Over the last decade, psychedelics have made a comeback in the world of research and academia. As they enter into a new phase of clinical trials, they bear the promise of improving people’s well-being by reducing their depression and anxiety, helping them overcome addiction, or even helping them cope with death and bereavement. This has caused a wave of new publicity, acceptance, and enthusiasm around psychedelic science.

Given that this area of research has been taboo for many decades, there is reason to be optimistic. There is an amount of new data coming in from numerous new clinical trials across various patient groups. As we anticipate the results of these investigations, it is equally important to remain critical, however, in order to ensure that this newly found enthusiasm does not reinstate the myth of the magic bullet that will ultimately cure all our mental ailments.

As research is being conducted in ever more places, some key challenges for the field are also becoming apparent. This piece wants to address those scientific issues as psychedelic science moves forward.

Science in Crisis

The scientific study of psychedelics is not immune from broader crises that are currently ongoing in the scientific realm, like the replication crisis, the lack of Open Science practices and the increasingly privatized funding of research.

The replication crisis comes from research that has shown that many results across different scientific studies cannot be reproduced. This has sometimes led to questionable research practices, such as modifying the results, fabricating data, or selective reporting of false positive findings, by individual actors. Prior hypotheses most often do not yield positive results, and researchers are often faced with unexpected findings.

Publishing these chance findings becomes problematic if the researchers do not clearly demarcate them as such, and conceal the failure of the initial hypothesis and post-hoc explanation of their findings. According to a meta-analysis conducted by Daniela Fanelli (2009), up to 72% of all scientists admit to witnessing questionable research practices concerning the behavior of their colleagues. Misconduct was reported most frequently in the areas of medical and pharmacological research, hence the area of psychedelic research is likely to be implicated. This is something to be acutely aware of.

Positivity bias

Many researchers in the field are understandably psychedelic enthusiasts. This bears a significant risk of selective reporting and motivated reasoning. The promise of psychedelics shown in clinical trials has already led to a nearly one-sided emphasis on the positive effects in the scientific literature, while ignoring the potentially adverse consequences such as mystic ego inflation, neuroticism, or the potential to induce false memories.

Combined with the earlier mentioned broader current problems in science, these over-positive tendencies are incentivized on a community-wide level due to a strong bias towards publishing positive findings, while the negative results are left unpublished in a file drawer.

This problem may be especially pertinent given the relatively high costs and investments involved in conducting psychedelic research, thereby creating a strong incentive for publishing positive results. And what may further limit the researcher’s degree of freedom, is that most studies on psychedelics are sponsored by private foundations with a vested interest.

Open Science practices

Many of these issues can be addressed by adhering to the guidelines of the Open Science Framework. This includes the preregistration of all hypotheses, the study design, data collection methods, and analysis pipelines to increase transparency throughout every step of the scientific process.

Many journals even offer the opportunity of depositing a research question and study design with a registration service or journal before conducting a scientific investigation. Future studies in the domain of psychedelic research would do well by making use of these practices in order to increase the credibility of their findings, and devote extra energy towards replicating some of the existing results via independent research groups.

Placebo-problem

The altered states resulting from psychedelics differ so profoundly from other substances, that there is an ongoing search for a good placebo. In a study of mystical experiences, methylphenidate hydrochloride (Ritalin) was used as a placebo (Griffiths, Richards, Mccann, & Jesse, 2006), in studies of psilocybin to treat anxiety in advanced stage cancer patients, niacin (vitamin B3, which produces flushing) was used as a placebo. And in a study of ayahuasca as treatment for depression researchers used zinc sulfate as a placebo, which may induce nausea and vomiting, playing into one of the commonly expected side effects of the hallucinogenic brew. (de Fontes, 2017).

Even within the classical pharmacological research framework for antidepressants, participants could often guess their test condition – which is known as ‘breaking blind’. This boosts the risk of reporting positively on their perceived mental state due to social desirability.

Psychedelic research is particularly prone to these dangers given the profound changes of subjective experiences, which cannot be easily mimicked with active placebos. This inherent risk will always beg the critical question if the subjective effects of psychedelics are determined by social desirability, prior expectations, or suggestibility of the participants.

Current research has partially addressed the placebo-problem by using different dose ranges. For instance, a microdose, minidose, and full-dose within the same cohort. However, the contrasting method of cognitive science and neuroimaging techniques itself, may be a source of ambiguity when interpreting modern day findings.

Comparing Altered States

On a fundamental level there is still a critical gap between an empiric understanding around altered states of consciousness, their underlying mechanisms and their application within clinical practice. We don’t know yet how the effects of psychedelics compare to other methods that have been used to induce altered states of consciousness, such as meditation, sensory deprivation, or breathing exercises. And we’re not good at measuring them.

The renowned theory of decreased Default Mode Network connectivity in response to psychedelics, may also have been driven by the effects of the placebo condition. Extreme boredom and mind wandering are associated with heightened activity of the Default Mode Network, which may create an exaggerated impression that psychedelics decrease the activity whereas in fact the placebo condition is increasing it.

Only relying on these types of contrasts may create a one-sided impression that Default Mode Network activity and ego-dissolution are primary mechanisms of action in psychedelics, while disregarding subjective accounts of indigenous ayahuasca practices wherein the ego remains intact.

Future research should address these nuances and develop more elaborate or diverse blinding methods, while an even more effective line of research could focus on comparing psychedelics to altered states across the full diversity of conscious experience.

This way, researchers may draw more elaborate conclusions by comparing the commonalities and differences between the neurophenomenology of different induction methods.

Systematic Bias

Like any other field, psychedelic research is not exempt from systematic biases that stem from cultural or socioeconomic differences amongst their respective participants. In the field of psychology, this problem is also known as the W.E.I.R.D bias: the majority of all participants are recruited from Western, Educated, Industrialized, Rich, and Democratic societies.

Given that tribal cultures compared to people from WEIRD populations exhibit significant differences in the most paradigmatic examples of psychology (such as the Müller-Lyer illusion), the subjective experience of psychedelics may be equally contingent on cultural differences.

In the area of clinical research, it is likewise important to represent a diverse sample of society that includes members of marginalized cultures or economic status, or risk inheriting biases that are systemic to society.

And while the contextual effects of set and setting are widely acknowledged within the psychedelic research community, future studies should aim to validate their underlying mechanisms in a cross-cultural manner.

The way forward

Much of the research on psychedelics has focused on extreme cases to make psychedelics more politically acceptable for research, like getting psilocybin approved for a study of terminally ill patients, and treating patients who are suffering from treatment-resistant depression. This has created large-scale clinical samples of patients where the etiology of their mental disorders is not represented in a fine-grained manner.

While it is important to test the efficacy of psychedelics on a large scale, it is equally important to maintain a fine-grained perspective as we investigate these substances in a stratified manner. These incremental advancements may require patience and a healthy dose of criticism.

In the long run, it may not only advance the research of psychedelics but elevate the quality of research beyond the caveats and systematic biases of their scientific domain.