Supplements for Depression By Andrew Novick


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  1. Supplements for Depression
  2. By Andrew Novick
  3. L-Tyrosine
  4. L-Tyrosine is an amino acid naturally found in food that serves as the precursor to the neurotransmitters dopamine and noradrenaline. A deficit in dopaminergic and/or noradrenergic activity is implicated in depressions involving lack of energy and motivation (1) and it is here where L-tyrosine might be the most helpful in dosages of 3.2g/day (2). L-tyrosine’s antidepressant effect by itself is modest because the rate-limiting enzyme in dopamine synthesis, (tyrosine hydroxylase) is normally 75% saturated (3). This minimizes possible benefits from extra consumption of L-tyrosine. Probably due to this biochemical barrier, in a double-blind, placebo-controlled trial, L-tyrosine failed to show significant antidepressant activity (4).
  5. However, just because L-Tyrosine might not be an effective antidepressant on its own does not mean it has no place in an antidepressant regimen. More evidence exists for the efficacy of L-Tyrosine when combined with other antidepressant compounds. For example, L-Tyrosine can potentiate increases in dopamine from methylphenidate, better known as Ritalin (5). L-Tyrosine can also potentiate the antidepressant effect of 5-HTP (6).
  6. DL-Phenylalanine
  7. L-Phenylalanine is converted to L-tyrosine by the enzyme phenylalanine hydroxylase. So why not just take L-Tyrosine and avoid the extra metabolic conversion? Well, what makes the therapeutic possibilities of L-Phenylalanine different from that of L-Tyrosine is its ability to convert to phenylethylamine (PEA) via decarboxylation. PEA is an endogenous trace amine with behavioral effects similar to amphetamine (6). Because PEA is rapidly degraded by the enzyme MAO-B, it is unknown whether supplementation with L-Phenylalanine has any mood-modulating effects relevant to increases in PEA. However, when given concurrently with the MAO-B inhibitor deprenyl, L-Phenylalanine leads to increases in brain PEA levels and produces a rapid antidepressant response (8). L-Phenylalanine by itself might also have antidepressant properties, albeit at higher dosages of 14g/day (9).
  8. D-Phenylalanine has demonstrated antidepressant efficacy without an MAOI in dosages as low as 200mg/day (10). D-phenylalanine can also inhibit the enzymes responsible for the degradation of endorphins (11) and increase the pain relieving effects of acupuncture and narcotics (12,13). Here it appears that D-phenylalanine is the more active isomer. Unfortunately, D-phenylalanine is not available as a sold-alone dietary supplement. However, preparations containing a 50:50 mix of the D and L versions are common. There is no evidence suggesting that L-phenylalanine interferes with the effects of D-phenylalanine.
  9. 5-Hydroxytryptophan
  10. 5-Hydroxytryptophan (5-HTP) is the immediate precursor to serotonin. Unlike L-tyrosine conversion to dopamine, 5-HTP is not subject to the rate limiting step in serotonin synthesis. 5-HTP is an effective supplement at raising serotonin levels in humans (14). A meta-analysis of studies on 5-Hydroxytryptophan for depression failed to find positive results due to the low amount of placebo-controlled studies (15). However, various open studies as well as some placebo-controlled studies have demonstrated that 5-HTP is an effective antidepressant in dosages from 50-300mg/day (16).
  11. Fish Oils
  12. Omega-3 fatty acids found mainly in fish are well known for their benefits in aiding weight loss, protecting the cardiovascular system, and improving inflammatory conditions. Omega-3’s can also be effective antidepressants. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the two omega-3 fatty acids found in fish oil. While depressed patients often exhibit low levels of DHA (21), a trial with sole DHA therapy failed to improve depressive symptoms significantly (18). EPA appears to have more promise, especially as an adjunct therapy to prescription antidepressants in dosages of 2g/day (22,23).
  13. The anti-inflammatory nature of omega-3 fatty acids might be responsible for their antidepressant activity. Major depression is often accompanied by an increase in pro-inflammatory cytokines and prostaglandins (19) and a diet rich in omega-3 fatty acids can reduce levels of these chemicals (20).
  14. Inositol
  15. Inositol is a precursor to an important second messenger system in the brain that helps regulate serotonin receptors (27). Depressed patients show decreased levels of inositol in spinal fluid (24) while mood stabilizers such as lithium and sodium valproate reduce levels of inositol in the brain, as manic people often show elevated myo-inositol (25). Inositol at dosages of 18g/day has been found to be an effective treatment for depression, obsessive-compulsive disorder and panic disorder (26). However, newer research has been less conclusive about inositol’s efficacy, as it has failed to show significant effects when used as an add-on strategy to antidepressants (27).
  16. Conclusions
  17. These are just a few of the many nutritional supplements that have application to depression and mental health. Because the nature of depression varies so much from person to person, care must be taken when picking the proper supplement. Atypical depressives who suffer from lack of energy may benefit from using L-tyrosine and/or DLPA. 5-HTP and Inositol may be more helpful in situations where anxiety is a primary concern. Fish Oil probably has application to all subtypes of depression.
  18. These supplements can be combined with antidepressants, although caution should be exercised when combining 5-HTP with an SSRI or MAOI as it could result in serotonin syndrome. For those looking to augment a prescription antidepressant, picking a supplement that affects a different receptor complex than the antidepressant could provide additional benefits. For example, those on SSRI’s like Prozac or Zoloft may wish to use L-tyrosine or DLPA to activate the dopaminergic/noradrenergic system. Similarly, those on a drug that already affects the catecholamines such as Wellbutrin, could add 5-HTP. The recent trend in antidepressant pharmacology is that hitting multiple neurotransmitter systems is better than affecting only one (29). However, many people with depression have specific symptoms that call for specialized treatment rather than a shot-gun approach.
  19. Those looking for consistent regimen for overall mental health can combine (cautiously) the supplements mentioned above. Here’s an example dosage scheme:
  20. Fish Oils 6g/day
  21. DLPA 500mg (3 times a day)
  22. 5-HTP 50mg (3 times a day)
  23. Inositol 4g (3 times a day)
  24. Although these supplements are very well tolerated, one should add one compound at a time, starting at a low dose in order to avoid side-effects.
  25. McLean A, Rubinsztein JS, Robbins TW, Sahakian BJ. The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression. Psychopharmacology (Berl). 2004 Jan;171(3):286-97. Epub 2003 Sep 04.
  26. Mouret J, Lemoine P, Minuit MP, Robelin N. [L-tyrosine cures, immediate and long term, dopamine-dependent depressions. Clinical and polygraphic studies] C R Acad Sci III. 1988;306(3):93-8.
  27. Carlsson A, Lindqvist M. Dependence of 5-HT and catecholamine synthesis on concentrations of precursor amino-acids in rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1978 Jun 27;303(2):157-64.
  28. Gelenberg AJ, Wojcik JD, Falk WE, Baldessarini RJ, Zeisel SH, Schoenfeld D, Mok GS. Tyrosine for depression: a double-blind trial. J Affect Disord. 1990 Jun;19(2):125-32.
  29. Woods SK, Meyer JS. Exogenous tyrosine potentiates the methylphenidate-induced increase in extracellular dopamine in the nucleus accumbens: a microdialysis study. Brain Res. 1991 Sep 27;560(1-2):97-105.
  30. van Praag HM. In search of the mode of action of antidepressants. 5-HTP/tyrosine mixtures in depressions. Neuropharmacology. 1983 Mar;22(3 Spec No):433-40.
  31. Janssen PA, Leysen JE, Megens AA, Awouters FH. Does phenylethylamine act as an endogenous amphetamine in some patients? Int J Neuropsychopharmcol 1999 Sep; 2(3):229-240.
  32. Birkmayer W, Riederer P, Linauer W, Knoll J. L-deprenyl plus L-phenylalanine in the treatment of depression. J Neural Transm. 1984;59(1):81-7.
  33. Sabelli HC, Fawcett J, Gusovsky F, Javaid JI, Wynn P, Edwards J, Jeffriess H, Kravitz H. Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements. J Clin Psychiatry. 1986 Feb;47(2):66-70.
  34. Beckmann H, Strauss MA, Ludolph E. Dl-phenylalanine in depressed patients: an open study. J Neural Transm. 1977;41(2-3):123-34.
  35. Ehrenpreis S. D-phenylalanine and other enkephalinase inhibitors as pharmacological agents: implications for some important therapeutic application. Acupunct Electrother Res. 1982;7(2-3):157-72.
  36. Kitade T, Odahara Y, Shinohara S, Ikeuchi T, Sakai T, Morikawa K, Minamikawa M, Toyota S, Kawachi A, Hyodo M, et al. Studies on the enhanced effect of acupuncture analgesia and acupuncture anesthesia by D-phenylalanine (2nd report)--schedule of administration and clinical effects in low back pain and tooth extraction. Acupunct Electrother Res. 1990;15(2):121-35.
  37. Russell AL, McCarty MF. DL-phenylalanine markedly potentiates opiate analgesia - an example of nutrient/pharmaceutical up-regulation of the endogenous analgesia system. Med Hypotheses. 2000 Oct;55(4):283-8.
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