This week, I aim to examine where we currently stand regarding psychedelics, the consciousness-altering substances that have made a significant transition from counterculture to a central subject of clinical investigation. Substances such as psilocybin—found in psychedelic mushrooms—are being researched for numerous health-related uses, including therapies for depression, PTSD, addiction, and even obesity.
In the past decade, scientific curiosity toward these substances has surged. However, many clinical trials involving psychedelics have been limited in scale and have faced numerous difficulties. Additionally, the outcomes of many trials have been disappointing or uncertain.
Two studies released earlier this week illustrate just how challenging it is to research these substances. In my opinion, they also indicate just how exaggerated the excitement surrounding these compounds has become.
Some experts in the field view the hype as not inherently negative. Allow me to clarify.
Both recent studies investigate the efficacy of psilocybin in addressing depression and aim to tackle a significant issue in psychedelic trials: what researchers refer to as “blinding.”
The most effective method to assess a new drug’s efficacy is through a randomized controlled trial. In these studies, some participants receive the actual drug, while others get a placebo. For a valid comparison, the participants shouldn’t know whether they are receiving the drug or the placebo.
This is virtually unattainable with psychedelics. Almost anyone can discern whether they have ingested psilocybin or a placebo. The visual distortions are unmistakable. Nevertheless, the researchers behind the two new studies have endeavored to mitigate this issue.
In one study, a team from Germany administered either a high or low dose of psilocybin, or an “active” placebo—which has its own physiological (but not hallucinogenic) effects—alongside psychotherapy to 144 participants with treatment-resistant depression. In their trial, neither the participants nor the researchers were aware of who received the drug.
Participants who received psilocybin experienced some improvement—but it wasn’t significantly superior to the enhancement seen in those who took the placebo. While those on psilocybin exhibited a greater reduction in their symptoms after six weeks, “the divergence between [the two results] renders the findings inconclusive,” the authors state.
Not the greatest news thus far.
The authors of the second study adopted an alternative method. Balázs Szigeti at UCSF and his associates examined what are termed “open label” studies concerning both psychedelics and conventional antidepressants. In these studies, participants were aware when they received a psychedelic—but also knew when they were on an antidepressant.
The team evaluated 24 such trials and found that … psychedelics proved no more effective than traditional antidepressants. Sad trombone.
“When I initiated the study, I aspired to be a really impressive psychedelic scientist to demonstrate that even considering the blinding issue, psychedelics outperform traditional antidepressants,” Szigeti states. “But regrettably, the data revealed the opposite.”
His study also underscores another concern.
In trials involving standard antidepressant medications, the placebo effect is notably potent. Symptoms of depression are frequently quantified using a scale, and in trials, antidepressants usually reduce symptoms by around 10 points on that scale. Placebos can lessen symptoms by approximately eight points.
When drug regulators examine these results, the conclusion is that the antidepressant medication alleviates symptoms by an extra two points on the scale compared to a placebo.
However, with psychedelics, the difference between the active substance and the placebo is significantly higher. This is partly because individuals receiving the psychedelic drug are aware they are receiving it and anticipate the improvement of their symptoms, according to David Owens, emeritus professor of clinical psychiatry at the University of Edinburgh, UK.
Moreover, it’s also in part due to the response of those who are aware they are not receiving it. It becomes quite apparent when one is on a placebo, Szigeti notes, leading to potential disappointment. The “nocebo” effect has long been identified by scientists as the “evil twin” of the placebo effect—essentially, if you expect to feel worse, you will.
The disillusionment stemming from receiving a placebo takes on a slightly different form, which Szigeti refers to as the “knowcebo effect.” “It resembles a negative psychedelic effect because you have realized that you are consuming the placebo,” he states.
This effect can skew the outcomes of psychedelic drug trials. While a placebo in a conventional antidepressant study alleviates symptoms by eight points, placebos in psychedelic trials only reduce symptoms by four points, according to Szigeti.
Should the active drug similarly relieve symptoms by about 10 points, it creates the impression that the psychedelic is diminishing symptoms by around six points in comparison to a placebo. It “creates the illusion” of a substantial effect, claims Szigeti.
So, why have those previous smaller trials garnered so much attention? Many have appeared in prestigious journals, accompanied by enthusiastic press releases and media coverage, even the inconclusive ones. I’ve often felt that those investigations might not have received such exposure if they were focused on any other substance.
“Yes, nobody would care,” agrees Szigeti.
This interest stems partially from the desperation among mental health professionals for new treatment options, according to Owens. There has been minimal innovation in the past 40 years or so, since the introduction of selective serotonin reuptake inhibitors. “Psychiatry is constrained by outdated theories … and we don’t need another SSRI for depression,” he asserts. Furthermore, psychedelics are inherently intriguing, according to Szigeti. “Psychedelics are captivating,” he remarks. “Culturally, they are thrilling.”
I have often been concerned that psychedelics are being overrated—that people may get the false impression they are silver bullets for mental health conditions. I worry that vulnerable individuals might be harmed by self-experimenting.
Szigeti holds a different perspective. Considering how effective the placebo effect can be, he argues that maybe the hype isn’t entirely detrimental. “The placebo response represents the expectation of a benefit,” he notes. “The higher expectation patients have, the better their outcomes will likely be.” He suggests that downplaying the hype might ultimately decrease the effectiveness of these substances.
“Ultimately, the aim of medicine is to assist patients,” he states. “I believe most [mental health] patients are indifferent to whether their improvement stems from expectancy and placebo effects or from an actual drug effect.”
Regardless, we must understand precisely what these substances are accomplishing. They may aid some individuals with depression. They may not. Research that acknowledges the challenges associated with psychedelic drug trials is crucial.
“These are potentially thrilling times,” asserts Owens. “However, it is vital that we conduct this [research] thoroughly. And this must be done with full awareness.”
This article initially appeared in The Checkup,MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
