Antidepressants are the most commonly prescribed class of drugs in the United States, prescribed more often than drugs that treat high cholesterol or headaches. However, with the bad press they’ve received in recent years, the slew of side effects they cause, and the increasing popularity of alternative and natural medicine, many are seeking alternatives to traditional antidepressants. Assuredly, many alternative antidepressants don’t work very well; St. John’s wort, a popular herbal remedy, has debatable efficacy, with most American studies showing that it is no more effective than placebo. However, there is important scientific evidence to support the use of two alternative antidepressants, tianeptine and psilocybin; yet these two drugs haven’t been researched in large clinical trials or adopted as conventional treatments in the United States. As we explore the critical research on traditional American antidepressants, as well as the trajectories of these two alternatives, we can begin to understand why these two treatments haven’t been approved for use in this country while other potentially less effective antidepressants remain the gold standard for mood disorders. The system in which drugs are researched, approved for use, and marketed to consumers has determined how, or even whether, we weigh the side effects and benefits of promising drugs. The medical establishment’s traditional definitions that conventional treatments are scientifically proven, while alternative treatments are not, do not hold in all cases.

Serotonin is a hormone naturally produced by the body found in the central nervous system, which includes the brain, and other parts of the body. It has long been thought that a deficiency in serotonin plays a role in depression and anxiety disorders. This idea is a facet of what is known in scientific circles as the monoamine hypothesis, or the neat and simple conjecture that imbalances of monoamines, including neurotransmitters such as serotonin, cause psychiatric disorders and that these disorders can be corrected with medication. The monoamine hypothesis, despite what the bouncy smiley faces on Zoloft commercials might lead you to believe, is contentious in scientific circles since there is no direct evidence for it. In fact, the only evidence for the monoamine hypothesis is that antidepressants, which increase serotonin in the post-synaptic gap, appear to alleviate depression and anxiety. As psychiatrist Daniel Carlat points out, this isn’t particularly good reasoning: “By this same logic, one could argue that the cause of all pain conditions is a deficiency of opiates, since narcotic pain medications activate opiate receptors in the brain. In fact, pain is caused by a multitude of mechanisms depending on which organ is involved.”

However, another major problem with the monoamine hypothesis is that the very assertion that antidepressants alleviate depression and anxiety is itself contentious in the scientific-medical community. Selective serotonin reuptake inhibitors (SSRIs) are one of the newest classes of antidepressant drugs and are generally thought to have the fewest side effects. They are considered the first-line drug treatment for depression in this country. Irving Kirsch, Associate Director of the Program in Placebo Studies at Harvard Medical School, spearheaded a project analyzing all the FDA-registered studies for six SSRIs, not just the 69% or so of studies on SSRIs that end up in academic journals (some of which are inaccurately reported to make a negative or inconclusive result appear positive). Kirsch used the Freedom of Information Act to request the unpublished data and his research, published in 2008, indicated that, as a group, those receiving SSRIs did end up with slightly lower depression scores than those receiving placebos. While statistically significant, the difference was not clinically significant for moderate to severe depression, meaning that the difference was small enough that it was not alleviating the depression to any meaningful or practical extent. For only the “most severely depressed” people did antidepressants cause a clinically significant reduction in depressive symptoms. The study summary reads:

These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective.

It’s worth noting that other researchers have independently reached similar conclusions.¹ Kirsch has also done research which compared active placebos, i.e. side-effect-producing placebos, to antidepressants. The logic here is that in supposedly double-blind studies where both the physician and the patient are kept figuratively in the dark, patients can often guess whether they are being given an antidepressant or a sugar pill based solely on whether or not they experience side effects, effectively removing the blinds from the study. To avoid this, researchers can use active placebos, which cause comparable side effects to the drug under study. When active placebos and antidepressants were compared head-to-head, no difference was found. Kirsch writes, “When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree.” Referring to studies in which antidepressants are compared to sugar pill placebos, Kirsch continues, “Rather than comparing placebo to drug, we have been comparing ‘regular’ placebos to ‘extra-strength’ placebos.”

There are some in the scientific-medical community, such as Peter Kramer, psychiatrist and author of the 1993 bestseller Listening to Prozac, who continue to advocate that antidepressants work, despite the research of Kirsch and others. Nonetheless, even Kramer will agree that there are issues with poor study design and data analysis for many of the clinical trials on antidepressants. (This is in fact why Kramer rejects Kirsch’s analysis.) To quote from a 2008 journal article on the selective publication of clinical trials on SSRI antidepressants, “Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased. Selective publication of clinical trials—and the outcomes within those trials—can lead  to unrealistic estimates of drug effectiveness and alter the apparent risk-benefit ratio.” Indeed, if we cannot trust that the body of research on these drugs is complete and unbiased, how can we do good science?

Selective publication is of course an issue in other areas of medicine, not just psychiatry. But, as a whole, researchers in psychiatry seem particularly prone to doing bad research and selectively publishing results. Even psychiatrists will admit that sample sizes tend to be small and trials tend to be of shorter duration with higher dropout rates than trials in other areas of medicine. In terms of publication, in medicine as a whole 22% of clinical trials are not published, versus the 31% to 40% of clinical trials that are not published on SSRI antidepressants (depending on the source and the time period in question). This means that about a third of the data gathered on these medications are not available to doctors, psychiatrists, or medical consumers. Even more concerning, this unpublished third contains most of the negative study results: 97% of positive studies on SSRIs are published, compared with only 33% of negative studies, meaning that the medical literature is skewed such that SSRIs appear far more effective than they actually are.

Furthermore, much of the relevant research on the long-term safety of antidepressants hasn’t been done, even after drugs have been approved. For SSRI antidepressants, the first of which was approved in 1987, there has been little incentive to research their long-term side effects. In 1994, Italian psychiatrist Giovanni Fava raised concerns that antidepressants might increase the long-term risk of a relapse of depression. Columbia professor and then-President of the Society of Clinical Psychopharmacologists Donald Klein explained in Psychiatric News why no one was interested in answering Fava’s questions: “the industry is not interested, NIMH is not interested, and the FDA is not interested. Nobody is interested. What balks everybody is that it would be expensive and difficult. I think the industry is concerned about the possibility of long-term risks.”

Even basic research on the etiology of mood disorders in psychiatry isn’t particularly rigorous. Psychiatrist Daniel Carlat, who stands by antidepressants as an effective treatment, concedes, “There is no question that among the medical professions, psychiatry is the most scientifically primitive. We have no more than the most rudimentary understanding of the pathophysiology of mental illness and we have resorted to tenuous and ever-shifting theories of how our treatments work.”

Given the increasing number of polemics on psychiatry, like Carlat’s book Unhinged: The Trouble with Psychiatry, it’s no wonder that people are turning to alternatives. Many in the scientific community scoff at those who eschew conventional treatments, seeing such people as lacking critical thinking skills and a basic understanding of science. While it is fascinating to gain insight into how people approach science, this sort of tone assumes a proven, scientifically superior therapy is the standard treatment. In psychiatry, we can make no such assumption. Forum postings indicate that even some of the most conventionally minded are seeking out alternatives to conventional, serotonin-increasing antidepressants.

One alternative drug that people have turned to is tianeptine. Tianeptine, an antidepressant made and marketed by the French company Servier, isn’t available by prescription in the US, the UK, Canada, or Australia. Nonetheless, it has piqued the hopeful interest of many who frequent English-language depression web forums because it works differently from other antidepressants: tianeptine is a serotonin reuptake enhancer, meaning that it decreases serotonin levels, rather than increasing them. The science isn’t entirely clear on whether or not tianeptine lowers serotonin levels permanently or how precisely the drug works, but it is clear that its mechanism of action is significantly different from that of other antidepressants.

Despite its lack of approval for prescription use in the US, tianeptine can be trivially obtained through one of many international online pharmacies at a cost of around $100 per month. It’s possible, but unlikely, that a shipment would be stopped and prevented from entering the country. And while it is technically illegal to import drugs from other countries, the FDA “typically does not object to personal imports of drugs that FDA has not approved under certain circumstances.”

A good deal of evidence in the medical literature indicates that tianeptine performs comparably to traditional antidepressants in head-to-head studies. Tianeptine does seem to have fewer side effects than even SSRIs, which as a whole are thought to have the fewest side effects of all classes of antidepressants. Most notably, tianeptine does not cause the sexual dysfunction that SSRIs cause in 36% to 98% of users, depending on the definition of sexual dysfunction. According to those who have ordered it from overseas and self-medicated with it, tianeptine is not a miracle drug or magic bullet for depression. Some have had good luck with it and found benefit from it over the course of months or years. Some have found it works, but that side effects such as hair loss make its continued use impossible. And some have found it doesn’t work and makes them feel irritable and unhappy.

Online forum users are quick to wonder why tianeptine hasn’t reached American markets if it seems to work as well as conventional antidepressants, apparently has fewer side effects, and has been approved in much of Europe, Latin America, and Southeast Asia. In the United States, the intricacies of international patent law have made it financially difficult for tianeptine to get FDA approval. Tianeptine is decades old, but it wasn’t until the late '80s and '90s that its antidepressant effects were discovered. Tianeptine is now off-patent, meaning that if Servier were to get the drug approved, any company could make and market the drug on their ticket. Given this, it isn’t financially worth it for Servier, or any other company, to sponsor the FDA clinical trials required for drug approval. It’s worth noting that it may be possible for tianeptine to be repatented with a different use in mind, such as irritable bowel syndrome. If this were the case, it would be lucrative for a company to sponsor its FDA application and tianeptine could be prescribed off-label for depression in the United States.

But what’s perhaps most interesting about tianeptine is that it calls into question the use of conventional, serotonin-increasing antidepressants by casting doubt on the idea that depression is caused by low levels of serotonin which can easily be ameliorated with the right drugs. Kirsch, a vocal critic of the monoamine hypothesis, has said regarding tianeptine, “If depression can be  equally affected by drugs that increase serotonin and by drugs that decrease it, it’s hard to imagine how the benefits can be due to their chemical activity.”

Tianeptine, widely researched over more than two decades and approved for use in a number of countries with comparable approval standards to the FDA’s, remains in relative obscurity among American doctors and is unlikely to ever be approved. This raises the question, what other potentially effective antidepressant drugs aren’t getting the attention they deserve?

While tianeptine enhances the reuptake of serotonin, another alternative antidepressant, psilocybin, works by binding to various serotonin receptors.² Psilocybin, while easily synthesized, is usually found in the form of magic mushrooms. The research on psilocybin, while assuredly less definitive than research on tianeptine as there have been few randomized controlled studies on it, appears promising for treating many conditions for which antidepressants are the current standard treatment: depression in cancer patients, end-of-life anxiety, and obsessive-compulsive disorder (OCD).

Most of the research on psilocybin has been funded by non-profits such as the Heffter Research Institute and MAPS; federal grants are rare. The lack of funding from for-profit organizations like the pharmaceutical industry may have to do with the fact that psilocybin, like tianeptine, isn’t easily patentable for psychiatric uses³ and therefore sponsoring the sorts of clinical trials likely to lead to its approval wouldn’t be profitable.

However, the current lack of federal funding is likely more political than anything else. The idea that psychedelics may have potential to treat mental illness certainly isn’t new, but it has become somewhat unpopular due to research in the ‘50s and ‘60s and the resulting counterculture movement. Harvard psychologists Timothy Leary and Richard Alpert performed research on psychedelic drugs—LSD, mescaline, and psilocybin—in the early ‘60s. In 1962, the experiments were shut down, and in 1963 Leary and Alpert were fired due to concerns that they violated ethical research practices, particularly ones that ensured the safety of human subjects. Public perception of Leary and Alpert’s psychedelic research studies appears to be that “the whole thing [was] a disaster” that “devolved into the drug free-for-all of the ’70s.” Likely as a result of such attitudes, there were no human clinical trials involving psilocybin from 1970 to 2006. The first study in 36 years on the therapeutic use of psilocybin was done at the University of Arizona, but the study wasn’t the result of any changes in government policy—the more than 30-year moratorium on psychedelic research appears to be the result of purely political concerns. It seems that researchers weren’t asking for funding and grant agencies weren’t providing it.

Despite the fact that the internet is littered with accounts and studies on the therapeutic benefits of psilocybin, much of the conventional wisdom nowadays still reflects outmoded attitudes that illicit drugs can have no possible therapeutic benefit. Psychiatrists, therapists, doctors, public-health experts, and self-help books tend to claim that taking antidepressants is a positive step for regaining mental health, whereas taking mind-altering illegal drugs can only jeopardize it. While psilocybin “produces its effects by disrupting normal functioning of the serotonin system,” “antidepressants restore adaptability in the human brain.” This raises the questions: If these statements can be made about one drug, why can’t they be made about the other? Is it possible that psilocybin may have therapeutic benefit? Time and extreme caution not to repeat mistakes of the past have allowed researchers to reopen such questions on the therapeutic use of psychedelic drugs. Researchers now have extremely strict guidelines for recruiting and giving psychedelic drugs to human subjects, and their research has yielded a number of interesting and promising results.

It’s unclear to what extent hallucinogenic effects contribute to psilocybin’s apparent effectiveness. Much of the research on depression after cancer treatment, comprised largely of case studies, has indicated that the feelings that people had while on psilocybin positively carried over into the rest of their lives and that the mystical experiences that many had were in and of themselves responsible for the lasting therapeutic effects. However, the research on psilocybin for the treatment of OCD is less clear on what role the hallucinogenic effects of the drug play. In a famous case study, a 34-year-old man took psilocybin in the form of magic mushrooms daily to keep obsessive-compulsive symptoms at bay. He did not experience hallucinogenic effects as he quickly acquired a tolerance to such effects of the drug; this suggests that doses of psilocybin high enough to induce hallucinogenic effects may not be necessary to achieve therapeutic benefits. He discontinued use of psilocybin after four years and his obsessive-compulsive symptoms took two years to fully return.

Regardless of whether the hallucinogenic effects of psilocybin play a role in reducing symptoms, psilocybin’s potential therapeutic benefits may well continue after the drug has left the system. This is not the case with antidepressants for which the likelihood of relapse is greatly increased after drug treatment is discontinued. In 2006, researchers at the University of Arizona gave 9 people diagnosed with moderate to severe OCD multiple hallucinogenic doses of psilocybin over the course of weeks. It was found that obsessive-compulsive symptoms were lowest 4 hours after the administration of the drug, and remained low for at least 24 hours, well after the drug left the system. Two of the patients noticed that their symptoms abated for the week between sessions and one remained in remission for over 6 months after the final dose.

Clearly, we should not evaluate psilocybin and tianeptine by the same (low) standards we’ve used to evaluate and approve traditional, serotonin-increasing antidepressants. To say anything scientifically definitive about psilocybin’s long-term potential to alleviate depression or anxiety would require large, randomized controlled studies. Also, despite the apparent safety of psilocybin, the long-term, consistent use of psilocybin required for lasting therapeutic benefit may have dangerous or unpleasant side-effects that we yet do not fully understand. With regard to tianeptine, Kirsch raises a good question: if, on the one hand, tianeptine appears to work as well as serotonin-increasing antidepressants and, on the other, serotonin-increasing antidepressants may not in fact work in less severe cases, what does that say about the effectiveness of tianeptine for that same group? Perhaps it too is nothing more than a side effect-producing placebo. Furthermore, we should not discount its side effects: hair loss, irritability, and vivid dreams.

Rather, if we are to determine that a treatment indeed contributes to mental health in ways that are as safe and effective as possible, we must demand comprehensive and unbiased studies, whose results are transparently made available to other researchers. Publication bias and failure to do research on long-term outcomes makes this impossible today. Furthermore, making new treatments available requires that we not ignore potentially promising drugs simply because they are off-patent, unpatentable, or illegal. Patent law and the FDA approval process don’t create financial incentives to research promising drugs such as tianeptine or psilocybin. Doing research on human subjects using schedule I drugs, such as psilocybin, is no easy task. There are a number of government hoops to jump through and the available funding, largely from non-profits funded by private donations, is modest. Instead of buying into a false dichotomy between proven, conventional treatments and unproven, alternative treatments, we can see that in psychiatry, where the science is particularly muddy, neither conventional nor alternative antidepressants have been rigorously tested. Alternative treatments aren’t necessarily alternative because they are worse than conventional treatments; they are alternative because there is little incentive to do the scale of research necessary to get them approved as conventional treatments.

¹ In 2002, Arif Khan et al. also requested all the FDA data on SSRIs and found similar results to Kirsch. A 2010 meta-analysis from the Journal of the American Medical Association of only published data on SSRIs also found that all but the most severely depressed fail to get much benefit from SSRIs beyond the placebo effect.

² Psilocybin is converted to psilocin in the body. Psilocin is not known to be a serotonin reuptake inhibitor (searching PubMed for psilocybin or psilocin and reuptake returns no relevant results).

³ Due to the complexity of patent law, I asked patent attorney Stephen Jenei whether or not psilocybin was patentable for psychiatric uses. His reply: “I can't give you a legal opinion here since you are not a client and I haven't researched the question but, as a general principle, you can patent new uses for known compounds. All patents would have to meet the same requirements for patentability such as being new, useful and non-obvious. I suspect that since psilocybin is known for use in treating various psychiatric disorders most uses are not patentable but there is the potential that some uses could meet the new plus non-obvious requirement. A natural material is not patentable in its natural state but a purified form—even from a natural source—could be patentable. Again, it has to meet the new and not obvious standard.”

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