SUBSCRIBE BY RSS rss feed | EMAIL
Natural Solutions Radio header image

SAMe Powerful intervention for Arthritis, Liver Health and Neurochemistry.

What is SAMe?

SAMe is the most active of all methyl donors. Our body naturally makes SAMe from methionine from protein rich foods. SAMe is a naturally occurring metabolite found in the human body. The adrenals, pineal gland and the liver contain the highest concentrations of SAMe in humans. It is produced in the normal physiology from the amino acid methionine in the presence of the cofactors B12 (the methylcobalamin form) and folate. Half of all methionine in the body is used in the liver to make SAMe. SAMe has been compared to ATP in its importance to the body. It is used in many different cellular processes, from replication to biochemical reactions that create melatonin and phosphatidylcholine.

Inadequate levels of SAMe in tissues and plasma and cerebral spinal fluid have been found to be highly correlated with conditions such as: depression, alzheimer's and dementia [3]. Suboptimal levels of SAMe in some individuals may be due to insufficient amounts of the precursor amino acid methionine [2] (diets low in protein, or diets containing mostly vegetarian protein which are typically low in methionine) and/or the necessary cofactors B12 (vegetarians, inadequate absorption) and folate and/or lack of a basic vitamin supplement [1].

For some individuals, even if they are supplementing methionine and/or getting sufficient amounts of methionine from animal proteins, SAMe synthesis is still not adequate due to a low activity of the enzyme SAMe synthetase. It was found that when this enzyme is saturated in the presence of high amounts of methionine coming from supplements or excess animal protein, it can cause blood methionine levels to rise to a toxic level [16].

Even if the body is producing normal or average levels of SAMe, certain physiological states create an increased demand for it, consequently supplementation is warranted by specific metabolic conditions, as will be discussed further in detail.

SAMe has been studied in Europe for over 40 years and was introduced in the US in 1998. SAMe supplementation within the range of 200-1500mg has been found to be a safe and effective intervention for: arthritis (both rheumatoid and osteo), various liver conditions, depression, opiate/alcoholic detox and dementia.

SAMe is an important physiological metabolite, participating in over 40 reactions in the body, among which some worth mentioning here are [1]:

  1. Methylation (DNA, proteins, phospholipids)
  2. Transulfuration (synthesis of Cysteine, Taurine, Sulfates)
  3. Polyamine synthesis (cell growth and differentiation)

I. SAMe and the Brain
SAMe has been proven to be a powerful natural intervention for improving brain function and alleviating various mood and brain performance conditions [3].

Let's look at why:

A. Cofactor in Neurotransmitter Synthesis.
SAMe acts as a methyl donor in the production of the following:

  1. Serotonin, which partially converts to Melatonin
  2. Dopamine which partially converts to Epinephrine and Norepinephrine (which are collectively called Adrenaline)
  3. Phosphatidyl Choline which converts partially to Acetyl-Choline

B. Cofactor in the synthesis of brain cell membrane builders
SAMe is involved in the production of various phosphatides:

  • Phosphatidyl Choline
  • Phosphatidyl Serine

C. Improves receptor binding of neurotransmitters [3].

D. Does not interfere with the neurotransmitter breakdown like most drugs (SSRI)
This makes SAMe less likely to cause an addiction effect as many drugs do.

E. Does not interfere with the activity of detoxification enzymes in the liver, as many drugs do
For example, Tricyclics inhibit Cytochrome P450 [12]. On the contrary, as discussed in detail in section II, SAMe improves some detoxification pathways in the liver making it the preferred treatment for patients taking multiple medications, hormones, social drinkers, and anyone exposed to chemicals (aren't we all?!).

F. Onset of benefits happens within 2-5 days versus 2 weeks for most drugs [39,40].
This makes it easier to titrate the effective dose.

A side effect of SAMe was found to be appetite suppression but this may be a benefit for many, as long as it does not lead to anorexia and malnutrition.

SAMe has been found to be as effective as tricyclic antidepressants in alleviating depression at doses of 200-1600mg [38]. The following drugs fall in the category of tricyclic drugs: Adapin®, Amitriptyline, Amoxapine, Asendin®, Desipramine, Doxepin, Elavil®, Imipramine, Janimine®, Ludiomil®, Maprotiline, Norpramin®, Nortriptyline, Pamelor®, Pertofrane®, Protriptyline, Sinequan®, Surmontil®, Tofranil®, Trimipramine Maleate, and Vivactil®.

SAMe has not been studied against SSRI's but has been found 70% more effective than placebo [39,40] in alleviating depression.

Preliminary studies indicate that SAMe may improve cognitive function in dementia in elderly patients [42].

Suggested Administration

As with any intervention, patients should start with the lowest dose of 200mg once or twice a day, am or am and midday. SAMe should not be taken in the evening, because its natural circadian rhythm is high during the day and low in the evening and throughout the night. The dose can be increased after 5 days or more, 200mg at a time, while evaluating its effects in various conditions. Absorption of SAMe is better on an empty stomach, however, taking SAMe with meals will slow its delivery in the blood stream and create a more natural increase in SAMe concentrations similar to that of an endogenous production making this ideal.

If necessary, SAMe should be discontinued gradually, like other prescription antidepressant medications, because complex feedback mechanisms cause changes to occur in brain enzyme levels and receptor numbers and activities due to the higher levels of neurotransmitters. As with any nutritional intervention, SAMe should not be utilized as a magic bullet monotherapy when treating depression.

When dealing with depression, other essential brain builders/messengers/cofactors should be considered : omega-3's which are critical for healthy cell membrane function (DFH Arctic Cod Liver Oil or Omega Synergy gelcaps), phospholipids which are cell membrane stabilizers(DFH Phosphatidyl Choline helps synthesize acetyl-choline), second messenger molecules (DFH Inositol), neurotransmitter precursors: Tryptophan, 5-HTP form DFH 5-HTP Synergy, Tyrosine, synergistic combination of precursors from DFH CraveArrest, DFH GABA and other beneficial nutrients including DFH Magnesium(various forms) and DFH Taurine.

Patients currently on drugs affecting brain neurochemistry, should proceed with caution when starting to supplement with SAMe while monitored closely by an appropriate health professional. For example, it was found that SAMe potentiates the action of tricyclics[41], which implies that a lower dose of the drug could be used if still necessary after a comprehensive nutrition intervention.

SAMe was found to be useful in the management of various symptoms of fibromyalgia, through improvement of sleep and reduction of pain, maybe due to increased serotonin levels [14-15]

Contraindications for certain mental imbalances

In patients with severe neurochemistry imbalances like manic and bipolar depression, SAMe could potentially increase anxiety and manic behavior due to increased production of all neurotransmitters. The effect of SAMe for Parkinson's is controversial and still under investigation [3].

Other rare side effects might include nervousness, dry mouth and constipation, which are all signs of excessive dopamine/adrenaline production. Patients that present with this reaction should not use SAMe, because they probably start out with high Dopamine levels and SAMe tends to boost both Serotonin and Dopamine. Rather, they should try selectively boosting serotonin with nutrients like Tryptophan, DFH 5-HTP Synergy, DFH Inositol. Other calming nutrients like DFH GABA, DFH Taurine and DFH Magnesium Glycinate would serve them well.

II. SAMe for the Liver

SAMe supplementation is especially important for patients with liver damage due to cirrhosis, hepatitis, fibrosis, etc, because in these cases the enzyme converting methionine to SAMe is severely impaired [16].

SAMe is a precursor for a number of metabolites that play a key role in the detoxification pathways of the liver such as cysteine, taurine and phosphatidylcholine. [17] Taurine is important in bile formation, which is the eliminating vehicle for the liver. [21] Phophatidyl choline is used by the liver to package toxins and for membrane stability [16].

The liver is susceptible to methyl deficiency. Methyl deficiency causes a reduction in SAMe levels, and an elevation in S-adenosylmethionine homocysteine (SAH). SAH is what's left over after SAMe donates a methyl group for biochemical reactions. An enzyme, SAH hydrolase, turns SAH into homocysteine. Homocysteine can be toxic if it builds up within the body, but is converted into cysteine (and eventually glutathione) if enough SAMe and B vitamins are present. If SAMe is super-deficient, nothing gets converted, and SAH and homocysteine backs up like a clogged drain. B6, B12 and folic acid not only help in the elimination of homocysteine after it donates a methyl group but also helps convert homocysteine into glutathione or it can be remethylated back into methionine. Now you can see why Designs for Health's SAMe contains these essential B vitamins!

Glutathione is considered to be the body's most important antioxidant and used for conjugating various substances that need to be eliminated by the liver such as drugs, hormones (endogenous, HRT and from animal foods), pesticides and various toxic chemicals [19].

In a placebo-controlled study in the Scandinavian Journal of Gastroenterology, 16 patients with liver disease (both alcoholic and non-alcoholic) were given 1,200 mg of oral SAMe per day for six months. Liver biopsies showed a significant increase in glutathione, and a significant reduction in oxidized glutathione. In the non-alcoholic, liver-damaged subjects, alanine aminotransferase (a liver enzyme indicating damage) was reduced. In a study in which 45 patients with alcoholic liver disease were treated with intravenous SAMe for 15 days, liver function improved significantly. SAMe also keeps the liver's antioxidant system functioning.

One of the biochemical consequences of cirrhosis is glutathione depletion. Glutathione is a very important antioxidant for the liver since the liver contains lots of fat and mitochondria, both of which generate free radicals. Without sufficient glutathione to quench them, the radicals damage the liver. Much of what is called cirrhosis is actually free radical damage from lipid peroxidation and oxidative stress.

SAMe's ability to be taken up by human liver cells and converted into glutathione was confirmed by researchers in Spain in 1991. They reported in Toxicology that supplemental SAMe maintains glutathione levels if added at the same time as alcohol (which drastically depletes glutathione).

Study after rat study shows that maintaining SAMe levels protects the liver. Acetaminophen (Tylenol) is notorious for causing liver toxicity. In a mouse study, deaths from high doses of acetaminophen were completely abolished if SAMe was given within one hour. If given within five hours, the number of deaths was significantly reduced. Rats treated with tetrachloride develop massive free radical damage very similar to what occurs with alcohol. If the same rats are given SAMe, damaging collagen deposits can be significantly reduced. How does SAMe work? Again, it works by increasing or maintaining glutathione levels, which lipoic acid does as well.

Conditions that SAMe may be helpful: fibrosis, cirrhosis [17] (biliary, alcoholic, or idiopathic), Hepatitis C, cholestasis, HRT, birth control, Gilbert's Syndrome [20]

Dosage: 200mg 1-2 times per day (am and/or midday)

People with liver disease have too much cholesterol in their cell membranes. A group in England has shown that SAMe dramatically reduces cholesterol. The cholesterol-to-phospholipid ratio decreased substantially in the erythrocytes of people with liver disease two weeks after they were treated with oral SAMe (1,600 mg). SAMe has been shown to decrease cholesterol in plasma as well. Thirteen patients with hyperlipidemia were given 30-minute infusions of SAMe. Total lipids and cholesterol fell significantly.

Even after a 80% destruction, the liver is known to have the capability to regenerate. Other instrumental nutrients in liver recovery are: DFH Lipoic Synergy, DFH N-Acetyl-Cysteine (NAC), DFH Phosphatidyl Choline, and DFH Milk Thistle.

III. SAMe and the Joints

SAMe was found very helpful in preventing and reversing the damage caused by both osteo and rheumatic arthritis through the following mechanisms[22-26]:

  • counteracts the destructive effect of the inflammatory cytokine TNF-alpha
  • regenerates the joint tissues by increasing the number of chondrocyte cells which are responsible with the production of the collagen matrix, proteoglycans and chondroitin sulfate.
References:

1. Lieber CS, Packer L. S-Adenosyl-L-methionine: molecular, biological, and clinical aspects-an introduction. Am J Clin Nutr 2002; 76(suppl):1148S-50S.

2. Finkelstein JD, Martin JJ. Methionine metabolism in mammals. J Biol Chem 1986;261:1582-7.

3. David Mischoulon and Maurizio Fava Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am

J Clin Nutr 2002;76(suppl):1158S-61S.

4. Baldessarini RJ, Neuropharmacology of S-adenosyl-L-methionine. Am J Med 83 (Suppl. 5A), 95-103, 1987

5. Reynolds E, Carney M, and 2. Toone B, Methylation and mood. Lancet ii, 196-199, 1983.

6. Bottiglieri T, Laundry M, Martin R, et al., S-adenosylmethionine influences monoamine metabolism. Lancet ii, 224, 1984.

7. Janicak PG, et al., Parenteral S-adenosylmethionine in depression: A literature review and preliminary report. Psychopharmacology Bulletin 25, 238-241, 1989.

8. De Vanna M and Rigamonti R, Oral S-adenosyl-L-methionine in depression. Curr Ther Res 52, 478-485, 1992.

9. Salmaggi P, et al., Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women.

Psychother Psychosom 59, 34-40, 1993.

10. Kagan FL, et al. Oral S-adenosylmethionine in depression: A randomized, double-blind placebo-controlled trial. Am J Psychiatry 147, 591-595, 1990.

11. Russo A, et al., Efficacy of S-adenosyl-L-methionine in relieving psychological distress associated with detoxification in opiate abusers. Curr Ther Res 55, 905-013, 1994.

12. Bottiglieri, T., et al. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 48(2):137-152, 1994.

13. Morrison, L. D., et al. Brain s-adenosylmethionine levels are severely decreased in Alzheimer's disease. Journal of Neurochemistry (USA). 67(3):1328-1331, 1996.

14. Jacobsen S, et al., Oral S-adenosylmethionine in primary fibromyalgia: Double-blind clinical evaluation. Scand J Rheumatol 20, 294-302, 1991.

15. Tavoni A, et al., Evaluation of S-adenosylmethionine in primary fibromyalgia: A double-blind crossover study. Am J Med 83 (Suppl. 5A), 107-110, 1987.

16. Charles S Lieber. S-Adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr 2002;76 (suppl):1183S-7S.

17 . Lieber CS. Ademethionine and alcohol. In: Lieber CS, ed. S-Adenosylmethionine in the treatment of liver disease. Milan, Italy: UTET, 2001:45-60.

18. Frezza M, et al., Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis: A double-blind, placebo-controlled study. Gastroenterology 99, 211-215, 1990.

19. Total glutathione before and after 6 months treatment with 1,200 mg oral SAMe. (Scand. J. Gastroent 24:407, 1989)

20. Bombarbieri G, Milani A, Bernardi L and Rossi L, Effects of S-adenosyl-L-methionine (SAMe) in the treatment of Gilbert's syndrome. Curr Ther Res 37, 580-585, 1985.

21. Angelico M, et al., Oral S-adenosyl-L-methionine (SAMe) administration enhances bile salt conjugation with taurine in patients with liver cirrhosis. Scand J Clin Lab Invest 54, 459-464, 1994.

22. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of s-adenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;37:82-94.

23. 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;5:39-49.

24. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis. Clin Rheumatol 1985;4:484-5.

25. Muller-Fassbender H. 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.

26. 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.

27. Solomon L, Drug induced arthropathy and necrosis of the femoral head. J Bone Joint Surg 55B, 246-251, 1973.

28. Konig H, et al., Magnetic resonance tomography of finger polyarthritis: Morphology and cartilage signals after ademethionine therapy. Aktuelle Radiol 5, 36-40, 1995.

29. Glorioso S, et al., Double-blind multicenter study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 5, 39-49, 1985.

30. Marcolongo R, et al., Double-blind multicentre study of the activity of S-adenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 37, 82-94, 1985.

31. Domljan Z, et al., A double-blind trial of ademethionine vs naproxen in activated gonarthrosis. Int J. Clin Pharmacol Ther Toxicol

27, 329-333, 1989.

32. Muller-Fassbender H, Double-blind clinical trial of S-adenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med 83 (Suppl. 5A), 81-83, 1987

33. Spillmann M, Fava M. S-adenosyl-methionine (ademethionine) in psychiatric disorders. CNS Drugs 1996;6:416-25.

34. Alpert JE, Mischoulon D. One-carbon metabolism and the treatment of depression: roles of S-adenosyl methionine (SAMe) and folic acid. In: Mischoulon D, Rosenbaum J, eds. Natural medications for psychiatric disorders: considering the alternatives. Philadelphia: Lippincott Williams & Wilkins, 2002:44.

35. Fava M, Borus JS, Alpert JE, et al. Folate, B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997;154:426-8.

36. Bottiglieri T, Godfrey P, Flynn T, Carney MWP, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 1990;53:1096-8.

37. 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.

38. Miccoli L, Porro V, Bertolino A. Comparison between the antidepressant activity of S-adenosyl-L-methionine (SAMe) and that of some tricyclic drugs. Acta Neurol (Napoli) 1978;33:243-55.

39. 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;56:295-7.

40. Alvarez E, Udina C, Guillamat R. Shortening of latency period in depressed patients treated with SAMe and other antidepressant drugs. Cell Biol Rev 1987;S1:103-10.

41. 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;44:257-62.

42. Fontanari D, DiPalma C, Giorgetti G, et al. Effects of S-adenosyl- L-methionine on cognitive and vigilance functions in elderly. Curr Ther Res 1994;55:682-9.

43. Lo Russo A, Monaco M, Pani A, et al. Efficacy of S-adenosyl methionine in relieving psychologic distress associated with detoxification on opiate abusers. Curr Ther Res 1994;55:905-13.

44. Agricola R, Dalla Verde G, Urani R, et al. S-adenosyl-L-methionine in the treatment of major depression complicating chronic alcoholism. Curr Ther Res 1994;55:83-92.

45. Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. S-Adenosyl-methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Mov Disord 2000;15:1225-9.


Copyright Issues?

Topics: