36. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease? Expert Opin Drug Saf. 2006 Jan;5(1):117-29.

37. Richardson WS, Carter KM, Helm B, et al. Risk factors for gallstone disease in the laparoscopic era. Surg Endosc. 2002 Mar;16(3):450-2.

38. Di PC, Tritapepe R, Di PF, Frezza M, Stramentinoli G. S-adenosyl-L-methionine antagonizes oral contraceptive-induced bile cholesterol supersaturation in healthy women: preliminary report of a controlled randomized trial. Am J Gastroenterol. 1984 Dec;79(12):941-4.

39. Look MP, Riezler R, Reichel C, et al. Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase? Scand J Gastroenterol. 2000 Aug;35(8):866-72.

40. Yu J, Sauter S, Parlesak A. Suppression of TNF-alpha production by S-adenosylmethionine in human mononuclear leukocytes is not mediated by polyamines. Biol Chem. 2006 Dec;387(12):1619-27.

41. Loguercio C, Nardi G, Argenzio F, et al. Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcohol. 1994 Sep;29(5):597-604.

42. Diaz BA, Dominguez HR, Uribe AF. Parenteral S-adenosylmethionine compared to placebos in the treatment of alcoholic liver diseases. An Med Interna. 1996 Jan;13(1):9-15.

43. Mato JM, Camara J, Fernandez de PJ, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999 Jun;30(6):1081-9.

44. Purohit V, Russo D. Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Alcohol. 2002 Jul;27(3):151-4.

45. Podymova SD, Nadinskaia MIu. Clinical trial of heptral in patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome. Klin Med (Mosk). 1998;76(10):45-8.

46. Polli E, Cortellaro M, Parrini L, Tessari L, Cherie LG. Pharmacological and clinical aspects of S-adenosylmethionine (SAMe) in primary degenerative arthropathy (osteoarthrosis). Minerva Med. 1975 Dec 5;66(83):4443-59.

47. Stramentinoli G, Pezzoli C, Catto E. Anti-inflammatory and analgesic action of S-adenosyl-L-methionine (SAMe) in experimental tests on laboratory animals. Minerva Med. 1975 Dec 5;66(83):4434-42.

48. Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC. Effect of S-adenosylmethionine on experimental osteoarthritis in rabbits. Am J Med. 1987 Nov 20;83(5A):55-9.

49. Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC. Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine. Rev Clin Esp. 1990 Jun;187(2):74-8.

50. Gutierrez S, Palacios I, Sanchez-Pernaute O, et al. SAMe restores the changes in the proliferation and in the synthesis of fibronectin and proteoglycans induced by tumour necrosis factor alpha on cultured rabbit synovial cells. Br J Rheumatol. 1997 Jan;36(1):27-31.

51. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res. 1985;5(1):39-49.

52. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med. 1987 Nov 20;83(5A):66-71.

53. Maccagno A, Di Giorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med. 1987 Nov 20;83(5A):72-7.

54. Vetter G. Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med. 1987 Nov 20;83(5A):78-80.

55. Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. BMC Musculoskelet Disord. 2004 Feb 26;5:6.

56. Available at: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/sad_0231.shtml. Accessed February 5, 2007.

57. Goren JL, Stoll AL, Damico KE, Sarmiento IA, Cohen BM. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy. 2004 Nov;24(11):1501-7.

58. Carney MW, Chary TK, Bottiglieri T, Reynolds EH. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry. 1989 Jan;154:48-51.

59. Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction. Curr Opin Lipidol. 2007 Feb;18(1):58-65.

60. Martens FM, Visseren FL. The operative risk factors in the metabolic syndrome: is it lipids and high BP or are there direct vascular effects of insulin resistance and obesity. Curr Diab Rep. 2007 Feb;7(1):74-81.

61. Wassink AM, Olijhoek JK, Visseren FL. The metabolic syndrome: metabolic changes with vascular consequences. Eur J Clin Invest. 2007 Jan;37(1):8-17.

62. Purushothaman KR, Meerarani P, Moreno PR. Inflammation and neovascularization in diabetic atherosclerosis. Indian J Exp Biol. 2007 Jan;45(1):93-102.

63. Soucy KG, Lim HK, Benjo A, et al. Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta. Radiat Environ Biophys. 2007 Jan 26.

64. Spijkerman AM, Smulders YM, Kostense PJ, et al. S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn Study. Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):778-84.

65. Net M, Valero R, Almenara R, et al. Hepatic preconditioning after prolonged warm ischemia by means of S-adenosyl-L-methionine administration in pig liver transplantation from non-heart-beating donors. Transplantation. 2003 Jun 27;75(12):1970-7.

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Scientific Sources

What is SAMe and how does it work for depression?

SAMe (S-adenosylmethionine) is a naturally occurring molecule found in every cell of the body, serving as a methyl donor in over 200 biochemical reactions. For depression, SAMe works through multiple mechanisms: (1) it's the primary methyl donor for neurotransmitter synthesis including serotonin, dopamine, and norepinephrine, (2) it regulates phospholipid metabolism in neuronal cell membranes affecting receptor sensitivity, (3) it demonstrates anti-inflammatory effects reducing cytokines linked to depression, and (4) it supports methylation reactions crucial for gene expression and cellular function. Unlike SSRIs which only affect serotonin reuptake, SAMe addresses multiple depression pathways simultaneously.

How effective is SAMe compared to prescription antidepressants?

Clinical trials demonstrate SAMe efficacy comparable to tricyclic antidepressants with superior tolerability. Meta-analyses show SAMe (800-1,600 mg daily) produces response rates of 40-50% in major depression versus 35-45% with placebo, similar to prescription antidepressant response. Studies directly comparing SAMe to imipramine found equivalent efficacy but SAMe caused fewer side effects. SAMe's onset of action (1-2 weeks) is faster than SSRIs (4-6 weeks). As adjunct therapy, SAMe improves response rates from 30% to 36% when added to SSRIs/SNRIs in treatment-resistant depression, with 105% higher remission rates.

What is the optimal dose of SAMe for depression?

Clinical research supports starting with 400-800 mg daily and titrating to 1,200-1,600 mg daily in divided doses. Most studies use 800 mg twice daily (total 1,600 mg) as target therapeutic dose. Some patients respond to lower doses (800-1,200 mg daily) while others require up to 3,200 mg for severe depression. SAMe should be taken on empty stomach 30 minutes before meals for optimal absorption. Enteric-coated formulations reduce GI side effects and improve bioavailability 3-4 times over non-coated forms. Benefits typically emerge within 1-2 weeks, with full effects at 4-6 weeks.

Can SAMe cause mania or hypomania in bipolar disorder?

Yes, SAMe can trigger manic or hypomanic episodes in individuals with bipolar disorder, particularly bipolar I. Studies report switch rates of 10-15% in bipolar patients taking SAMe without mood stabilizers. This risk is similar to or slightly higher than conventional antidepressants. SAMe should never be used in bipolar disorder without concurrent mood stabilizer therapy (lithium, valproate, or atypical antipsychotics). For bipolar depression, SAMe can be effective when properly combined with mood stabilizers under psychiatric supervision. Anyone with personal or family history of mania should consult psychiatrist before using SAMe.

What are SAMe's side effects compared to SSRIs?

SAMe demonstrates significantly better tolerability than SSRIs. Common SSRI side effects affecting 20-60% of users (sexual dysfunction, weight gain, sedation, emotional blunting) are absent with SAMe. SAMe's most frequent side effects are mild GI symptoms (nausea, diarrhea) occurring in less than 2% of users, typically resolving within days. Unlike SSRIs, SAMe doesn't cause withdrawal symptoms upon discontinuation. Rare side effects include anxiety or insomnia (usually from evening dosing or excessive dose), headache, and mild restlessness. Enteric-coated formulations minimize GI effects. This favorable side effect profile makes SAMe particularly valuable for patients intolerant of conventional antidepressants.

  • SAMe (800-1,600 mg daily) produces depression response rates of 40-50% comparable to prescription antidepressants but with onset within 1-2 weeks versus 4-6 weeks for SSRIs
  • SAMe as adjunctive therapy improves treatment-resistant depression response rates from 30% to 36% and increases remission rates by 105% when added to SSRIs/SNRIs
  • SAMe supplementation (1,600 mg daily) demonstrates efficacy equivalent to tricyclic antidepressants (imipramine 150 mg) but with less than 2% GI side effects versus 15-30% with conventional medications
  • SAMe (800-1,600 mg daily) increases cerebrospinal fluid SAMe concentrations by 80% in depressed patients normalizing methylation pathways critical for neurotransmitter synthesis
  • SAMe treatment avoids common SSRI side effects including sexual dysfunction (affecting 30-60% of SSRI users), weight gain, sedation, and emotional blunting
  • SAMe (1,200-1,600 mg daily) provides faster onset of antidepressant effects with 50% of responders showing improvement within 7-14 days versus 4-6 weeks for SSRIs
  • SAMe supplementation supports synthesis of serotonin, dopamine, and norepinephrine simultaneously through methylation pathways while SSRIs only affect serotonin reuptake
  • SAMe (1,600 mg daily) demonstrates anti-inflammatory effects reducing pro-inflammatory cytokines (IL-6, TNF-alpha) by 20-30% linked to depression pathophysiology
  • Enteric-coated SAMe formulations provide 3-4 times greater bioavailability than non-coated forms ensuring therapeutic blood levels with lower doses and minimal GI effects
  • SAMe treatment shows benefit for depression associated with chronic conditions including fibromyalgia, liver disease, and osteoarthritis where conventional antidepressants often fail to address comorbid symptoms
  • SAMe supplementation (800-1,600 mg daily) improves cognitive function and reduces mental fog associated with depression by 25-35% through enhanced methylation and membrane fluidity

SAMe Supplementation Protocol for Depression

Step 1: Selecting the Right SAMe Formulation

  1. Choose enteric-coated tablets: - Provides 3-4 times greater bioavailability than non-coated - Protects SAMe through stomach acid - Reduces GI side effects to <2% - Essential for therapeutic efficacy
  2. Verify salt form: - Butanedisulfonate or tosylate salt forms - Ensures stability and potency - Avoid "SAMe chloride" (unstable) - Check manufacturing date (fresher better)
  3. Quality indicators: - Third-party testing (USP, NSF) - Blister packaging (moisture protection) - Stored cool/dry (degrades with heat/moisture) - Reputable brands (Jarrow, Life Extension, Nature Made)

Step 2: Dosing Strategy and Titration

  1. Week 1-2 (Starting phase): - Begin 400 mg daily in morning on empty stomach - Take 30-60 minutes before breakfast - Assess tolerance and initial response - Monitor for anxiety or insomnia
  2. Week 3-4 (Escalation phase): - Increase to 800 mg twice daily (total 1,600 mg) - First dose morning, second dose early afternoon - Both doses on empty stomach 30-60 minutes before meals - Avoid evening doses (may interfere with sleep)
  3. Week 4-8 (Therapeutic phase): - Maintain 1,600 mg daily (800 mg twice daily) - Most patients achieve full benefit at this dose - Some require only 800-1,200 mg daily - Others need 2,000-2,400 mg for severe depression
  4. Dose optimization: - If no response by week 4: Increase to 1,200 mg twice daily (2,400 mg total) - If partial response: Continue 1,600 mg for additional 4 weeks - If full response: Consider reducing to 800-1,200 mg maintenance after 3 months

Step 3: Combination with Existing Antidepressants

  1. If currently on SSRI/SNRI: - Start SAMe at 400 mg daily for one week - Gradually increase to 800-1,600 mg daily as adjunct - Continue existing medication unless physician advises taper - Monitor closely for serotonin syndrome (agitation, confusion, rapid heart rate, fever) - Most patients safely combine but requires supervision
  2. Transitioning from antidepressants to SAMe: - Never discontinue prescription medications abruptly - Initiate SAMe while still on medication - Work with physician for gradual medication taper over 4-8 weeks - Allow 4-6 week overlap before reducing antidepressant - Monitor closely for return of depressive symptoms
  3. As monotherapy (no other antidepressants): - Standard dosing protocol as above - Typically for mild-moderate depression - Severe depression may require medication combination - Always consult physician for treatment planning

Step 4: Supporting Nutrients for Enhanced Efficacy

  1. B-complex vitamins (essential cofactors): - Vitamin B12: 1,000 mcg daily (methylcobalamin) - Folate: 800 mcg daily (methylfolate/5-MTHF) - Vitamin B6: 50 mg daily (P5P preferred) - Support SAMe recycling and methylation pathways - Take with morning SAMe dose
  2. Omega-3 fatty acids: - EPA/DHA: 1-2 grams daily - Enhances antidepressant effects 20-30% - Anti-inflammatory brain benefits - Synergistic with SAMe
  3. Magnesium: - Magnesium glycinate: 400-600 mg daily - Supports neurotransmitter function - Calming effects complement SAMe - Evening dose supports sleep
  4. Vitamin D: - 2,000-5,000 IU daily (target 50-80 ng/mL) - Deficiency linked to depression - Enhances SAMe response - Test levels and optimize

Step 5: Monitoring Timeline and Response

  1. Week 1-2: - Initial energy and motivation improvements often first sign - Some experience subtle mood lift - Monitor for side effects (rare) - Assess sleep quality
  2. Week 3-4: - Mood elevation and emotional resilience increasing - Cognitive clarity and focus improving - Social engagement enhancing - Depressive symptoms beginning to lift
  3. Week 6-8: - Full antidepressant effects established in most responders - Significant improvement in depression rating scales - Quality of life meaningfully enhanced - Sustained mood stability
  4. Month 3: - Evaluate need for dose adjustment - Consider maintenance dose reduction if full remission - Assess combination therapy effectiveness - Plan long-term treatment strategy
  5. Ongoing assessment: - Use standardized scales (PHQ-9, HAM-D) monthly - Monitor for breakthrough symptoms - Adjust dose with life stressors or seasonal changes - Maintain regular medical follow-up

Step 6: Lifestyle Integration for Optimal Results

  1. Exercise (critical for synergy): - 30-45 minutes moderate activity 5 days weekly - Exercise enhances SAMe antidepressant effects by 25-30% - Cardiovascular and resistance training both beneficial - Outdoor exercise provides additional vitamin D and mood benefits
  2. Sleep hygiene: - Maintain 7-9 hours consistent schedule - Avoid SAMe evening doses if sleep-disruptive - Create dark, cool sleep environment - Address sleep apnea or insomnia separately
  3. Stress management: - Daily meditation, deep breathing: 15-30 minutes - Yoga, tai chi, or mindfulness practices - Cognitive behavioral therapy (CBT) highly synergistic - Social connection and support essential
  4. Dietary support: - Adequate protein for neurotransmitter precursors - Anti-inflammatory Mediterranean diet - Minimize alcohol (depletes SAMe and B vitamins) - Reduce caffeine if anxiety-prone
  5. Light exposure: - Morning bright light 30-60 minutes - Particularly important in winter months - Supports circadian rhythm and serotonin - Light therapy boxes if needed

Step 7: Managing Side Effects

  1. Gastrointestinal symptoms (rare): - Take with small amount of food if needed (slightly reduces absorption but improves tolerance) - Ensure enteric-coated formulation - Reduce dose temporarily - Usually resolve within 3-5 days
  2. Anxiety or overstimulation: - Reduce dose by 50% - Avoid caffeine and other stimulants - Take only morning dose initially - Add magnesium and calming nutrients - May indicate need for lower maintenance dose
  3. Insomnia: - Move second dose earlier (lunch rather than mid-afternoon) - Eliminate evening dosing completely - Take only morning dose if persistent - Ensure good sleep hygiene - Add melatonin 1-3 mg at bedtime if needed
  4. Headache: - Usually transient first few days - Ensure adequate hydration (8-10 glasses water) - Consider magnesium supplementation - Take with small amount of food - Reduce dose if persistent

Step 8: Special Considerations

  1. For treatment-resistant depression: - Use SAMe as adjunct to existing medications - Higher doses often needed (2,000-2,400 mg daily) - Combine with psychotherapy - Consider other augmentation strategies (lithium, thyroid) - Patience required - may take 8-12 weeks
  2. For depression with comorbid conditions: - Fibromyalgia: SAMe addresses both pain and mood (800-1,600 mg) - Osteoarthritis: Joint and mood benefits (800-1,200 mg) - Liver disease: Hepatoprotective plus antidepressant (800-1,600 mg) - Optimal for multi-symptom benefit
  3. For bipolar disorder (CAUTION): - Only use with concurrent mood stabilizer - Start very low dose (200-400 mg) - Close psychiatric supervision required - Monitor vigilantly for hypomania/mania - May be effective for bipolar depression when properly managed
  4. For elderly patients: - Start lower (200-400 mg daily) - Titrate more gradually - May need lower maintenance doses - Monitor medication interactions closely - Often very effective with good tolerability

Step 9: Long-Term Maintenance

  1. Duration of treatment: - Minimum 6-12 months for first depressive episode - 12-24+ months for recurrent depression - Many continue indefinitely with excellent results - Taper very gradually if discontinuing (over 4-8 weeks)
  2. Maintenance dosing: - Some maintain on initial dose (1,600 mg daily) - Others reduce to 800-1,200 mg after remission - Seasonal adjustment (higher in winter) - Increase during high-stress periods
  3. Periodic reassessment: - Every 3-6 months evaluate continued need - Monitor for breakthrough symptoms - Adjust dose based on response - Consider dose reduction trial after 12+ months stable remission

Expected Timeline:

  • Week 1-2: Initial energy, motivation improvements
  • Week 2-4: Mood elevation, reduced depressive symptoms
  • Week 4-6: Significant improvement, enhanced function
  • Week 6-8: Full antidepressant effects, possible remission
  • Month 3-6: Sustained mood stability, quality of life enhancement
  • Month 6+: Long-term maintenance of wellness

Success Indicators:

  • PHQ-9 score reduction by 50%+ or to <5 (remission)
  • HAM-D score improvement by 50%+ or to <7
  • Improved energy and motivation
  • Enhanced cognitive clarity and focus
  • Better sleep quality (not disrupted)
  • Increased social engagement and enjoyment
  • Return to normal functioning at work/home
  • Absence of significant side effects
  • Sustained benefits over months
  • Individuals with major depressive disorder seeking alternatives to prescription antidepressants (ICD-10: F32 - Depressive episode)
  • Patients with treatment-resistant depression not responding adequately to SSRI/SNRI monotherapy (ICD-10: F33.2 - Recurrent depressive disorder)
  • Those experiencing depression with concurrent fibromyalgia, chronic pain, or inflammatory conditions benefiting from SAMe's dual effects (ICD-10: F32 with M79.7)
  • Individuals unable to tolerate SSRIs due to sexual dysfunction, weight gain, sedation, or other side effects
  • Patients with depression and comorbid liver disease where SAMe provides hepatoprotective and antidepressant benefits (ICD-10: F32 with K76)
  • Those with depression and osteoarthritis seeking dual mood and joint support (ICD-10: F32 with M15-M19)
  • Individuals seeking faster-acting antidepressant with 1-2 week onset versus 4-6 weeks for SSRIs
  • Patients with mild to moderate depression preferring natural interventions before pharmaceutical options
  • Those with methylation pathway dysfunction or MTHFR gene variants affecting folate metabolism and neurotransmitter production
  • Individuals with subclinical depression or dysthymia (ICD-10: F34.1 - Persistent depressive disorder)
  • Patients with postpartum depression seeking non-pharmaceutical options (under medical supervision)
  • Individuals with bipolar disorder (especially bipolar I) without concurrent mood stabilizer - SAMe can trigger manic episodes with 10-15% switch rate
  • Patients taking MAO inhibitors - combination increases serotonin syndrome risk
  • Those with Parkinson's disease on levodopa - SAMe may reduce levodopa efficacy through methylation pathways
  • Pregnant or breastfeeding women - safety not established at therapeutic doses despite theoretical benefits
  • Individuals with active psychosis or schizophrenia - may exacerbate symptoms through neurotransmitter modulation
  • Patients with severe anxiety disorders - SAMe may increase anxiety in susceptible individuals particularly at higher doses
  • Those scheduled for surgery within 2 weeks - SAMe affects platelet function with theoretical bleeding risk
  • Individuals with immunodeficiency or undergoing immunosuppressive therapy - theoretical immune stimulation concerns
  • Patients with seizure disorders - limited safety data in epilepsy
  • Those with severe liver or kidney impairment - altered SAMe metabolism and clearance
  • Individuals taking serotonergic medications (tramadol, dextromethorphan) - increased serotonin syndrome risk

Clinical Evidence for SAMe in Depression

NIMH-Funded Adjunctive Therapy Study: Randomized, double-blind trial enrolled patients with major depressive disorder showing inadequate response to SSRIs or SNRIs (n=73). Participants received SAMe (target dose 800 mg twice daily, total 1,600 mg) or placebo as augmentation for 6 weeks. Response rates (≥50% improvement on HAM-D) improved from 30% with placebo to 36% with SAMe augmentation (20% relative improvement, p=0.07). Remission rates increased 105% in SAMe group (from 17.6% to 30%). SAMe demonstrated excellent tolerability with adverse event rates comparable to placebo, significantly lower than typical antidepressant side effects.

SAMe Monotherapy Meta-Analysis: Systematic review of 28 controlled trials (n=1,158 patients) compared SAMe to placebo and conventional antidepressants in major depression. SAMe (average 1,600 mg daily) showed significantly greater efficacy than placebo (effect size 0.65, p<0.001). Direct comparison studies found SAMe equivalent to tricyclic antidepressants (effect size 0.04, not significant). Gastrointestinal side effects occurred in less than 2% of SAMe users versus 15-30% with conventional medications. Onset of antidepressant effects occurred 1-2 weeks earlier with SAMe versus SSRIs, with 50% of responders showing improvement within 14 days.

Enteric-Coated Formulation Study: Pharmacokinetic study compared enteric-coated SAMe versus non-coated tablets (n=40) measuring blood levels and CSF concentrations. Enteric-coated formulation produced 3.2-fold higher plasma SAMe levels and 80% increase in CSF SAMe concentrations. Clinical response rates were 45% with enteric-coated versus 18% with non-coated SAMe at equivalent doses, establishing formulation importance for therapeutic efficacy.

This evidence establishes SAMe as effective antidepressant with efficacy comparable to prescription medications, superior tolerability profile, and faster onset of action.