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Can psychedelic drugs help with depression?

Research into hallucinogens has had something of a renaissance, though the studies so far have been small — and practical issues remain.

This article was originally posted in the Montreal Gazette.

The World Health Organization estimates roughly five per cent of the planet’s adult population lives with depression. Antidepressant medications like tricyclics and SSRIs are effective for many people but treatment failures are not rare — hence the interest in developing new treatments. The past few years have seen a growing interest in hallucinogens like psilocybin, found in “magic mushrooms.”

Those with a certain memory will recall that hallucinogens were once widely researched. In the 1960s researchers founded the Harvard Psilocybin Project, but the series of experiments quickly veered into unethical territory by experimenting on prisoners and with researchers handing out drugs to their graduate students. Its ignominious end, and the similarly ill-advised research on LSD, effectively spiked research into hallucinogens for decades.

However, they now have had something of a renaissance. The past two years have seen four interesting studies exploring the possibility of using psilocybin to treat depression.

In 2021, a Phase-2 study of 59 people in the New England Journal of Medicine compared two doses of psilocybin three weeks apart to the antidepressant escitalopram (Cipralex). The medications did equally well in treating depressive symptoms. But follow-up was only six weeks, and given that it takes four to six weeks for antidepressants to begin to have an effect, it’s possible a longer trial would have seen escitalopram outperform psilocybin.

Later that year, another study of 27 patients tested two doses of psilocybin, one to two weeks apart, along with 11 hours of supportive psychotherapy. Patients receiving the psilocybin/psychotherapy treatment program improved. But they were compared against patients on a wait list; in other words, they were compared against no treatment.

In 2022, a slightly larger trial in the NEJM compared a single dose of 25 mg versus 10 mg versus 1 mg of psilocybin, again coupled with psychological support. The 25 mg but not the 10 mg showed a benefit at three weeks, although the benefit faded by 12 weeks.

Finally, a recent study in the Journal of the American Medical Association tested a 25 mg dose of psilocybin against a placebo in 104 people, with both pre- and post-dose counselling. There was a benefit that persisted up to six weeks after the intervention, with minimal side-effects.

All the studies so far have been small and relatively short. They generally test psilocybin coupled with psychotherapy against a placebo or nothing, not against any active treatment. The interventions are also resource intensive. There are hours of pre- and post-dose counselling, and generally on the day of intervention research subjects spend hours, generally most of the day, in a monitored setting (sometimes in a sensory deprivation environment) to experience the effect of the psilocybin.

Side-effects so far have been rare, but suicidal ideation and self-harm have been reported and worries about side-effects have made researchers cautious. Another inherent problem is that it is difficult to do a proper placebo control in these studies. Unsurprisingly patients can usually tell if they got a hallucinogen or a sugar pill, and that lack of blinding can skew the results.

But taken as a whole, and despite these limitations, there does appear to be a benefit to psilocybin. The question now is not so much whether it works but how it can be used. If it requires hours of preparatory therapy and hours of psychoanalysis afterward, as well as a whole day of clinically monitoring during your “trip,” it may be difficult to apply this therapy broadly. Say what you will about antidepressants, but there are few barriers to their use given their low cost and generally low side-effect profile.

People who remember the blind alley of psychedelic research of decades past may be skeptical. But the evidence, tentative as it is, does seem to be cementing the effectiveness of psychedelics. Whether we can translate the theory into a workable practical therapy remains to be seen.


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