Depression and Arthritis
By Will Block

. . . [we] may not hope from outward forms to win,
the passion and the life,
whose fountains are within.

- Samuel Coleridge, Dejection: An Ode

All of us in our lifetimes, at one point or another, experience depression. Although no two depressions are exactly alike, our experience occurs when we feel as if there is no way to avoid discomfort or pain. We may even come to think that we deserve it. If this condition persists and we feel truly hopeless about our problems, clinical depression is likely to follow. Then things may spiral downward, and our self-deprecation may become a self-fulfilling prophecy. If, in our hopelessness, we develop a tendency to give up, to stay put, to take no action because we feel we can do nothing that matters, things get worse still. Using Coleridge's imagery, with our passion fading and the fountains of life receding, even our physical health may become impaired.

It has long been known that depression is rooted in the biochemistry of the brain. This discovery, at first a ray of light, has become a beacon, allowing us not only to explore and illuminate some of the deepest, darkest recesses of our minds, but also to counteract depression through chemical intervention - preferably not through prescription drugs, with all their undesirable side effects, but through safe nutritional supplements, including those that already exist naturally in our bodies.

If we become depressed and find ourselves succumbing to the immobilizing grip of hopelessness, we must remember that depression feeds off a deficiency of serotonin, the brain's principal mood-controlling neurotransmitter. We can act on that knowledge by giving our brains the nutritional raw material from which more serotonin can be made, and we can weather the storm. There can be hope where previously there was none. (For more information on this subject, see prior issues of this magazine and the book Life Enhancement's 5-HTP Archives.

Be forewarned: because the aging process not only diminishes our serotonin reserves but also colludes with depression to weaken our immune system, we may soon have something more about which to be depressed. A likely candidate is arthritis, which has been associated in the scientific literature with depression - the two are almost always seen coupled in chronic fatigue syndrome, for example.1 Both can lower our quality of life dramatically. These twin afflictions have tormented many a soul and body, including those of the artist Vincent van Gogh, whose life ended tragically at the age of 37 (see Figure 1).

Even considering the link between arthritis and depression, it comes as somewhat of a surprise (a pleasant one, certainly) that cognitive-behavioral psychotherapy has been shown to be an effective adjunctive treatment for rheumatoid arthritis outpatients.2 Yet treating depression does not really treat arthritis. The primary effects of psychotherapy pertain more to improved coping and emotional stabilization than to reduced joint inflammation and pain.

It is understandable that arthritis could cause depression, but can depression cause arthritis? The conventional answer is no. Yet there is a single nutrient that has been found to hit the nails of both depression and arthritis on the head. This nutrient is S-adenosylmethionine, a chemical compound found throughout the body and normally produced in adequate amounts for all our needs. There are times, however, when extra amounts of it can be helpful. As a nutritional supplement in cases of depression and arthritis, it has been found to confer benefits for both mental health and joint health.

Luckily, S-adenosylmethionine has a nickname: SAMe or SAM-e (pronounced sammy or just sam; some spell it SAM to begin with). The physiologically active form of the essential amino acid methionine, SAMe is an essential participant in many biochemical pathways in the body. Its primary role is to carry out an important chemical process called methylation, in which a methyl group (--CH3) is transferred by a methyl-group donor molecule (SAMe in this case) to another molecule, often with dramatic physiological results. In the brain, SAMe affects neurotransmitter membrane function, increasing the production of serotonin and dopamine.

SAMe's chemical mechanism of action is different from those of the serotonergic (serotonin-stimulating) amino acid 5-HTP and the antiarthritics glucosamine and chondroitin. SAMe can thus augment those compounds in helping to combat depression and restore proper joint and cartilage function. Curiously, it also stimulates the production of antioxidants.

SAMe has been in wide use in Europe - especially in Italy, where it was discovered in 1952 - for many years. It is available over-the-counter in the United States, but until recently, the special, stabilized form of SAMe that physicians prefer was not available here, and it is still not always easy to obtain.

At Columbia University, psychiatrist Dr. Richard Brown has been using SAMe to treat patients with symptoms of depression, and the results have been impressive. For mild depression, he uses doses of 200 to 400 mg per day, increasing them to as much as 1200 to 2000 mg per day in severe cases. Improvement is often seen in as little as 4 to 14 days, and no side effects have been noted. According to Dr. Brown, SAMe may be of value, in even higher doses of 3600 mg, for Parkinson's disease. He is surprised that more physicians don't know about SAMe, especially since many of his patients are themselves physicians, who delight in its lack of side effects.

A randomized, double-blind study has shown SAMe to be a more rapidly acting antidepressant than the tricyclic drug imipramine (an old standard) in treating major depression.3 Eighteen patients, nine of whom received SAMe and the other nine imipramine, were evaluated at the end of two weeks of treatment. Six of the nine patients receiving SAMe had a clinically significant improvement in depressive symptoms, compared to just two of those receiving imipramine, and there were fewer side effects with SAMe. In another study in which the effects of SAMe were compared with those of imipramine, it was shown that not only was SAMe again superior, but its action was felt more quickly.4

Figure 1. The depression of Vincent Van Gogh, the post-impressionist painter, has been attributed to his excessive consumption of the liqueur absinthe, derived from the wormwood plant. Curiously, wormwood has been used to treat arthritis, a condition of van Gogh's also attributed to his eating his paints. They contained high levels of lead, the toxicity of which is associated with gouty arthritis. Van Gogh died a suicide.

The well-established speed of action of SAMe as an antidepressant is a very important factor in its use. A problem with many prescription antidepressants is that they take so long to have an effect that severely depressed patients who are candidates for suicide actually go ahead and do it. And in a sense, who can blame them? They feel as badly about life as it's possible to feel, they've bought an expensive drug to make them feel better, and it hasn't worked. Hopelessness squared.

SAMe improves joint function in osteoarthritis and appears to help in cases of fibromyalgia, according to Dr. Todd Bottiglieri of the Baylor Research Institute in Dallas, Texas.5 Quoting Dr. Bottiglieri, SAMe is ". . . comparable in effect with the NSAIDs,* . . . [but] without the side effects. . . . It stimulates proteoglycan synthesis and synovial fluid . . . and appears to have direct anti-inflammatory effects."

Knowledge of the antiarthritic properties of SAMe has been accumulating since as far back as 1975, when an open trial conducted in Italy reported on the anti-inflammatory effects of just 60 mg of SAMe per day for a period of 14 days.6 Most of the 90 patients with severe degenerative arthropathies (chronic, progressive degeneration of the stress-bearing portion of a joint) reported anti-inflammatory effects without side effects. Then, in a "double-crossover" investigation, SAMe was compared to indomethacin (an NSAID) in 15 of the arthropathic subjects. Both compounds were similar, if not exactly alike, in their therapeutic effects, but without side effects for SAMe.

In a randomized, double-blind, multicenter clinical trial, SAMe proved to be the equal of ibuprofen in 150 patients with hip and/or knee osteoarthritis.7 Both compounds were given orally, 400 mg thrice daily for 30 days, but SAMe exhibited a more marked activity than ibuprofen in the management of the various painful manifestations of the joint disease. Again, there were few side effects, none of any consequence.

Another long-term (24 months), multicenter open trial of SAMe involving 10 general practitioners found benefits for 108 patients with osteoarthritis of the knee, hip, and spine.8 As the period of the study ended, 97 patients remained. They had received 200 mg of SAMe thrice daily for the first two weeks, followed by 200 mg twice daily until the end of the study. Well tolerated and effective, SAMe produced improvement within the first two weeks and through the end of the study. Therapy did not have to be continued in any of the subjects, and most side effects disappeared during the course of the study. SAMe also improved the depressive feelings often associated with osteoarthritis.

Having noted that people with Alzheimer's disease have reduced levels of SAMe in their cerebrospinal fluid, researchers at the Clarke Institute of Psychiatry, University of Toronto, set out to investigate the status of SAMe and its methylation reactions in the brains of Alzheimer's patients.9 In the postmortem brain tissue of 11 such patients, they found decreased levels of both SAMe (in the range of -67% to -85%) and its demethylated product, S-adenosylhomocysteine (-56% to -79%). This was true in all the brain regions examined, compared with age-matched controls (of whom there were 14).

The researchers conjectured that the reduced levels of SAMe were caused by its excessive utilization in the biosynthesis of polyamines, which are thought to play a role in the formation of the tangled amyloid plaque found in the brains of Alzheimer's patients. SAMe is known to play an important role in the synthesis of polyamines, a class of molecules that are also important in the regulation of cell proliferation and cell differentiation.

Elsewhere it has been hypothesized that inadequate methylation caused by a deficiency of SAMe might also play a role in Alzheimer's.

In has been noted that the incidence of folic acid deficiency is high in patients with various psychiatric disorders, including depression, dementia, and schizophrenia.10 Folic acid deficiency is known to lower brain levels of SAMe as well as serotonin. Therefore it has been suggested that supplementing with folic acid (a B vitamin) may help conserve SAMe.

Another nutrient that may help conserve or increase the activity of SAMe is vitamin B12 (cyanocobalamin), which is known to play an important role in methionine synthesis and is related to folic acid in its activity. The biochemical basis of the interrelationship between cyanocobalamin and folate is the maintenance of two functions: nucleic acid synthesis and methylation reactions.11 Cyanocobalamin is particularly important in the brain, where it helps to maintain the concentration of SAMe, which, in turn, causes methylation reactions. When these reactions are inhibited, the result is a neuropathy associated with cyanocobalamin deficiency.

In vitamin B6 (pyridoxine) deficiency, decreased SAMe inhibits the methylation of homocysteine - excessive amounts of which are now believed to be a principal cause of cardiovascular disease - which leads to a large elevation of homocysteine in the blood.12 This does not occur when adequate levels of pyridoxine are present.

Indeed, the same vitamins that reduce the formation and effect of homocysteine on plaque formation and cardiovascular disease help SAMe to reduce homocysteine levels yet further. Therefore, it is probably a good idea to take added folic acid, vitamin B6, and vitamin B12 along with SAMe to optimize its utility in the body.13

If it sounds as though we have described you in this article, you may owe it to yourself to obtain the considerable benefits of SAMe, a vital nutrient for mind and body. Both of them will thank you for it.

* NSAID = nonsteroidal anti-inflammatory drug. Examples are aspirin, acetaminophen, ibuprofen, and naproxen.


  1. Buskila D, Neumann L, Alhoashle A, Abu-Shakra M. Fibromyalgia syndrome in men. Semin Arthritis Rheum 2000 Aug;30(1):47-51.
  2. Leibing E, Pfingsten M, Bartmann U, Rueger U, Schuessler G. Cognitive-behavioral treatment in unselected rheumatoid arthritis outpatients. Clin J Pain 1999 Mar;15(1):58-66.
  3. Bell KM, Plon L, Bunney WE Jr, Potkin SG. S-Adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry 1988 Sep;145(9):1110-4. Potkin SG, Bell K, Plon L, Bunney WE Jr. Rapid antidepressant response with SAMe. A double-blind study. Ala J Med Sci 1988 Jul;25(3):313-6. Erratum: Ala J Med Sci 1988 Oct;25(4):496.
  4. Reuter's Healthline. Nutraceutical SAM-e confers mental health, joint benefits. 1999 Mar;
  5. Polli E, Cortellaro M, Parrini L, Tessari L, Cherie-Ligniere G. Pharmacological and clinical aspects of S-adenosylmethionine (SAMe) in primary degenerative arthropathy. Minerva Med 1975 Dec 5;66(83):4443-59.
  6. Glorioso S, Todesco S, Mazzi A, Marcolongo R, Giordano M, Colombo B, Cherie-Ligniere G, Mattara L, Leardini G, Passeri M, 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.
  7. Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med 1987 Nov 20;83(5A):89-94.
  8. Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J Neurochem 1996 Sep;67(3):1328-31.
  9. Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 1989;13(6):841-63.
  10. Weir DG, Scott JM. Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull 1999;55(3):669-82.
  11. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr 1994 May;59(5):1033-9.
  12. She QB, Nagao I, Hayakawa T, Tsuge H. A simple HPLC method for the determination of S-adenosylmethionine and S-adenosylhomocysteine in rat tissues: the effect of vitamin B6 deficiency on these concentrations in rat liver. Biochem Biophys Res Commun 1994 Dec 30;205(3):1748-54.

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator