(Image: Depressed Boy via Shutterstock)The National Institutes of Health should fund rigorous trials of four promising dietary supplements used to treat depression so consumers can make an informed choice, with knowledge of their benefits and side effects.

The word “natural” – though somewhat degraded by food processors’ efforts to use it promotionally – still retains cachet, especially when it comes to pharmaceuticals. And make no mistake: Many of the natural products on the market, here and abroad, are drugs – no less so than the creations that come out of Pfizers’ and Astra’s test tubes. This applies with particular force to four natural substances that are used to treat depression: tryptophan, 5-hydroxytryptophan (5-HTP), St. John’s Wort, and S-adenosyl methionine (SAMe).

Proponents of natural substances endow them with two properties that may or may not apply: 1) Natural substances are safer than red-blooded prescription drugs; and 2) They are no less effective than “real” drugs.

Tryptophan, 5-HTP, St. John’s Wort and SAMe are classified by the US Food and Drug Administration as “dietary supplements.” The FDA has evinced scant interest in these substances. The agency lacks the manpower to keep abreast of prescription drugs and the foods we eat, because at budget-cutting time it is the victim of politicians who are in the pocket of Big Pharma and agribusiness, so it is hardly surprising that it neglects the dozens of companies, ranging from bucket shops to reputable operations that manufacture dietary supplements.

One consequence, writes David Mischoulson, MD, PhD, of Harvard and Massachusetts General Hospital, in a seminal paper, is that the FDA has not examined clinical studies, so that optimal doses are undefined, and contra-indications, drug-drug interactions and possible toxicity are unevaluated. What is more, different brands may have different amounts of the active ingredient and indeed may be manufactured under disparate conditions of quality control.

Some of the supplements on the market go right through you without being absorbed. When I was doing research with natural substances for treating several psychiatric and neurological diseases, my collaborators and I were very careful to obtain our supplements from a reliable manufacturer. In one telling instance, a formerly depressed patient was doing very well on the tryptophan that we dispensed. The patient ran out of tryptophan and, instead of obtaining more from us, bought a bottle from a local health food store. The patient was soon depressed again. When he obtained our brand of tryptophan, his depression went into remission in a couple of weeks

Tryptophan, 5-HTP, St. John’s Wort, and SAMe increase the level of brain serotonin (5-hydroxytryptamine or 5-HT) – a crucial neurotransmitter that has been implicated not only in depression, but also in panic attacks, obsessive-compulsive disorder, insomnia, premenstrual syndrome and other conditions.

Serotonin is also found in the gut, lungs and blood platelets. All four natural substances can put you in your doctor’s office or the emergency room – or even the morgue – from a condition known as the serotonin syndrome. The syndrome is diagnosed by presenting symptoms and by a history of exposure to serotonergic compounds, including “dietary supplements.”

Central nervous system manifestations include anxiety, agitation and seizures; bodily symptoms include racing heartbeat, fever and high blood pressure; musculoskeletal symptoms are rigidity and myoclonus (jerking back and forth). Treatment depends on the symptoms. Valium (diazepam) is fundamental for treating anxiety, agitation and musculoskeletal complications. It is imperative to treat the muscular symptoms as soon as possible because they can cause breakup of the muscle tissue, and the breakdown product is lethal to the kidneys.

If Valium is inadequate, patients are hooked up to a respirator and infused with a drug of the curare type, which renders all the skeletal muscles (including the muscles of breathing) flaccid. Fortunately the outlook is good: Even in the most severe cases, the serotonin syndrome usually resolves within 24 hours.

It is a curious medical coincidence that a drug that was marketed as an antihistamine – Periactin (cyproheptadine) – should prove to block serotonin at its receptor sites. Periactin has proven to be very useful for treating the serotonin syndrome.

Having absorbed the worst news about serotonergic drugs and dietary supplements, let us consider the supplements themselves.

Tryptophan and 5-HTP

Tryptophan, an amino acid, is found in virtually all classes of food: milk, eggs, meat, fish, rice, potatoes, sunflower and sesame seeds, soy products, white bread. Tryptophan is converted to serotonin by a two-step process:

The first step, which governs the speed of the reaction, is driven by the enzyme tryptophan hydroxylase. An understanding of serotonin synthesis gave rise to the technique of treating depression by precursor loading.

Starting in the early 1970s, psychiatrists started administering tryptophan to depressed patients. Tryptophan readily crosses the blood-brain barrier, and raises the level of serotonin in the brain according to the above reaction. Tryptophan was investigated in unipolar (major) depression, bipolar depression (the depressive phase of what was then called manic-depressive disorder), and dysthymia (a relatively mild depressive disorder).

Case reports and controlled trials compared tryptophan to placebo, to prescription antidepressants, and to both; tryptophan also was used as an add-on to enhance the effectiveness of prescription antidepressants. Several review articles of the substantial literature drew somewhat conflicting conclusions. The reasons for the discrepancies are first, that tryptophan requires a saturable carrier molecule to transport it across the blood-brain barrier, and second, tryptophan hydroxylase can be compromised by a deficiency of vitamin B6, an excess of cortisol and increased tryptophan breakdown products. Furthermore, almost all of the studies investigated small numbers of patients and did not attain today’s rigorous experimental design – though these early studies look pretty decent when one balances them against fraudulent data of multi-center, drug company-sponsored trials of new drugs. In any event, tryptophan was generally found to be effective in 50 percent to 60 percent of patients – about the same as the response rate to prescription antidepressants. In Europe and Canada, tryptophan has long been regarded as an effective antidepressant, where it is known as Optimax. Based on unpublished observations by me and my colleague, Frank A. Kulik, MD, we found tryptophan comparable to tricyclic antidepressants in mild-to-moderate depression. We did not investigate tryptophan in severely depressed patients.

Jonathan Stewart, MD, a pioneering psychopharmacologist at Columbia and New York State Psychiatric Institute, told Truthout that tryptophan can be safely combined with tricyclic antidepressants (TCAs). However, Mischoulon cautioned Truthout about the danger of the serotonin syndrome if one combines tryptophan with an SSRI or with the powerful antidepressant Effexor.

The recent research of the Mass General Group, buttressed by a generally consistent body of earlier literature, suggests that 5-HTP is an effective alternative to prescription antidepressants, with a faster onset and fewer side effects, making it particularly attractive for the elderly and infirm. Furthermore, 5-HTP is manifestly an effective add-on to TCAs in treatment-refractory patients.

Tryptophan fell into disrepute in the 1990s, when a load of contaminated tryptophan, courtesy of Showa Denko KK, Tokyo, found its way into hundreds of tryptophan products. Thousands of people fell ill from the eosinophilia-myalgia syndrome (EMS), a condition marked by severe muscle pain and a glut of blood corpuscles (eosinophiles). The condition affects the lungs, nerves and skin, and there were a number of fatalities.

It’s worth noting that the EMS did not occur in Canada and other countries where tryptophan is regulated as a drug, not a dietary supplement. The FDA yanked tryptophan from the market in 1989 and eventually allowed it to be sold again (as a dietary supplement) in 2001. Mischoulon told Truthout that today the cause of EMS is known and tryptophan is perfectly safe.

There exists a large body of case reports and comparatively small clinical trials of 5-HTP for treating depression. Mischoulon explained that 5-HTP is preferable to tryptophan because it does not require a carrier molecule to enter the nerve cell, and because it is unaffected by the conditions that can interfere with tryptophan metabolism. The groundbreaking experiments were carried out in the late 1970s and early 1980s by H.M. Van Praag and his colleagues in the Netherlands.The psychiatrists conducted both open and double-blind experiments, and generally obtained a response rate of about 60 percent – the same as TCAs. (SSRIs are considered by most psychopharmacologists to be about 10 percent more efficacious, but their major advantage is not efficacy, but better patient tolerance). Most subsequent studies – and the literature is so redundant that it reminds one of the reinvention of the wheel – come up with the same percentage. Besides Van Praag’s studies, the most interesting early report comes from Japan, where the investigators studied a mixed bag of unipolar and bipolar patients, and found that 68 percent experienced moderate-to-marked improvement.

Early and recent studies generally concur that tryptophan and 5-HTP usually “kick in” within about two weeks, as compared to four weeks or longer for TCAs and SSRIs. Furthermore, the natural substances have fewer and more benign side effects – occasional gastric distress and frequent sleepiness. The latter side effect has been exploited to good effect as an alternative to prescription sleeping medications. Kulik and I tried tryptophan as a sleep aid for ourselves as well as several patients and found it to be effective, but the required dose made the cost prohibitive compared to many prescription sleeping pills.

The older literature contains studies in which 5-HTP was combined with TCAs, monoamine oxidase inhibitors (MAOIs) and, when they came on the market, SSRIs – all without ill effect. A really important development was that these studies led to rigorous clinical trials of 5-HTP/TCA combinations by Mischoulon and his colleagues at Mass General. In a telephone interview, Mischoulon told me that a reasonable starting dose of 5-HTP is 50 mg, though the group has found that patients require a full therapeutic dose – 200 to 300 mg/day in tandem with the TCA – to elicit a therapeutic response. The Mass General group has not studied 5-HTP/SSRI or 5-HTP/MAOI combinations because of concern over the serotonin syndrome, although there are recent, scattered reports of safe 5-HTP/SSRI combinations. Such reports notwithstanding, H.M. Van Praag warned Truthout in a recent e-mail: “Beware of the serotonin syndrome.”

St. John’s Wort

St. John’s Wort has been used for centuries by European physicians to treat mild-to-moderate depression. The active ingredients are derived from the flower of the Hypericum perforatum plant. Among the multiplicity of chemicals contained in the floral extract are two – hypericin and hyperiforin – that inhibit the reuptake of serotonin (as well as norepinephrine, another important neurotransmitter that has been strongly implicated in depression, along with yet other neurotransmitters) Because the preparation of St. John’s Wort is not standardized by the FDA, different brands have different ratios of hypericin to hyperforin. The clinical implications are unclear.

As of 2009, there were some 40 published clinical trials of St. John’s Wort, most of them conducted in Europe. Twenty-six were placebo-controlled and 14 compared St. John’s Wort to a prescription antidepressant. Most of the latter studies found St. John’s Wort comparable to TCAs and SSRIs; furthermore, the placebo response rate was comparable to the prescription antidepressants. These data were subject to several “meta-analyses,” in which all the data are pooled and analyzed statistically.

The meta-analyses did not spell good news for St. John’s Wort. The analysts discovered that the studies conducted in Germany, where St. John’s Wort is prescribed more than anywhere else, gave the substance higher marks than studies from other countries. The analysts therefore suggest that German clinicians included milder degrees of depression than Major Depressive Disorder as defined by the American Psychiatric Association’s Diagnostic and Statistical Manual, 4th Edition, revised. Surprisingly, the analysts did not suggest the alternative explanation, namely that German clinicians are more experienced in the use of St. John’s Wort, and target prospective patients with greater accuracy.

The meta-analyses concurred that St. John’s Wort has fewer side effects than prescription drugs, but has more drug-drug interactions. In the words of Professor Stewart, it is a “dirty drug.” It is true that St. John’s Wort has unwelcome interactions with warfarin (a blood thinner), theophyline (a drug for Chronic Obstructive Pulmonary Disease), digoxin, oral contraceptives, and drugs that are used to treat HIV, cancer chemotherapy and organ transplant. Nevertheless, this might be writing off St. John’s Wort too quickly.

Truthout interviewed Maria A. Sullivan, MD, PhD, a researcher at the same institutions as Stewart, and also a private practitioner in psychopharmacology and psychotherapy. Sullivan told Truthout about an uncontrolled German study of 6000 women under the care of 1000 outpatient gynecologists. The combination of the herb black cohosh plus St. John’s Wort improved physical and mood symptoms of menopause on standard rating scales; in this study, it was the addition of St. John’s Wort that lifted the women’s mood. Sullivan also alerted Truthout to a Swiss review of the literature in 2005; the authors found “no hint” of fetal deformation from either prescription antidepressants or, on the basis of a few available cases, from St. John’s Wort.

Sullivan suggests St. John’s Wort holds some promise for treating unipolar depression in women who are either pregnant or who are entering a symptomatic menopause complicated by mood disorder.

SAMe

SAMe is a natural constituent of living cells, participating in the biosynthesis of neurotransmitters, DNA and RNA, hormones, proteins and phospholipids (constituents of cell membranes). SAMe does so by “feeding” methyl groups (chemical entities consisting of a carbon atom, three hydrogen atoms, and a free electron that renders a methyl group highly reactive). Specifically, SAMe is involved in the production of the neurotransmitters dopamine, norepinephrine, and, yes, serotonin.

Though SAMe has been prescribed by European psychiatrists for decades, it was not until 1998, when it was marketed as a dietary supplement, that the substance caught fire in the United States. Many of the clinical trials of SAMe have been conducted in the last decade. Most of them used a placebo control and some included a prescription antidepressant as a comparator. An enthusiastic review of the literature was published in 2012.

Most of the clinical trials have found SAMe superior to placebo and equal in efficacy to TCAs. Mischoulon told Truthout that the Mass General group has completed a trial of SAMe vs. SSRIs and is currently analyzing the data. In the meantime, the group has completed two studies using SAMe as an add-on for patients who did not evince an adequate response to TCAs and SSRIs, respectively. SAMe proved to be an effective potentiator of both classes of drugs. Sullivan also told Truthout of clinical experience where SAMe was safely combined with MAOIs and SSRIs, respectively. If such experience holds up in clinical practice, SAMe will be an especially safe and effective agent for augmenting prescription antidepressants.

There is one catch, Sullivan noted, that is often overlooked when prescribing SAMe. Folate and vitamin B12 are necessary for the biological production of SAMe. The clinician should ensure that his or her patient takes a B-complex vitamin plus a folate supplement (Sullivan noted that B-complex preparations contain plenty of B12, but little folate.) In the absence of these vitamin co-factors, SAMe is shuttled along a different metabolic pathway, Indeed, Sullivan told Truthout that some psychiatrists who use SAMe find that the addition of folate enhances SAMe’s efficacy.

SAMe goes to work faster than prescription antidepressants – four days to two weeks, depending on the route of administration, compared with up to four to six weeks for TCAs and SSRIs. Side effects are generally mild and benign. Anxiety is a frequent complaint, probably because SAMe promotes the synthesis of two excitatory neurotransmitters, dopamine and norepinephrine. Other side effects include gastrointestinal distress, insomnia, sweating and dizziness, but side effects are seldom severe enough for patients to terminate therapy or drop out of a clinical trial. Like any effective antidepressant – and this includes tryptophan, 5-HTP, and St. John’s Wort – SAMe can cause a switch to mania in bipolar (manic-depressive) patients. One important area where information seems to be lacking is the interaction of SAMe with other medications; so far, no such interactions have surfaced. Another blind spot is SAMe’s safety in pregnancy and breastfeeding.

Conclusions

More and more Americans are using natural substances to treat physical and emotional illnesses. The wisdom of this practice is open to question because natural substances are marketed as dietary supplements and manufactured without adequate regulation by the FDA. In general, the manufacturers of natural substances – all of which are off patent – do not subsidize the large multicenter clinical trials that the FDA demands for prescription drugs. However, considering the cooked data and the payola to academic clinicians to put their names on these doctored studies, that may not be a tragic loss. Furthermore, the FDA has been allowing the outsourcing of these multicenter trials to medically benighted countries where the FDA lacks the manpower to monitor the trials. By contrast, many of the studies of natural substances are notable for their high caliber and their ability to hold up under replication by other investigators.

These considerations apply with particular force to four “natural” antidepressants: tryptophan, 5-HTP, St. John’s Wort and SAMe. The largest body of data can be found for tryptophan and its biochemical brother, 5-HTP. To a considerable degree the same considerations apply to both: faster onset than prescription antidepressants, few side effects or drug-drug interactions, superiority to placebo and possibly, if not probably, equal efficacy to prescription antidepressants, especially when deployed as an add-on to a TCA or, at greater risk of the serotonin syndrome, an SSRI. Sedation is a frequent side effect of both substances, making it well suited for anxious depressions or for depressions complicated by insomnia. The paucity of side effects makes 5-HTP (or tryptophan) especially attractive for the elderly or infirm.

SAMe is an effective antidepressant with few side effects and no known drug-drug interactions. Though it is a serotonergic molecule, there have been no reports of the serotonin syndrome, even when SAMe is combined with a TCA or an SSRI. The rapid onset of action – especially when SAMe is given by injection – and the benign side effect profile make SAMe, like 5-HTP, an appealing choice for the elderly or infirm. However, the frequent reports of anxiety suggest that it might be a good choice for “retarded” depressions.

St. John’s Wort blossomed in the 1990s, but its plethora of drug-drug interactions limits its use. However, it may be a good drug for mild-to-moderate depression in menopausal, pregnant or breastfeeding women.

Though the FDA has not given its imprimatur of approval to any natural substance that I have written about in this article, the National Institutes of Health maintain considerable interest in natural substances for treating many diseases – including depression – under the aegis of the National Center for Complementary and Alternative Medicine. Lately, the NIH commissioned the review in the present article. What is more, the National Library of Medicine abstracts articles on alternative medicine and clinical nutrition on its powerful data base, Pub Med. Because manufacturers of dietary supplements are generally small companies without the means to fund the kinds of trials demanded by the FDA before the agency will approve a natural substance for an indication like depression, it devolves upon other branches of the federal government to fund such trials.