Mind-altering substances are (still) falling short in clinical trials

Psychedelics are experiencing a kind of scientific renaissance today. From psilocybin found in magic mushrooms to LSD — substances that once were associated exclusively with the counterculture of the sixties — have landed on the serious desks of scientists and research clinics around the world. The promises are staggering: treatment of depression, post-traumatic stress disorder (PTSD), addictions, and even obesity. However, the problem is that the reality of clinical research turns out to be much more complicated than the enthusiasm of the media and investors.

Over the past few years, we have witnessed a wave of optimism around psychedelics as potential medicines. Startups were raising billions of dollars, media wrote about breakthroughs, and patients waited in queues for clinical trials. Meanwhile, when you look at the actual results from phase III trials — the most important ones before approval by regulatory bodies — the picture becomes much less rosy. Several recent failures in key clinical trials show that the road from laboratory to pharmacy will be much longer than everyone expected.

When hype meets the reality of clinical research

The history of psychedelics in medicine is a history of disappointments mixed with moments of hope. In recent years, we have witnessed a resumption of research into psilocybin and MDMA — substances banned for decades — thanks to support from the Food and Drug Administration (FDA) in the United States. The agency granted both substances the status of "breakthrough therapy", which means accelerated research pathways and greater flexibility in the approval process.

However, accelerated pathways do not mean that substances will automatically reach the market. They must still go through all phases of clinical trials, including costly and time-consuming phase III studies. This is precisely where the problem appears. Several large companies — including Compass Pathways with psilocybin and Lykos Therapeutics with MDMA — encountered significant obstacles in their key studies. The results were weaker than expected, and in some cases, companies failed to achieve their original research goals.

Interestingly, this is not the first failure in this field. A few years ago, similar problems affected ketamine — a substance that for years was considered an anesthetic tool, and then was supposed to become a miraculous cure for depression. Reality turned out to be more complex, and access to these therapies remained limited and expensive.

The placebo effect trap and difficulties in study design

One of the biggest challenges in psychedelic research is the very nature of these substances. Psychedelics have very pronounced subjective effects — the patient knows that they took something because they experience hallucinations, changes in perception, or deep emotional experiences. This makes blind randomization — the classical method of clinical research — practically impossible. How do you blind a patient when their brain is experiencing intense changes in perception?

This difficulty has enormous consequences. The placebo effect in psychiatry is already naturally strong — patients expecting treatment often feel better simply by the fact of participating in a study. Add to this the intense psychedelic experience, and the placebo effect becomes potentially so strong that it is difficult to distinguish the real effect of the substance from the effect of expectations and context. Researchers try to circumvent this problem by using "active placebo" — a substance that also causes altered experiences, but theoretically has no therapeutic properties. The problem is that such a substance is difficult to find, and if we do find it, it may have its own adverse effects.

Additionally, psychedelics require a very specialized therapeutic approach. We cannot simply give a patient a pill and wait. Usually, a psilocybin or MDMA session requires patient preparation, the presence of an experienced therapist during the experience, and intensive post-integration therapy. This means that clinical trials are extremely expensive, and standardization of procedures is difficult — each therapist may work slightly differently, which affects the results.

Why the numbers don't always add up

Let's look at specific data. Studies of psilocybin in treatment-resistant depression showed promising results in phases I and II — sometimes as much as 50-70% of patients showed significant improvement. However, when we moved to phase III with larger patient groups and more rigorous study design, the numbers began to drop. Some studies showed only 30-40% improvement, which is better than placebo, but not as dramatically better as expected.

The problem is that depression is a very heterogeneous condition. Patients may respond to different therapies in completely different ways. Psychedelics may work phenomenally for one patient and be completely ineffective for another. When we mix these patients in a large research sample, the average result may be disappointing, even if for a subgroup of patients the substance really changes lives.

Additionally, we must remember about regression to the mean. Patients with treatment-resistant depression who enter clinical trials on psychedelics are often in critical condition. Their depression is deep, traditional treatment did not work. In such a state, even small changes can seem enormous. However, when we measure effects in a controlled manner, it may turn out that part of the "improvement" is simply natural mood fluctuations or the effect of engagement in the treatment process itself.

Finance and market realities behind the scenes

It is also worth looking at the financial side of the coin. Startups working on psychedelics had to raise enormous sums of money to finance clinical trials — each phase III trial costs tens, if not hundreds of millions of dollars. Investors expected quick returns and breakthrough results. When the results turned out to be less impressive, the stocks of these companies fell, and financing became more difficult.

This created a certain pressure on scientists and companies. I'm not talking here about conscious falsification of data — that would be unethical and illegal — but about an unconscious tendency to interpret data in the most positive light, to select the most successful results for presentation, or to design studies in such a way as to maximize the chances of positive results. This is natural, but problematic.

Moreover, psychedelics are banned substances in most countries. This means that the regulatory process is extremely complicated. The FDA in the US has become more open, but in Europe the situation is more restrictive. In Poland, psychedelics remain completely banned, even for research purposes, which means that Polish scientific institutions cannot participate in these studies. This limits access for Polish patients to potential new therapies and reduces the participation of Polish scientists in global scientific discourse.

Comparison with other psychiatric therapies

To understand the scale of the problem, it is worth comparing psychedelics with other new psychiatric therapies. Ketamine, for example, was an approved anesthetic drug for decades. When its effects on depression began to be studied, the studies were smaller and less formalized, because it was not about approving a new drug, but about new applications of an existing drug. This allowed for faster access to ketamine for patients with depression, but also means that the evidence for its effectiveness is less rigorous than for psychedelics.

On the other hand, psychedelics are entirely new substances from a regulatory point of view. The FDA requires a full package of data from phase I, II, and III trials. This is correct from a safety perspective, but also means that the approval process is long and expensive. Traditional antidepressants, such as SSRIs, were approved at a time when standards were less rigorous. If we subjected them to the same tests today, perhaps they would not pass the approval process.

It is also worth noting that traditional antidepressants have an efficacy rate of about 50-60% — which means that half of patients do not respond to them or respond poorly. If psychedelics achieve similar or slightly higher rates, but with greater side effects and requiring intensive therapy, the question is: do they really represent a breakthrough, or rather an alternative for a selected group of patients?

Side effect: disappointment and missed opportunities

Recent failures in psychedelic research have serious consequences. First, some companies may completely stop working on these substances if they cannot show sufficiently promising results to justify further investment. This means that some potentially valuable research directions may be abandoned.

Second, disappointment can lead to too quick rejection of the entire class of substances. Media like to tell stories about breakthroughs and crashes — if psychedelics are perceived as "another promise that didn't come true," it may discourage investors and scientists from further research. This would be a shame, because even if psychedelics are not a miracle cure for depression, they may prove useful in other conditions or for specific patient subgroups.

Third, patients waiting for new therapies may feel disappointed. For someone with treatment-resistant depression who has heard for years about the potential of psychedelics, learning that research is not going as well as expected can be very frustrating. Some patients may even seek access to these substances outside the medical system, which carries significant risks.

A realistic perspective on the future of psychedelics in medicine

Despite recent failures, we should not completely reject psychedelics as potential therapeutic tools. However, we must be realistic about what to expect from them. Psychedelics may prove useful for specific patients, in specific conditions, in combination with appropriate psychological therapy. They may not be a universal cure for depression, but they may be a valuable tool in a psychiatrist's arsenal for a selected group of patients.

Much suggests that the future of psychedelics in medicine will be more modest than enthusiasts promised. Instead of a revolution, we will have an evolution — a slow, systematic process of integrating these substances into psychiatry, most likely as an addition to traditional therapies, not as a replacement for them. For patients in Poland, the situation is even more complicated, because access to psychedelics even in the context of scientific research remains practically impossible.

The key challenge for the industry will now be to take a more honest and scientific approach to research. Instead of seeking spectacular results, scientists should focus on understanding for whom psychedelics work, under what conditions, and why. This requires less sexy, more detailed research — research that may not attract media attention, but will have real scientific value. Without this, psychedelics may end up as another promise that did not fully come true, instead of becoming a real therapeutic tool.