Staunch Advocates of Therapeutic Psychedelics Need a History Lesson

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Psychedelic supporters are elated.

Psilocybin, the drug produced naturally by "magic mushrooms", has now been decriminalized in almost a dozen cities as well as the state of Oregon, and all this has occurred only the past two years. The number of clinical trials exploring therapeutic uses of psilocybin, MDMA (ecstasy), and LSD has exploded since 2017, and some early studies are posting remarkable results. One randomized controlled trial published in 2020 exploring psilocybin as a treatment for major depressive disorder found that 71% of participants had their symptoms reduced by 50% or more after four weeks. A 2020 systematic review of studies on LSD suggested it has strong potential as a treatment for alcoholism. Another trial published in May looking at MDMA therapy for severe PTSD reported a significant benefit over placebo treatment. "We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation," the researchers wrote.

All of this is great news, but it does warrant some skepticism. Most of the glowing results are from phase I or II trials, which are conducted on smaller numbers of subjects and often lack the rigorous controls seen in later stage phase III trials. There's also concern that psychedelics' apparent benefits in the short-term will not continue long-term. But perhaps the greatest critique of psychedelic research is the lack of genuine placebos. Simply put, people know when they've received a placebo or an actual psychedelic, because the mind-altering effects are so obvious. With this awareness, subjects might be more inclined to perceive benefit from the treatment.

Moreover, as Wayne Hall, an Emeritus Professor at the National Centre for Youth Substance Use Research at the University of Queensland, recently wrote in a review article published to the journal Psychological Medicine, psychedelic research has actually been in this position of excitement before, but it fizzled out. In 1950s, 60s, and 70s, more than 1,000 scientific articles were published on utilizing psychedelics as a psychiatric treatment. What became of all that scholarship?

"A common claim made by advocates of psychedelic drugs is that promising research... was prematurely ended by Richard Nixon’s ‘War on Drugs’," Hall writes. But a reading of the scientific literature and a journey into history dispels this tidy narrative.

"Research on psychedelic drugs in psychiatry was abandoned for a number of reasons that acted in concert," he continued. A huge reason was tighter regulation of the pharmaceutical industry in response to the thalidomide disaster in the early 1960s. Amendments to the Food and Drug Act (FDA) established the rigorous requirements that pharmaceutical drugs face today before being allowed for sale. Thalidomide was prescribed as a medication for pregnancy-related morning sickness without actually being tested on pregnant women. As a result, more than 10,000 children would be born with deformities caused by thalidomide.

The FDA amendments mandated enhanced rigor in clinical trials, which forced a lot of psychedelic research off the table due to shoddy methods. Subsequent randomized, placebo-controlled clinical trials in the 1970s were not as positive as earlier trials from the 1950s and 60s. It was only then that psychedelics and associated research began to fall out of favor in the 70s and through the end of the 20th century, mostly from a cultural shift, as well as from the passage of the Controlled Substances Act, which made most psychedelics schedule I controlled substances.

While Hall notes that the current crop of psychedelic research is "encouraging", he cautions that it could lead to public policy getting too far ahead of the science, as is currently apparent with calls to legalize psychedelics for medical use.

"These policies would enable the medical use of psychedelics to get well ahead of any evidence on their efficacy and safety for common psychiatric indications, as has happened with medical cannabis," he says.

Hall also worries that doctors may start prescribing psychedelics haphazardly, should they receive FDA approval.

"If psilocybin is approved to treat intractable depression patients, it is unlikely that its use will be restricted to approved indications. For example, prescribers will be able to use psilocybin off label as a first-line treatment for depression and as a treatment for anxiety disorders.

These are serious drugs, after all, and clinicians have a responsibility to ensure they're not doing more harm than good.

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