When it comes to natural antidepressants, St. John’s wort has probably attracted the greatest following. Scientifically named Hypericum performatum, St. John’s wort is a common medicinal herb indigenous to much of the US (wort is the Old English word for plant, and flowers from the hypericum herb were traditionally gathered for an annual summertime feast commemorating John the Baptist’s birth—hence, its unusual name^v). For centuries it has been used to treat various psychiatric conditions. More recently, St. John’s wort has established itself as a leading antidepressant in Germany. Even in the US, the last decade has seen an astounding rise in this plant’s popularity. Between 1995 and 1997, annual American sales jumped from $20 million to $200 million.^vi In 2002, St. John’s wort was the fifth most frequently used herbal supplement in the US.^vii

Hypericum appears to be effective in treating mild to moderate depression with studies showing 23-55% better responses than placebo therapy.^viii When compared to standard antidepressants like imipramine (Tofranil) and fluoxetine (Prozac), St. John’s wort typically provides similar benefits in mild to moderate depression—although the prescription medication often shows evidence of slightly greater efficacy.^ix,x When it comes to severe depression, recent studies raise concerns that St. John’s wort is not reliably effective.^xi,xii

Most reported side effects are rare; they include nausea, rash, fatigue, restlessness, and increased likelihood of sunburn.^xiii,xiv However, in a recent trial, headache was the most common side effect (noted in 41% of Hypericum users).^xv

St. John’s wort is safest when no other supplements or drugs are being used. In this context only rarely have dangerous side effects been noted such as mania or extreme high blood pressure (“hypertensive crisis”).^xvi,xvii Nevertheless, few people (as low as 1.1% in some series) tend to discontinue St. John’s wort because of side effects.^xviii

Among the greatest concerns with St. John’s wort is its tendency to interact with a variety of prescription medications. Since it is often self-administered (without medical consultation), it‘s especially important for all users and potential users of Hypericum to be aware of these potential drug interactions.

Potentially devastating drug interactions may occur when St. John’s wort is used with other antidepressant medications. Among the most feared complications is the “serotonin syndrome,” a condition apparently resulting from excessive serotonin levels that over-stimulate the nervous system. Severe physical and mental symptoms associated with this disorder include shivering, muscle spasms, confusion, agitation, sweating, fever, rapid heartbeat, heart rhythm problems, kidney failure, seizures and even coma.^xix,^xx Reports suggest that the use of Hypericum concurrent with other medications (particularly the SSRI antidepressants like Prozac and its relatives) may rarely trigger this devastating complication.^{xxi,xxii,xxiii,xxiv}However, because a single antidepressant prescription can on rare occasions cause serotonin syndrome, it is hard to know how much blame to ascribe to St. John’s wort.^xv

Although s-adenosyl-methionine (SAMe or “Sammy”) has not attracted as large a following as St. John’s wort, it takes first place on my list of natural depression-fighting supplements. SAMe supplementation both increases neurotransmitter levels (norepinephrine, dopamine, and serotonin) and improves brain cell membrane fluidity.^xxvi,xxvii These combined significant changes enhance brain function and result in significant mood and outlook improvements.

Although only available as an over-the-counter agent in the US since the late 1990s, SAMe has been used extensively in Europe for some 30 years.^xxviii It has amassed an impressive list of medical credentials. For example, researchers Delle Chiaie and colleagues coordinated two multicenter evaluations for SAMe involving nearly 600 patients from over 70 hospital and university centers throughout Italy.^xxix Their careful double blinded studies pitted SAMe against a proven tricyclic anti-depressant, imipramine, used at its full standard European dosage of 150 mg daily.

Oral SAMe (800 mg twice daily) proved equally effective as the drug regimen. Over 60% of the depressed patients in each group improved at least moderately over the course of six weeks. However, SAMe emerged as superior in the side-effects category; only 5% of users experienced treatment-related problems compared to 20% with imipramine. Other research confirms SAMe’s favourable side-effect profile.^xxx When problems do occur, they are usually tolerable; these include mild insomnia, lack of appetite, diarrhea or constipation, excessive gas, nausea, dry mouth, sweating, dizziness, and nervousness.^xxxi,xxxii Symptoms can often be minimized by starting at a lower dosage (such as 200 mg twice daily) and gradually increasing to 800 mg twice daily if necessary.^xxxiv In my experience, it often takes only 400 mg a day to get good results. A number of my patients, by using SAMe at this dosage, have experienced dramatic improvement in their depression.

Another noteworthy SAMe benefit is its rapidity of action. Some patients appear to improve within a few days of starting the supplement and most do so within two weeks.^xxxv Compare this to conventional prescription antidepressants that often take 4-6 weeks before registering significant benefits. For this reason, some practitioners start SAMe at the same time as a prescription drug in an attempt to achieve a quicker response.^xxxvi

In summary, I find SAMe to be an excellent, well tolerated agent. However, a few caveats are in order. First, SAMe is not advised for those with a history of mania or bipolar disorder as it can trigger mania and agitation in such individuals.^{xxxvii,xxxviii} Second, s-adenosylmethionine is fairly expensive. Expect to pay about $50.00 a month if you’re taking 400 mg a day. Finally, as with prescription drugs, unless underlying depression causes are identified and addressed, SAMe users who discontinue the supplement with often experience a sudden relapse of their depression.

5-hydroxytryptophan (5-HTP) has long been employed as an alternative antidepressant. Its use is based on sound physiology. Our brains use L-tryptophan to make 5-HTP which can then be converted into the mood-elevating neurotransmitter, serotonin.^xxxix Furthermore, 5-hydroxytryptophan appears to be superior to tryptophan as a serotonin-raising agent. It passes much more readily from the blood stream to the brain and is more efficiently converted into serotonin.^xl

As compelling as this rationale sounds, it’s harder to come up with definitive evidence of 5-HTP’s benefits from actual patient studies. Indeed, Australian researchers Shaw and colleagues tried to do exactly this.^xli,xlii They used a computerized database search to uncover any study ever published where either 5-HTP or tryptophan was used to treat depression. After locating 108 papers, they were disappointed to find only two met the highest standards for quality research. Although both those studies suggested 5-HTP and tryptophan provided benefit, limited evidence left serious questions about how effective these agents really were.

5-HTP is generally well tolerated. Side effects are generally mild, including intestinal upset, nausea, heartburn, excess gas, diarrhea, and loss of appetite.^xliii However, the greatest 5-HTP concerns stem from its close chemical resemblance to L-tryptophan, a compound linked to the chronic debilitating eosinophiliamyalgia syndrome (EMS)—presumably because of impurities introduced at a single Japanese supplement manufacturing lab.^{xliv,xlv,xlvi,xlvii} These concerns have been buttressed by scientific reports suggesting that some 5-HTP preparations may contain contaminants posing EMS-like risks.^{xlviii,xlix,l} In light of such information, I recommend avoiding any chemically synthesized HTP.

However, historically, 5-HTP was not manufactured in labs; instead, it was extracted from an African plant named Griffonia simplicifolia. Many reputable supplement manufacturers still obtain their 5-HTP from this source. I recently reviewed documentation from a major German supplier (Kaden Biochemicals) that extract their 5-HTP from Griffonia (as well as a report from an independent US lab which tested Kaden’s products). Those materials presented a strong case that 5-HTP obtained from natural plan sources is unlikely to have significant toxic implications.^li,lii

Nonetheless, as far as the current state of evidence, I’m more impressed with SAMe than 5-HTP when it comes to efficacy and safety. However, a number of rational practitioners are convinced 5-HTP plays an important role in depression treatment and reports good success using it. For example, noted naturopathic doctors, Murray and Pizzorno, include 5-HTP in their natural approaches. They base their botanical supplement protocols around either St. John’s wort (for individuals under 50 years old) or Ginkgo biloba (for those 50 and over). St. John’s wort, 300 mg of a 0.3% hypericin standardized extract, is used three times daily. Ginkgo biloba (an extract with 24% ginkgo flavonglycosides) is taken at a dosage of 80 mg three times daily. Regardless of age they add 5-HTP in “severe cases.”^liii Murray and Pizzorno recommend starting 5-HTP at a dosage of 50 mg three times per day, and increasing as needed to 100 mg three times daily.^liv Their maximum recommended dosage of 5-HTP is 200 mg thrice daily.^lv

Many alternative medicine practitioners report good effects using Ginkgo bilabo to treat depression. In addition to these clinical reports, preliminary scientific evidence suggests mood elevating effects from Ginkgo—including a recent double-blinded study from Germany.^lvi. This herb may be a particularly wise choice in older individuals who may also reap Ginkgo-induced cognitive benefits.^lvii

Furthermore, Ginkgo may also help treat antidepressant-induced sexual dysfunction; so far, however, studies have come to conflicting conclusions in this regard.^lviii,lix Furthermore, I have noticed my depressed patients who have trouble concentrating or experiencing difficulties making routine decisions seem to improve with this remedy.

Ginkgo is generally well tolerated with only mild, reversible side effects like intestinal upset, headache, dizziness, palpitations, constipation, and rash. However, there are rare documented cases of serious bleeding, including into and around the brain. Because Ginkgo interferes with normal platelet function, avoid this herb (or use it only under careful medical supervision) if you’re taking warfarin (Coumadin), aspirin, or other anti-inflammatory drugs. Drug interactions may also occur with thiazide diurectics (a class of water pills often used for high blood pressure), migraine medications, and certain antidepressants (desyrel and MAO inhibitors).^{lx,lxi,lxii,lxiii} Standard dosing for Ginkgo is 40 to 80 mg three times daily using a preparation standardized to 47% flavonglycosides (for a maximum daily dosage of 240 mg).