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How the FDA Confuses Skepticism for Science—And Obstructs Innovation
By Gregory Ferenstein
There’s a wild irony underlying the Food and Drug Administration’s impending approval of the popular psychedelic club drug, MDMA, to treat post-traumatic stress disorder. More well-known as “ecstasy,” multiple clinical trials find that MDMA-assisted psychotherapy is two to three times more effective than any other known treatment.
The stories behind the statistics back up the extraordinary findings. For instance, Jonathan Lubecky, a formerly suicidal veteran, was virtually cured of his crippling PTSD after a single, six-hour therapy session in which he also took a potent psychedelic.
The results of the clinical trials are so unprecedented that the FDA granted MDMA a rare “breakthrough” designation, which gives highly effective drugs an accelerated pathway so that doctors can prescribe them. Yet, MDMA took a rather unorthodox route to medicalization: Had people not experimented with ecstasy illegally, we may never have discovered how a molecule originally intended to stop bleeding was actually one of the most effective strategies for treatment-resistant mental health illnesses.
As is often true of unexpected-use cases, scientists and early trial participants will report unusual side effects. The early pioneers of many psychedelics, including MDMA and LSD, began to experiment liberally and, during the decades after the drugs were made illegal, discovered life-saving strategies in the underground. To put it another way, it is currently the plan to allow thousands (potentially millions) of critically ill patients to access a treatment that has developed in blatantly illegal ways and for illnesses that no one could have predicted.
The critical lesson here is that the heart of science is unexpected discovery. Science is a wild exploration of the unknown, and many of its most important findings are those we cannot predict. And yet, this very truth goes completely unrecognized by the legal guardrails the FDA places on drug approval.
A pillar of the FDA’s approval process is the idea that scientists must definitively prove a valid use for a drug before innovators are allowed to sell it on the open market. Congress granted the FDA authority in the 1960s to regulate drugs not just for safety but also to stem the proliferation of “shame marketing.”
Writing on the history of clinical trial development, the former head of the Office of Drug Evaluation, Robert Temple, lamented the early days when there were no objective standards on drug outcomes. “You would be horrified [at the clinical trial data] submitted to the agency. There was often no protocol at all. There was almost never a statistical plan.”
Over the years, this authority morphed into a sophisticated set of trial requirements, often repeated, randomized, placebo-controlled designs, which, on average, can cost nearly $1 billion and a decade to complete. To be sure, this is very different from how credible, licensed physicians make decisions.
Doctors often prescribe drugs “off-label,” or for reasons not formally approved by the FDA. Once a drug is allowed for one use case, doctors are given broad discretionary authority to use it for other illnesses. For instance, the use of beta blockers for heart disease was widely prescribed off-label before it was formally recognized. (This class of drugs was originally developed to treat high blood pressure.)
Doctors learn about off-label uses through a variety of data sources, including presentations at conferences, talking to their colleagues over the phone, case reports and mining electronic medical records. Such observational data may not convince skeptics. If a doctor shares a presentation on a new technique at a conference, only a fraction of the audience may find it convincing enough to recommend it to their patients.
Repeated, randomized, placebo-controlled clinical trials are considered the “gold standard” because they control for nearly every possible reason why someone would doubt the efficacy of a treatment. After all, maybe a patient just got lucky, or maybe they reported better outcomes because they wanted to feel better (i.e. the placebo effect). That is, the FDA’s minimum bar for approval is to use the most stringent academic standard of hypothesis testing.
Unfortunately, this approach confuses skepticism with science—a confusion that has obstructed countless innovations. Psilocybin, the active ingredient in ‘magic mushrooms,’ illustrates just how confining these standards are for medical innovators. As with MDMA, psilocybin in conjunction with therapy is emerging as one of the most effective treatments for a wide variety of mental health illnesses, from alcoholism to depression.
The drug is commercially available in the Netherlands, Mexico and Jamaica. During my early days studying the emerging psychedelics industry, I flew to the Netherlands to attend a psychedelic mushroom retreat; countless tourists go every year to get world-class therapy unavailable in the United States. The Dutch system is so unregulated that hallucinogens are sold in the equivalent of 7-Eleven’s, where tourists can hop off a train, buy a potent drug, and wander the streets of a city completely unsupervised.
Humans have been consuming mushrooms for thousands (potentially millions) of years. They have virtually no known lethal dosage and are widely considered one of the safest drugs. Doctors, scientists and consumers use them all over the world for both recreation and life-saving medical treatment.
But these facts don’t matter, according to FDA scientific standards. To conduct clinical trials, nonprofit researchers had to raise tens of millions of dollars for randomized trials. How could such an inexpensive therapy cost so much money? For starters, the FDA is allergic to using botanicals, meaning researchers aren’t allowed to use mushrooms. That’s because it’s hard to measure the amount of psilocybin in a given batch of mushrooms.
For actual therapists, this natural variation doesn’t matter much; it’s quite common in therapy sessions for patients to start out with about half of what they’ll eventually need, then see how they feel and take more until they're satisfied with the dose.
But, it could be argued that each patient got slightly different amounts of the active drug, and the FDA requires exacting measurement. So, it has forced those seeking clinical trials to create a synthetic version of pure psilocybin, which is orders of magnitude more expensive to grow. (The requirement is so bizarre that a legislator has introduced a bill in Pennsylvania that would allow researchers to use alternatives to synthetic psilocybin.)
There are also some skeptics in the medical community who worry that psychedelic-assisted therapy is largely a placebo; perhaps, it is simply positive expectation and willpower that cures people of crippling diseases. But this flies in the face of the fact that many certified therapists have witnessed life-changing behavior in patients, many of whom desperately tried many alternatives before turning to psychedelics.
And, even after there have been multiple placebo-controlled trials on psilocybin, the FDA still requires repeated confirmation on larger populations, just in case all of these positive results were random luck.
There will always be skeptics of an emerging treatment. Debate is a healthy part of scientific discovery. But the FDA’s approach is to only approve drugs after skeptics have been satisfied. As a result, many scientists, physicians and activists are fed up with delays. In the middle of a mental health crisis, clinical trials have been taking so long that the voters of Oregon last year approved a ballot measure to legalize psilocybin therapy before FDA approval. Similar laws are advancing in California and New York.
Oregon, and other states that will likely approve psychedelic therapy soon, will provide vast treasure troves of scientific data—and hence opportunities for discovery. Indeed, researchers will have unprecedented access to all sorts of new ways that medical professions use these substances to treat mental illness.
To be sure, there are other options for the FDA. For instance, the agency could choose to prioritize science and adopt a system like Japan’s, where a treatment under investigation is allowed provisional commercialization once it is known to be safe but not necessarily effective for any particular use.
As Frank Herbert, the legendary science fiction writer and author of “Dune,” once wrote: “Highly organized research is guaranteed to produce nothing new.”
Science needs room for debate and experimentation outside the bounds of what we expect to find. But that would mean the FDA would allow doctors to prescribe treatments despite the existence of skeptics—and so far, it shows no signs of change.