In recent medical news, JAMA Psychiatry published a clinical trial studying the effects of psilocybin (magic mushrooms) on alcohol addiction. It showed that with only two sessions of psilocybin there was a significant reduction in subsequent drinking episodes. It utilized the strongest kind of trial methodology, the randomized "double-blind" placebo controlled design. The message: psilocybin works. Or at least that’s how the major news outlets interpreted it.
In reality, the trial had a critical flaw that was either downplayed or ignored by the media. During the experiment, both the participants and the experimenters became “unblinded”. They were able to figure out whether they were in the psilocybin group or the placebo group. Meaning, the trial was not "double-blind". An issue so problematic with this type of research that it precludes us from making any inferences regarding the effectiveness of psilocybin. Let me explain.
The details of the trial
The trial recruited 95 participants. All of which received 12 psychotherapy sessions, and 2 drug sessions. For the drug sessions, half the participants were randomized to get high-dose psilocybin, and the other half to get placebo. Benadryl was used as the placebo since it causes drowsiness; an attempt to mimic psyilocybin.
At the end of the 32 week trial, the only adverse events reported in the psilocybin group were spikes in blood pressure during the sessions. The main outcome was the percentage of heavy drinking days (PHDD). The result: the psilocybin group drank heavily 9.7% of days, and the placebo group (Benadryl) drank heavily 23.6% of days. A reduction of 13.9% (P value = .01) in the psilocybin group. Taking these results at face value, it would appear that psilocybin can reduce the urge to drink by 13.9%. Which is a modest reduction.
The degree of unblinding in the trial
As mentioned above, the major problem with this trial was “unblinding”. Participants were able to figure out whether they were in the treatment group or the placebo group. Unblinding can manifest itself in any clinical trial, but it is almost inevitable with psychedelics. Psychedelics produce a very powerful experience, difficult, if not impossible to mimic with placebo. This makes it easy for the participants to decipher what they are taking. If they are tripping, they are taking psilocybin; if they are groggy, they are taking Benadryl.
This is exactly what happened in this trial. A survey of the participants revealed that 95% of them accurately guessed which group they were in. In fact, even the experimenters were able to guess which group the participants were in - also around 95% of the time. The authors freely admit this issue and comment on it in the “limitations of the study” section:
“Several limitations of the study warrant discussion. First, Benadryl was ineffective in maintaining the blind after drug administration, so biased expectancies could have influenced results. Control medications such as methylphenidate, niacin, and low-dose psilocybin likewise did not adequately maintain blinding in past psilocybin trials, so this issue remains a challenge for clinical research on psychedelics.” - Bogenschutz et all.
The general effects of unblinding in trials
Research on unblinding in clinical trials estimates that, on average, unblinding makes the active drug appear about twice as effective as it really is. We use this correction factor to correct unblinding in our trial. Simply, we cut the results in half. When this is done, the difference between the psilocybin group and the placebo group is no longer statistically significant. The effect disappears. Psilocybin is no better than placebo at helping alcohol addiction.
The effects of unblinding in psychedelic and addiction trials
In reality, cutting the results of our trial in half is only a conservative estimate. Psychedelic and addiction trials each carry with them additional issues when unblinding occurs. Trials combining the two, like this one, are critically affected.
The problem starts right from the beginning, the recruitment process. Participants are recruited by giving them the option to volunteer for a 'psychedelic trial'. Those with negative or neutral beliefs toward psychedelics probably will not apply, those with 'pro-psychedelic' beliefs probably will. As such, the recruitment process fills the trial with participants that are ‘primed’ to be enthusiastic about psychedelics.
When the trial begins, this psychedelic 'primed' group gets split into two; those who get mushrooms and those who do not. When they figure what group they are in, it significantly changes their attitudes, beliefs, and efforts. Those realizing they are getting mushrooms, will be excited, expecting to get better, and ready to make a special effort for themselves and their experimenters (Hawthorne effect). Conversely, those realizing they are getting placebox will feel let down, without support, ready to fail, and unlikely to make any special effort.
If the condition to be treated was cancer, for instance, the differing attitudes, beliefs and efforts would not particularly matter. You can’t ‘will’ a tumor away. But with addiction, you can ‘will’ yourself into not taking another drink. Indeed, success with addiction is highly effort-dependent.
You can’t ‘will’ a tumor away, but you can ‘will’ yourself into not picking up another drink.
Point being, it’s easy to see that without psychedelics actually working, a group of people 'primed’ for psychedelics will make more of an effort and be more successful at quitting alcohol, if they find out they were in the psychedelics group and not the placebo group. For this reason, adequate blinding is paramount in trials of psychedelics and addiction; far more than other kinds of trials. Yet, blinding was almost completely absent in this trial, bringing serious doubt to the reported results.
A watershed moment
I don’t want to downplay the importance of this trial. Drug addiction is a huge problem worldwide. It causes devastation to patients, family members, and society at large. Currently, there are very few, if any, effective evidence-based treatments. We are desperate for good treatments, and psychedelics may offer a potential solution. This trial represents a watershed moment because it is one of the first attempts to apply the scientific method to psychedelics.
Prior to this, our main source of knowledge was anecdotal evidence. This created the two polarized viewpoints we are familiar with. One viewpoint - psychedelics are dangerous - is based on cherry-picked anecdotes of worst-case scenarios, such as, surfacing of harmful repressed memories, false memories, psychotic events, and accidental death. These anecdotes led to campaigns of propaganda against psychedelics and other drugs (The anti-marijuana movie “Reefer Madness” is the best example of this). And finally, a complete ban on psychedelic use in the 1960’s, making it illegal to even conduct research on them.
The other viewpoint - psychedelics are a panacea - is also based on cherry-picked anecdotes. But, cherry-picked anecdotes of best-case scenarios, such as, miraculous addiction cures, treatment of depression, and spiritual awakenings. Everyone is happy, full of love, for themselves and for others, forever. From sixties hippies like Timothy Leary to modern day biohackers like Tim Ferris. They view psychedelics as powerful agents that somehow only do good, and do no harm.
The problem with anecdotal evidence is that it is highly unreliable, even when not cherry-picked by biased individuals. When we experiment with treatments in uncontrolled settings, we often falsely infer causation and ignore the non-specific effects of treatment. (see my prior email to understand how this happens).
Nice try, but still not good enough
Although this trial is a far better attempt at producing evidence than anecdotes from Joe Rogan and Mike Tyson, the question remains, is it good enough? Is it good science? Unfortunately, the answer is, no. Good science is falsification. Meaning, it is a sincere attempt to try and prove our ideas wrong. This is achieved by designing and executing experiments that truly challenge our ideas. To use a boxing analogy, a prize fighter must choose a worthy opponent if he wants to prove how good he is. He wouldn’t consider a win against a drunken, blind-folded amateur as evidence that he is the best fighter. Nor should we consider an experiment that stacks our idea in favor of winning, as a win.
This is exactly what happened in the psilocybin trial. The recruitment process, the unblinding, and the effort-dependent nature of addiction, stacked the experiment unfairly in favor of the mushroom group. In fact, this trial is such a weak attempt at challenging the psychedelic hypothesis, that a source referencing this trial as “evidence” psychedelics work, should have their understanding of evidence-based medicine, and possibly their motives, questioned.
A source referencing this trial as “evidence” psychedelics work, should have their understanding of medical science, and possibly their motives, questioned.
In the future, we will need to overcome these serious epistemic hurdles. Unfortunately, it will present a big challenge. It’s hard enough to design trials that adequately challenge the psychedelic hypothesis, let alone find the money to fund them, and the ethical review boards to approve them.
Using our past experience with other psychotropics
Given the current absence of trials that can truly challenge the psychedelic hypothesis, it is reasonable for us to approach the problem in a different way. We can try to predict if psychedelics will work by comparing them with similar drugs. Psychedelics fall into a category of drugs called psychotropics. Drugs that alter our mental state by altering neurotransmitter levels in the brain.
Starting with cocaine, and Freud's belief that it was a panacea for mental disorders, we notice a pattern. First, we lionize these drugs, and then, realize they have side effects and do not work as well as we expected. In fact, the famous saying, "If all you have is a hammer, everything looks like a nail", was psychiatrist Abraham Maslow's response to the overuse of antipsychotics when they first were introduced in the 1940's. We also see this pattern with opioids, amphetamines (Adderall), anti-depressants, benzodiazepines (mothers' little helper), and recently, marijuana.
The neuroscience maxim that can be inferred from this experience is that the brain is too complex an organ to be repaired by the indiscriminate drowning of every neuron with a single neurotransmitter. Like fixing a smart phone with a hammer. Given this, it’s reasonable to predict that our experience with psychedelics will follow suit. They will work in some patients, and not in others. They will work in some conditions, and not in others. When they do work, they will work modestly, not dramatically, and like all medicines, natural or not, they will have side effects. Certainly, far from a panacea.
The brain is too complex an organ to be repaired by the indiscriminate drowning of every neuron with a single neurotransmitter.
Be careful
Unfortunately, when the media incorrectly interprets studies like these, they are sending the wrong message to the public. 'Psychedelics work, they are safe, and science says so'. They are giving psychedelics a false halo of science. This, along with the general aphorism fueling much of the supplement and alternative medicine industry, "what's the harm", gives people the green light to go out and try them.
However, one needs to understand that the 'safety' inferred from these trials does not include long term safety, and does not include safety outside of the setting of a clinical trial. Remember, the participants recruited for these trials are highly screened, healthy individuals, that are dosed appropriately, with pharmaceutical grade drugs, in a monitored environment.
Furthermore, these clinical trials are specifically testing 'psychedelic-assisted' psychotherapy. A labor intensive process of multiple psychotherapy sessions, where the therapist applies insights gained from psychedelics, to optimize the psychotherapy. We can't infer that just taking psychedelics alone will help. In fact, it is plausialbe that a psychedelic experience without expert guidance could lead to incorrect interpretations with harmful effects.
Currently, the only way to try psychedelics legally, in a controlled environment, and with expert guidance, is to join an academic trial. These are few and far between, and even if you could find one, sorry, you probably won't meet the selection criteria. If for some reason you are selected, there is a 50% chance you will end up in the placebo group, a 95% chance you will figure out you are in the placebo group, and a 100% chance of critically affecting the results of another psychedelics trial.