Hallucinogens: Overhyped and Underwhelming

I use the term “hallucinogen,” rather than “psychedelic.” That distinction is deliberate. “Psychedelic” is a cultural term, coined in the 1950s and associated with a particular social movement and set of expectations about consciousness, spirituality, and personal transformation. “Hallucinogen,” by contrast, is a clinical description of what these drugs do: They alter perception and consciousness and, at sufficient doses, can produce hallucinations and other profound changes in mental state.Nassir Ghaemi, MD, MPHLanguage matters because expectations matter. When we call these drugs “psychedelics,” we can unconsciously import expectations of extraordinary therapeutic effects. My concern is that the enthusiasm surrounding hallucinogens has outpaced the evidence.Recognizing HypePsychologists Scott Lilienfeld and Donald Meichenbaum described characteristics of therapeutic “hype”, including exaggerated claims of effectiveness, assertions of powerful or transformative effects, excessive reliance on authorities and experts, scientific-sounding jargon, anecdotal evidence, and resistance to criticism.Much of this should sound familiar to anyone who has followed the recent discussion of hallucinogens.I am not arguing that these drugs have no clinical effects. Rather, I want to distinguish symptomatic treatment from disease modification.This distinction is fundamental to medicine. Aspirin can rapidly relieve a headache; corticosteroids can rapidly suppress inflammation. Those are useful effects, but neither necessarily modifies the underlying disease. By contrast, treatments such as lithium in bipolar disorder, disease-modifying therapies in multiple sclerosis, statins for cardiovascular prevention, and effective cancer therapies are judged by what they do to the longer-term course of illness.For psychiatric treatments, I would therefore like to see evidence extending beyond a few days or weeks. A 6-week trial can demonstrate symptomatic efficacy. It cannot demonstrate that a drug changes the long-term course of a psychiatric illness.We do not have convincing evidence that hallucinogens are disease-modifying treatments.Ketamine and EsketamineKetamine is a useful place to begin because its antidepressant effects can be remarkably rapid. Small, randomized trials have demonstrated reductions in depressive symptoms and suicidal ideation. But large trials have not been conducted, so the evidence base is weak, despite massive off-label use and out-of-pocket payment with a market of billions of dollars per year in the US. But rapidity is the opposite of disease modification.The same holds for esketamine, the S-enantiomer of ketamine. Its acute antidepressant effects are present, but the magnitude of benefit in large clinical trials has been much less dramatic than the transformative claims sometimes associated with ketamine. The amount of benefit with esketamine in its large clinical trials (about 4 points better than placebo on depression rating scales in its most effective trial) is marginally better than current standard antidepressants (which tend to be about 2-3 points better than placebo). This is not transformative. Furthermore, esketamine was not better than placebo in a clinically meaningful way in 2 out of 3 acute depression trials (less than a 3-point benefit vs placebo), producing a basically negative result. Yet the FDA still approved it because it was positive in one study, and also in another longer-term trial called a “randomized discontinuation” study.I have discussed the invalidity of this design elsewhere, but basically it is a false design because it is almost always positive: Patients who initially respond to the drug are subsequently selected for continuation or discontinuation, and of course they do worse if you stop the drug to which they responded. Similarly, if you take placebo responders, they do worse if you give them an antidepressant and stop placebo. It’s like studying chocolate cake but excluding anyone who doesn’t like chocolate cake. The results are always positive, unless the study is terribly conducted. None of this proves anything, although the FDA accepts it and it got esketamine over the approval hump. What About Psilocybin?Psilocybin has generated even greater enthusiasm. Some early trials have produced striking results, particularly when psilocybin is administered with substantial psychological support. But there are important factors often ignored. First, head-to-head studies showed that psilocybin is not more effective than a selective serotonin reuptake inhibitor (SSRI), escitalopram. It is similar in efficacy. This finding disproves the belief that these drugs are markedly more effective than our current standard of care. Further, in treatment-resistant depression, psilocybin was shown to be no more effective than nicotinamide, which was given to the active control group. So, psilocybin may be better than nothing (placebo) in standard depression, but not so in resistant depression, and it is not better than a standard SSRI. Notice how these basically negative studies, showing little to no efficacy with psilocybin, make it into the most prominent medical journals — JAMA, The New England Journal of Medicine — with small sample sizes (50-100 patients). With a SSRI, those studies would be rejected out of hand by those journals. This speaks to the cultural fad and bias related to these agents, discussed further below. Even the claim that psilocybin is better than nothing — placebo — is questionable if we look carefully at the placebo blinding problem with hallucinogens. One of the central methodological problems in hallucinogen research is blinding. If a participant receives a substantial psychoactive dose of psilocybin, it is often obvious that the participant has received the active drug. A person receiving an inert placebo generally knows that something very different happened.That can amplify expectancy effects.Recent meta-analytic evidence supports this concern. In a comparison of trials of psilocybin, esketamine, and SSRIs, control-group outcomes were substantially worse in psilocybin trials, suggesting that functional unblinding and expectations may contribute to the apparently large treatment effects observed with psilocybin. When placebo rates from standard antidepressant trials were used, psilocybin and other hallucinogens were only weakly more effective than placebo. Indeed, psilocybin has shown promising results in controlled studies, including a randomized trial in which effects persisted for several weeks. The appropriate conclusion, in my view, is that this is an important research finding — not that we have discovered a transformative treatment for depression.MDMA for Posttraumatic Stress Disorder (PTSD)The same issue arises with a small (n = 104) randomized trial of MDMA for PTSD, conducted by passionate advocates for hallucinogens, which received much media attention.In that study, psychotherapy itself produced substantial improvement. Patients received extensive, supportive interactions in carefully constructed environments that are very different from ordinary clinical practice.Therefore, when an MDMA-plus-therapy group has an impressive response rate, the clinically relevant question is not whether 70% or 80% of patients improved. It is how much better they did than patients receiving the control intervention, which in this case was about 50% with just three sessions of supportive psychotherapy.Clinicians might ask themselves how often they see marked response in PTSD with just three sessions of supportive psychotherapy. This happened in one half of participants in this study given placebo plus psychotherapy, which might suggest a high level of enthusiasm and passion on the part of both researchers and patients. The added benefit of MDMA was just 30 percentage points more than placebo. So, the result is not an 80% massive response, as advocates claim, but really 30 percentage points more than placebo, which is not transformative. That difference is much smaller than the headline response rate, which supports the FDA decision to decline to approve MDMA-assisted therapy for PTSD in 2024 (along with some unethical practices of researchers in the conduct of the study).Reducing Suicidal Ideation Is Not the Same as Preventing Suicide. Another area where I think we need greater precision is suicidality.Esketamine can reduce suicidal ideation in some patients. But suicidal thoughts, suicide attempts, and completed suicide are different clinical outcomes.Most people (about 90%) who experience suicidal thoughts do not attempt suicide, and most people who attempt suicide (about 90%) do not die by suicide. Therefore, improvement on a suicidal-ideation rating scale cannot automatically be interpreted as prevention of suicide.We have unusually important evidence in this area. Lithium clearly decreases completed suicide (a pseudoscientific biased meta-analysis notwithstanding) and prevents overall mortality from any cause, whereas other treatments may reduce suicidal behavior or ideation without demonstrating the same effect on completed suicide.I would like to see hallucinogen research move beyond measuring changes in suicidal thoughts toward adequately powered studies of suicide attempts and mortality.Beyond the HypeMy concern is not that hallucinogens are useless. It is that we have begun to describe them in ways that exceed what the evidence currently demonstrates.They may provide rapid symptomatic relief. That is potentially valuable. But that’s not the main area of need in psychiatry. Rapid and impressive symptomatic effects are the opposite of disease modification.We have dozens of symptomatic drugs, and hallucinogens are not appreciably more effective than those agents, except perhaps for a few days or weeks of more rapid effect. What we don’t have our drugs that treat the underlying disease, and make depression go away for years and decades on end. We don’t have many disease-modifying drugs (lithium being a rare exception that is widely ignored).That is the standard I would apply to hallucinogens as well.Rather than asking whether these drugs are “transformative,” I think we should ask a more clinically useful question: Do they change the course of psychiatric illness better than the treatments we already have?So far, the answer is no.Cultural enthusiasm surrounding hallucinogens is driving the field, not science. Enthusiasm should not substitute for evidence. We should demand the same thing from these agents that we demand from every other serious medical intervention: rigorous trials, meaningful clinical outcomes, adequate controls, long-term follow-up, careful attention to safety, and, most importantly, evidence that they do more than temporarily improve symptoms.That would be genuinely transformative. Nassir Ghaemi, MD, MPH, is founder of Psychiatry Letter, and a lecturer on psychiatry at Harvard Medical School, Cambridge Health Alliance, in Boston. Dr Ghaemi is also an employee at Bristol Myers Squibb. The views presented here are his own and do not necessarily reflect those of his employers.