5-htp vs st john’s wort

Are St. John’s Wort and 5-HTP Effective for Depression?

You should discuss these options with your treating physician so that you know and understand the expected outcome.

Q2. I have been on Lexapro for years, and I feel wonderful. I haven’t had an orgasm in quite some time, however. Believe me, I try, and my husband has been wonderful and patient. But should I switch to a different drug?

Your question is all too common with individuals on antidepressants. It also represents one of the challenges of taking any medication: maximizing the treatment benefits while minimizing the side effects.

Lexapro falls into the category of antidepressants called selective serotonin reuptake inhibitors, or SSRIs. This class of drugs has fewer side effects than older antidepressants, such as tricyclics (TCAs) or monoamine oxidase inhibitors (MAOIs). Unfortunately, sexual dysfunction is one of these side effects; it is reportedly the number-one reason that patients decide to discontinue taking SSRIs.

In reassessing your situation, the first step is to talk to your physician. Discuss the possibilities of reducing your current dose of Lexapro to see if it helps with your sexual functioning, trying a different SSRI, or even switching to a serotonin-norepinephrine reuptake inhibitor (SNRI) to see how you respond to it. Most physicians admit that prescribing medications is as much art as science; as such, trial and error often plays a key role in finding the best “fit” for each individual.

Under the guidance of your physician, another option might be to discontinue your antidepressant altogether and try another form of therapy. If you were to consider this, I would urge you to begin individual therapy to help monitor and manage your depression should it return. I would also recommend that you start exercising regularly if you do not already do so. Exercise has been shown to positively influence serotonin and can help ease mild to moderate depression.

I hope that one of these options can help you find a balance between the necessary management of your depression and improved sexual functioning and satisfaction.

Q3. I am taking mirtazapine. I do not like the side effects of this drug and want to stop taking it cold turkey. I feel like the doctors who put me on it have not been monitoring me appropriately, and therefore I’m taking matters into my own hands. I just want to stop this med. Are there any major withdrawal issues or other negative reactions to stopping it that I should be aware of?

— Kari, Connecticut

I’m sorry to hear that you feel that you need to take matters into your own hands — treatment with antidepressants goes best when the person taking the medication and their doctor are able to work as a team. Are you sure that it’s not worth it to try one more time to let your doctors know that you are unhappy with how you are feeling on this medication?

For the record, mirtazapine (Remeron) — unlike some other antidepressant medications — is not known for being difficult to stop and generally does not require tapering off. The side effects that you do not like should disappear within a few days after you take the final dose of medication; anything after that is more likely to be a reflection of your condition than the medication.

Q4. I’m battling the worst case of depression that I’ve ever had, and everyone I’ve talked to says I should be on medication. I’ve heard too many horror stories, though, about people on antidepressants experiencing changes in personality, gaining weight, or having other problems. Is there a safer alternative to antidepressants that I can try before going that route?

Depression itself can be like a horror story, including the effects that it can have on your family and other relationships and your workplace performance, as well as the way that it can negatively affect your physical health. And of course, the risk of suicide is associated with severe depression. Although it sounds as if the decision about whether to take an antidepressant medication is not an easy one for you, for most people the consequences of untreated depression far outweigh the risks of taking an antidepressant.

That said, antidepressants aren’t for everyone, and there are alternatives. For example, counseling and psychotherapy are effective treatments for many depressed people. In fact, controlled studies that directly compared these treatments showed that the chances that depressed people will respond to cognitive-behavioral therapy or interpersonal psychotherapy were comparable to the chances they’ll respond to antidepressants.

One way or the other, it’s important to get some help — perhaps starting by talking with your primary care doctor or a psychotherapist who’s been highly recommended; if you’re still skeptical, your minister or someone you consider wise and experienced in this area may be able to offer advice. If you see your primary care physician and decide not to take an antidepressant, ask him or her to recommend an experienced counselor or therapist who has worked well with other people with depression. (You can also search for psychotherapists in your area on Revolution Health, an Everyday Health partner Web site.)

And there are other steps you can take to help yourself — for example, getting regular aerobic exercise and spending time with others doing things that you used to enjoy.

You can find more information at Everyday Health Depression Center, including details about antidepressants and other treatments. The Web site of the Depression and Bipolar Support Alliance also has useful information on both treatment and self-help.

Q5. I took 62.5mg of Paxil for eight months. It gave me anxiety, for which I had to take Ativan. I then stopped taking Paxil, and I started getting “brain zaps.” They lasted at least a month, and felt like electrical zaps to my brain. Could this be a withdrawal symptom?

— Josephine, New Jersey

Yes, it is very likely that these sensations were part of your body’s response to the discontinuation of Paxil (paroxetine). Although this type of symptom can be frightening, annoying, and uncomfortable, it’s not dangerous and typically disappears faster than you describe, usually in a week or two.

If you take a medication like Paxil again, try to allow four to six weeks for a slower withdrawal to minimize the recurrence of symptoms association with discontinuation.

Q6. What do I do when I run out of Effexor(venlafaxine) 300 mg and have to wait until medication comes via snail mail? I know it was my fault not ordering in time before I ran out. What are my alternatives when this happens?

Of all the antidepressants that are now in wide use, Effexor is one of drugs that is most likely to be associated with an uncomfortable discontinuation syndrome, perhaps particularly so at doses as high as 300 mg per day. You should do whatever you can to keep from running out of medication because, in addition to the uncomfortable discontinuation symptoms, you may be at higher risk of suffering a full relapse.

The simplest answer to your problem is to try to minimize the chance of running out, such as having an automatic reorder with the pharmacy, putting into place a series of prompts or reminders to help you get your orders in on time, or asking a loved one or significant other to help you keep track of this. On occasion, doctors will provide their patients with sample packs of medication (which can be used in a pinch) or will call in a small prescription for enough medication to bridge the gap.

If worse comes to worst, you’d be better off reducing the dose for a few days than you would be if you ran out entirely. For example, you could take 150 mg per day, assuming that is the capsule strength that you are prescribed, or, even better, 225 mg per day if you have the 75 mg capsules.

Q7. I have read a lot about the benefits of taking Saint John’s wort and vitamin D3 for mild depression. What is your opinion? Are there studies that prove they work?

— Ethel, Ohio

I don’t know about vitamin D3, but there is a lot of evidence that Saint John’s wort has antidepressant effects, particularly in less severe depression.

Although it’s not regulated like a medication, the herb Saint John’s wort should be taken seriously if you’re using it as your antidepressant. This means letting your primary care doctor know that you’re taking it (it can interact with some other medications, reducing their effectiveness) and making sure that you take a full therapeutic dose for an adequate duration. In addition, you should not take it in combination with other antidepressants.

Q8. I have been on Cymbalta (duloxetine) for a year now, along with Depakote (divalproex) for mania and Seroquel (quetiapine) for paranoia. Before going on Cymbalta, I was my normal creative self: writing stories, taking pictures, and painting. Then my insurance decided that they were not going to approve the Cymbalta. I had to stop taking it. Now I’m getting suicidal. However, all my creativity is coming back and I feel I can write again. I know I can’t sacrifice my health for my creativity. But can you tell me if there are any anti-depressants that don’t have the effect of killing your artistic abilities?

Cymbalta, which is thought to treat depression through two chemical pathways (norepinephrine and serotonin), is one of the newer antidepressants and, because it is still under patent, it is more expensive than many other antidepressants that are now available as generics.

Although it is possible that only Cymbalta will work for you, it is more likely that another type of antidepressant will be helpful, so you should talk to your doctor about finding another medication. Among the others, venlafaxine is the closest to Cymbalta. It is available in a patent-protected form (once daily Effexor XR) or a generic form that must be taken several times a day.

Of course, the so-called serotonin-selective antidepressants (fluoxetine, sertraline, paroxetine and citalopram are available as generics) or the novel drug bupropion (all forms are available as generics) may work for you, as might a higher dose of Seroquel.

Q9. I have been on clomipramine for the past 15 years. I once tried to come off of it, but I ended up in the hospital. I recently found out that I am pregnant (which was not planned), and my doctor has changed me over to imipramine. However, I read that this drug comes with an increased risk of birth defects. I want to stop taking it immediately. My doctor said it was absolutely safe, so now I feel that I can’t trust him. What should I do?

— Ann, England

The tricyclic antidepressant clomipramine (Anafranil) is probably no more or less risky to your pregnancy than its close cousin imipramine (Tofranil). Imipramine has been has been more widely used, however, so over the past 40 years or so there have been more pregnancies in women on imipramine than on clomipramine.

Both are by far likely to be safe for the developing fetus, though neither is absolutely safe when you’re pregnant (not even aspirin or acetaminophen or higher doses of vitamins are absolutely safe). In the United States, these drugs are classified as having a C rating for pregnancy, which means that there are small and nonspecific risks, but no known or clear-cut risks. On the other hand, the risks of untreated depression for pregnancy are much greater than those of your medications.

Q10. I’m on 200 mg of Zoloft for depression and 100 mg of Seroquel a night. But I keep telling my doctor that I don’t feel anything. I miss the feelings of love and happiness. What should I do?

— Glenda, Virginia

Some people do experience a sense of emotional blunting — not feeling anything, as you so aptly describe it — while taking antidepressants such as Zoloft (sertraline), and either a dose reduction or a change to a different type of antidepressant may be helpful.

Though it may be difficult for you, you should tell your doctor that you’re not happy with particular side effects of your current medication combination and ask him or her to work with you on finding a better treatment regimen. There are many treatments for depression, and you may not have this problem with other antidepressants or combinations.

See more about antidepressants and other treatments for depression.

Learn more in the Everyday Health Depression Center.

An Herbal Power Duo for Depression: 5-HTP and St. John’s Wort

Photo by Arif Riyanto

The complexity of human bodies cannot be understated; the sheer number of chemical reactions that must operate properly every second is almost too much to comprehend. In an attempt to shed light on some of this complex machinery, I want to explore the biochemical importance of one particularly ubiquitous compound: serotonin.

Belonging to the cell class neurotransmitter, serotonin is used to transmit messages between nerve cells. (Think of it almost as the body’s postman, delivering specific messages to specific addresses across the body.) Serotonin is known to affect a whole host of biological processes including mood, anxiety, reward response, eating and sexual behaviour, gastrointestinal motility and sleep. Because of its far-reach, it is important that its presence in the body is regulated. Naturally occurring chemicals derived from plants have given us this ability, as compounds like 5-HTP and herbs like St. John’s Wort have been identified as serotonin powerhouses.

5-Hydroxytryptophan (5-HTP)

Derived from the seeds of the African plant Griffonia simplicifolia, the amino acid 5-HTP is a precursor in the biosynthesis of serotonin. Usually taken in dosages of 50-100 mg/day, it is thought that increasing the amount of 5-HTP in the body results in an increase in serotonin levels, as serotonin is made from 5-HTP.

St. John’s Wort

Found in temperate climates, Hypericum perforatum is a sprawling, leafy herb with black-spotted yellow flowers that has been used for medicinal purposes for millenia. In Ancient Greece, it was common practice for St. John’s Wort (SJW) to be dried and its flowering tops soaked in olive oil, producing a deep red solution. Using this method of extraction, SJW was used to treat wounds, infections, inflammation, melancholy and depression in Ancient Greece throughout the middle ages and into the 18th and 19th centuries.

With technologies available to us today, scientists have been able to understand the biochemistry behind these profound discoveries made thousands of years ago.

Active ingredients: Hypericin and hyperforin

There are many chemical components to SJW that have biochemical implications. Flavonoids found in the flowers and leaves, for example, exhibit antiviral and antioxidant properties that help explain why SJW extracts have been so successful at treating some illnesses. The two chemicals hypericin and hyperforin, however, affect serotonin levels present in the body, offering an explanation for the antidepressant quality of SJW.


In the body, there are a class of enzymes called monoamine oxidase (MAOs) that are involved in the degradation of amine neurotransmitters, like serotonin. When there are excess MAOs present in the body, too much serotonin is degraded, leading to a serotonin deficiency. Starved of serotonin, the body begins to exhibit the symptoms of depression, including malaise, disinterest and sadness.

Hypericin is a naphthodaianthrone compound found in the black dots along the flowers of the SJW plant and is responsible for giving the oil extracts its deep red hue. When hypericin enters the body, it acts as an inhibitor for MAO-A and -B enzymes, which prevents them from breaking down serotonin. With more serotonin freed up, it can more readily produce dopamine and more easily carry out its bodily functions, reducing depression symptoms in most users.


In recent research, it has been found that the phloroglucinol compound, hyperforin, even more so than hypericin, accounts for the therapeutic effects of SJW. Common pharmaceuticals used to treat depression fall in a class called selective serotonin reuptake inhibitors (SSRIs), which effectively block the reabsorption of serotonin by the brain, increasing serotonin levels in the body. Unlike SSRIs, hyperforin inhibits serotonin absorption by elevating intracellular concentrations of specific ions. Because these ions are responsible for regulating serotonin absorption, when the concentration gradient is decreased, the absorption of serotonin is decreased as well. In this way, the levels of serotonin are increased in the body. Because of this process, there is an overall increase in 5-HT receptors as well, offering a potential long-term benefit to using hyperforin as a treatment for depression.

5-HTP and St. John’s Wort: An Herbal Power Duo for Depression

When used together, the increase in 5-HTP in the body induced by the supplement combined with the increased number of receptors available for action caused by SJW can increase serotonin levels dramatically. Because of this, these two supplements are often used in conjunction with each other to treat mild and moderate cases of depression.

Considerations for 5-HTP and St. John’s Wort

Side-effects from using these compounds include diarrhea, dizziness and nausea, as well as the potential to worsen some existing medical conditions like ADHD, obesity or Parkinson’s. Because of their interaction with cytochrome p450, an enzyme that clears drugs and ingested chemicals from the bloodstream, it is not recommended that these supplements be taken alongside other prescription medications. In clinical studies, these side-effects tended only to occur when used long-term. Either way, it is always a good idea to consult your doctor before adding any supplement to your regimen.

(Image: Depressed Boy via )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 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.


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.

What are the Effective, Natural Alternatives to Antidepressants?

The Mood Cure‘s chapter eleven, on alternatives to antidepressants, and its chapter three, on raising serotonin levels, are both essential reading for anyone looking for options to antidepressant drugs. Here is a section from chapter eleven that will introduce you to the serotonin-fueling nutrients.

How Well Do Natural Serotonin Boosters Perform Compared with the SSRIs?

Adapted from The Mood Cure

Millions of 5-HTP, tryptophan, and St. John’s wort takers can attest to the extraordinary mood-enhancing benefits of these natural remedies that I discuss at length in chapter 3. Their experience is supported by scientific research favorably comparing the benefits of these and other natural remedies, including exercise and light therapy, to the benefits of SSRI’s. Here are a few of the scientific findings:

  • 5-HTP can raise serotonin levels 540%, compared to Paxil’s 450% and Prozac’s 150% 250%. It also outperformed the SSRI Luvox as an antidepressant, 68 percent to 62 percent
  • Tryptophan Between 50 and 60 percent of former SSRI takers relapse into depression, OCD, SAD, PMS, insomnia, bulimia, aggression, addiction, anxiety and panic unless adequate tryptophan is made available.
  • St. John’s wort has tested just as effective for depression relief as Prozac and more effective than Zoloft.
  • Exercise alone can raise serotonin levels nicely. A 90-minute walk can increase levels by 100 %. A daily 40-minute walk prevents relapse into depression (after a successful round of SSRI taking) twice as well as does taking Zoloft.
  • Bright light therapy can be a little more effective than Prozac in relieving winter depression (70% vs. 65%)

Speed, Safety, and Effectiveness

In all the studies, the benefits of the natural approaches took effect more quickly than the benefits of the SSRIs and proved much safer. For example, 5-HTP, is associated with 0% sexual dysfunction, while the SSRIs are associated with 50-70% sexual dysfunction. In several studies both St. John’s wort and 5-HTP have had fewer side effects than the placebos!

This kind of research supports our clinic’s experience of 15 years that natural methods can easily meet or exceed the benefits of SSRIs for many, perhaps most, people. Probably because our clients combine 5-HTP, tryptophan, Saint-John’s wort with so many other serotonin-supportive supplements and foods, plus light and exercise plus any needed counseling or medical care, they typically do much better off SSRI’s than on them. And so should you. But, largely because patented pharmaceuticals are so much more lucrative as investments, there’s been much less interest in promoting non-patentable nutrients, despite their safety and effectiveness.

The Antidepressant Nutrients: The Saga Of Tryptophan Therapy

If natural antidepressant brain foods work so well, why aren’t we just using them in the first place, instead of the drugs? It’s an interesting story.

Prior to 1989, although Prozac had been introduced with much fanfare, its pharmaceutical reps couldn’t persuade the country’s M.D.s to use it. Why? Because they were already sold on something else-the amino acid tryptophan from which serotonin is made in the brain. Psychiatrists and other physicians resisted Prozac’s lures, since over-the-counter tryptophan supplements were providing successful antidepressant and sleep aid with virtually no side effects. One of our medical consultants tells the story of how she finally agreed to try a tiny, 10 mg., dose of Prozac. The rep had insisted that a little Prozac could be useful “…just to make the tryptophan work better.” And it did. At higher doses, a small trial of Prozac showed that combining it with tryptophan caused mild adverse reactions in five subjects. Hardly alarming. Especially when we consider the millions who’ve had adverse reactions to SSRIs alone. In fact, a Canadian study found that 20 mg of Prozac combined with 2-4 grams of tryptophan speeded up antidepressant benefits and preserved the deep, or slow-wave, sleep that Prozac alone tends to disrupt. And without any evidence of the excess serotonin syndrome! In the U.K., standard psychiatric practice includes the addition of tryptophan when SSRIs or other antidepressants don’t work well alone.

Into this happy scene, one day in 1989, came a very badly contaminated batch of tryptophan. The guilty Japanese amino acid manufacturer admitted later, in court, that it had knowingly sent it to the United States. It did enough damage (including killing over forty people) to terrify users and physicians all over the United States, prompt the FDA to call for a voluntary ban on sales, and create a huge new market for Prozac, which appeared on the cover of Newsweek magazine the next week. The Japanese company at fault, Showa Denko, never made another batch of tryptophan, but, because of their “error,” the other tryptophan-producing companies, with unblemished records, lost their U.S. markets. More important, millions of Americans and their doctors lost an irreplaceable resource for depression and insomnia relief.

In 1991, Prozac’s U.S. manufacturer, Eli Lilly, published a study exonerating tryptophan and acknowledging its benefits. But few doctors saw it and their fears persisted. Yet in other countries, like the U.K., Canada and, Finland tryptophan sales and research never stopped, and no problems ever recurred. In fact, in these countries, there has been much successful research on the use of tryptophan to treat the really tough “resistant” cases of depression and scientific conferences on tryptophan research are held in Europe on a regular basis.

There is some very good news though. In 1995, tryptophan became available again in the U.S., by prescription from specialized compounding pharmacies. It was finally also made available without prescription in 2000. It is now available in many health stores and on-line!

What About 5-HTP and St. John’s Wort?

Although it has been widely used and highly regarded in Europe for decades, 5-HTP became available in U.S. health food stores and pharmacies in 1997. Most of our clients can’t tell the difference between tryptophan and 5-HTP. Mood-wise, they can both erase all symptoms of low serotonin, from depression and anxiety to insomnia and irritability. The third powerful natural serotonin booster, the herb St. John’s wort, has also been extensively researched and enthusiastically used in Europe for at least 20 years. As I’ve mentioned before, it actually outsells Prozac in Germany, and it’s been selling very strongly in the U.S. as well for many years.”

Supplements for depression: What works, what doesn’t

EPA and DHA, essential to brain function and cardiovascular health, are the main ingredients in fish oil. STORY HIGHLIGHTS

  • Claims made by supplement manufacturers often aren’t backed up by scientific evidence
  • Some supplements may improve your symptoms if you experience mild depression
  • Serious depression generally requires professional help


  • Mental Health
  • Mental Health Treatments

(Health.com) — The multibillion-dollar market for dietary supplements is filled with products that claim to boost mood or improve depression. Some products are even billed as an alternative to prescription antidepressants.

Don’t believe everything you read on a label. Often the claims made by supplement manufacturers aren’t backed up by solid scientific evidence, and the potency and contents of supplements can vary widely. (Some are anything but “natural.”) Serious depression generally requires professional help, whether or not that includes antidepressant medication.

That said, some supplements — such as St. John’s wort and SAMe (pronounced “sammy”) — have been tested fairly extensively and may improve your symptoms if you experience mild depression or related conditions such as seasonal affective disorder.

Below, we break down the evidence (or lack thereof) supporting the most popular supplements used to treat depression and mood.

Folic acid
What it is: The synthetic form of folate, a B vitamin (B9) found in fruits, leafy vegetables, and other foods, that affects the neurotransmitters known as monoamines. Folic acid is sold in stores as a capsule or tablet.

The evidence: Folate deficiency is common among depressed people, especially those who don’t respond to antidepressants. Folic acid has never been tested as a stand-alone treatment for depression, but it has been compared with placebo as an addition to Prozac. In one study, patients who received folic acid responded better than those who received placebo — but only the female patients. Nearly 95 percent of the women who received folic acid responded to the combo treatment, compared to about 60 percent of the women who received the placebo.

Other forms of folate that are more chemically complex have been tested on their own. In one early ’90s study involving elderly depressed patients, a type of folate known as 5-methyltetrahydrofolate (5-MTHF) was found to be roughly as effective as the antidepressant trazodone.

The bottom line: The evidence for the use of folic acid in depression is limited and inconclusive. (The Natural Standard Research Collaboration, an independent research group, has given the evidence a “C” grade.) 5-MTHF and a related form of folate called L-methylfolate — which is available as the “prescription medical food” Deplin — may be helpful as an addition to antidepressants, but you should be wary of nonprescription products that list 5-MTHF, L-methylfolate, or “optimized folate” as the main ingredient.

What it is: Gamma-aminobutyric acid (GABA), a neurotransmitter involved in inhibition and stress relief. GABA is sold as a capsule, pill, or powder.

The evidence: Low GABA levels have been linked to depression and anxiety. Although supplement makers claim on their labels that GABA provides “Positive Mood Support” and “Supports a Calm Mood,” there is no evidence that GABA supplements have an effect on depressive symptoms; no studies have been conducted in humans to date.

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The evidence for its use in anxiety isn’t much stronger. A pair of small studies conducted by a maker of GABA supplements in Japan reported that GABA did have an anti-anxiety effect. In the first study, the researchers found that taking GABA had a relaxing effect on brain waves. In the second, people afraid of heights were asked to walk across a narrow pedestrian bridge after taking GABA or a placebo. The participants who took GABA had lower levels of anxiety (as measured by a stress marker in saliva samples).

The bottom line: A connection between naturally occurring GABA and depression and anxiety has been established. Although prescription medications such as Depakote (an anticonvulsant used to treat bipolar disorder) and benzodiazepines (used to treat anxiety) affect GABA levels, there is very little evidence that commercial GABA supplements impact mood in the same manner.


What it is: An organic, glucose-like compound that facilitates the transmission of serotonin and other neurotransmitters. People ingest about 1 gram of inositol a day from fruits and vegetables, whole grains, meat, and other foods, and it is also sold as a capsule and powder.

The evidence: The brains of people with depression and bipolar disorder have been shown to have below-average levels of inositol, which prompted researchers to investigate whether inositol supplements could help treat depression.

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The initial research was promising. A small study published in 1995 found that taking 12 grams of inositol a day — an amount equivalent to a fistful of the capsules sold in health stores — improved depression symptoms more effectively than placebo. Surprisingly, no one has ever tried to replicate this success. Instead, researchers have studied whether inositol enhances the effects of antidepressants or mood stabilizers — and those studies found no differences between inositol and placebo.

The bottom line: Inositol’s effectiveness has not been proven. Future research may yet reveal uses for the compound, but in the meantime experts caution against using it as a supplement for depression.


What it is: The polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are essential to brain function and cardiovascular health. Combined in roughly equal amounts, EPA and DHA are the main ingredients in fish oil, but they are also sold in formulas that include more of one than the other.

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The evidence: A link between omega-3 consumption and mood is supported by two main sources of evidence: People with depression have been shown to have lower levels of omega-3 fatty acids, and countries that eat a lot of fish per capita (such as Japan) have lower rates of depression.

The research on omega-3 supplements is mixed, however. In several controlled trials, EPA, DHA, or a combination of the two have been shown to improve the symptoms of depression and bipolar disorder better than placebo — but in nearly all of those studies, the omega-3s were added to antidepressant medications or mood stabilizers, so it’s unclear whether omega-3s had an independent effect. And in a recent study published in the Journal of the American Medical Association (JAMA), omega-3s plus Zoloft fared no better than placebo plus Zoloft.

The two studies that have used omega-3s on their own for depression have also generated mixed results. One found that 2 grams a day of DHA for six weeks was no better than placebo; the other — which was conducted in children ages 6 to 12 — found that a combination of EPA and DHA did outperform placebo.

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The bottom line: Although some of the research on omega-3s and mood disorders is encouraging, it remains unclear just how effective omega-3s are, and what formulation and combination of treatments are most beneficial. But omega-3s have few side effects and have cardiovascular and other health benefits, so they may be worth a try (after consulting your doctor first).


What it is: A spice, made from the dried stigmas of crocus plants, that is used in cooking and also in traditional Persian medicine to treat symptoms of depression (among other conditions). Although they can be found online, saffron supplements are not widely available.

The evidence: Little research has been conducted on saffron’s effect on mood. But in a series of small controlled trials conducted in Iran in recent years, the spice has performed surprisingly well in treating mild to moderate depression. Delivered in 30-milligram doses a day, saffron has outperformed placebo and has demonstrated an antidepressant effect comparable to Prozac and imipramine (an older tricyclic antidepressant), at least in the short term.

The bottom line: Although more research is needed, saffron appears to be a promising treatment for milder cases of depression. That said, using the world’s most expensive spice as a dietary supplement seems impractical and pricey.


What it is: S-adenosylmethionine (SAMe), a naturally occurring compound that affects neurotransmitters, including serotonin and dopamine. In the United States, SAMe has been sold over-the-counter as a tablet since 1998.

The evidence: As with most of the substances on this list, lower levels of SAMe have been associated with depression. In studies, SAMe has been shown to be roughly as effective as tricyclic medications (an older generation of prescription antidepressants). But in many of those studies, the SAMe was injected, and it’s unclear whether orally ingested SAMe capsules have the same effect.

A 2002 review of the research on SAMe and depression conducted by the federal Agency for Healthcare Research and Quality concluded that SAMe was more effective than placebo at relieving the symptoms of depression and no better or worse than tricyclics. The report noted that more research on oral forms of the compound and research comparing SAMe to newer antidepressants (such as SSRIs) was needed.

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The bottom line: SAMe has proven to be useful for the treatment of depression, but questions about its overall effectiveness and delivery methods remain. SAMe does have some side effects. Most notably, it can exacerbate mania or hypomania in people with bipolar disorder, so you should not take SAMe without consulting a physician.

St. John’s wort

What it is: A yellow-flowered plant, Hypericum perforatum, that has been used for medical purposes since antiquity and as an alternative treatment for depression for decades. St. John’s wort is available as a capsule, tea, or liquid extract.

The evidence: St. John’s wort is by far the most studied alternative remedy for depression, and for the most part the results have been favorable. In studies involving people with mild to moderate depression, St. John’s wort has consistently outperformed placebo, and it has held its own against prescription antidepressants. It has been shown to be similarly effective — and in a few cases, more effective — than fluoxetine (Prozac), imipramine, and Celexa.

The effectiveness of St. John’s wort in more severe cases of depression has been questioned, however. A highly publicized study of people with “moderately severe” depression published in JAMA in 2002 found that neither St. John’s wort nor sertraline (Zoloft) were significantly more effective than a placebo. Due to this and other trials, it is generally recommended only for milder cases of depression.

The bottom line: For mild — but only mild — cases of depression, its effectiveness may rival that of antidepressants. (The Natural Standard Research Collaboration has given the evidence supporting its use for mild depression an “A”; for severe depression, a “D”.) St. John’s wort generally has few side effects, but it can interact with other drugs, so — as with any supplement — check with your doctor before trying it.


What it is: An amino acid — most famous for being found in Thanksgiving turkey — that helps produce serotonin, the neurotransmitter targeted by drugs such as Prozac (SSRIs). It is sold over-the-counter in capsule form as L-tryptophan and 5-HTP, which represent different stages in the serotonin production process.

The evidence: Studies have shown a connection between tryptophan depletion and depressive symptoms (especially in women), but the evidence for the use of tryptophan supplements is thin. A 2004 review of tryptophan studies that examined more than 100 trials found only two that were of high quality and did not include other supplements. Tryptophan did outperform placebo in those studies, but the studies were small.

There are some concerns about the safety of tryptophan supplements, which have been found to contain impurities and contaminants. In 1990, the U.S. Food and Drug Administration (FDA) temporarily pulled all L-tryptophan products off the market after more than 1,500 people who took L-tryptophan supplements developed a blood disorder called eosinophilia myalgia syndrome. Ultimately, more than two dozen people died.

The bottom line: The overall evidence is inconclusive and safety concerns persist, although the authors of the 2004 review did note that tryptophan could play a role in patients with mild cases of depression who can’t (or don’t want to) take antidepressant drugs.

Copyright Health Magazine 2011

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