Before any clinical trials for psychedelics are begun, there is a standard but critical vetting process. A hopeful participant can get excluded from a trial because of uncontrolled hypertension; a history of additional risk factors such as heart failure; evidence or history of significant medical disorders; symptomatic liver disease; or because they are abusing illegal drugs.
Other exclusion criteria can include any potential participant who is suffering from schizophrenia, a psychotic disorder, or epilepsy.
And there is almost always a vetted participant in a psychedelic clinical trial that just can’t handle the experience—even if they have been given a placebo. For example, two participants, both randomized to the placebo group for the MDMA Phase III clinical trial for PTSD by MAPS, reported three serious adverse events during the trial. One participant in the placebo group reported two adverse events of suicidal behavior during the trial, and another participant in the placebo group reported one event of suicidal ideation that led to self-hospitalization.
Five participants in the placebo group and three participants in the MDMA group reported adverse events of special interest (AESIs) of suicidal ideation, suicidal behavior, or self-harm in the context of suicidal ideation.
Another study by researchers at Johns Hopkins Medicine found that the participants liked the psilocybin experience so much, that they would do it again—called the “motivation to use.” Researchers recorded nine subjective effects related to the motivation to use psilocybin: liking visual effects, positive mood, insight, positive social effects, increased awareness of beauty (both visual and music), awe/amazement, meaningfulness, and mystical experience.
These clinical trial drop-out events, and these motivation to use events, are something that researchers have to factor into psychedelic drug development, as well as the psychedelics industry going forward into mainstream medicine.
Humans appear to generally be OK with psychedelics. There is the ancient history of psychedelics to consider as these clinical trials continue, according to another study discussing hominin evolution. Psychedelics have been used by humans for thousands of years and there is little evidence that they caused any negative consequences. In fact, the opposite is true.
Psychedelics use occurred in an ever-changing, and at times quickly changing, environmental landscape and entailed advancement into a socio-cognitive niche, such as the development of a socially interdependent lifeway based on reasoning, cooperative communication, and social learning. In this context, psychedelics’ effects in enhancing sociality, imagination, eloquence, and suggestibility may have increased adaptability and fitness.
But there are still questions to explore about the human psychedelic experience, and steps to take to provide safety for participants and, in the future, provide safety and efficacy for patients.
“Before making such drugs widely available as medicines, it is important to know why people have regularly taken these drugs for hundreds of years, so we can predict factors that might lead to future problematic nonmedical use,” said Roland Griffiths, the Oliver Lee McCabe III professor in the Neuropsychopharmacology of Consciousness at the Johns Hopkins University School of Medicine, and director of the Johns Hopkins Center for Psychedelic and Consciousness Research.
Among all of the positive psychedelic experiences people have during clinical trials are good trips with a certain downside to them, according to Mike Arnold, director of Silo Wellness, a mushroom company that also stages psychedelic retreats in Jamaica (for psilocybin) and Oregon (for ketamine, but mushrooms will follow as soon as they are legal).
One of the risk factors he reported in an article is that there are people experiencing psychedelics who think they are not only communing with God, but have some sort of special relationship with the divine, like the ancient Gnostics, he said, adding that their grandiose notions can lead them to believe they now possess the secrets of the universe. He concluded that sort of thinking can be dangerous.
So what is going on here? Why do some people embrace all the good in psychedelics, and some drop out of studies because of seemingly random bad experiences? It may be simple genetics.
A study published in the American Chemical Society Chemical Neuroscience journal reported that serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR), which is essential for the actions of classical psychedelic drugs, had sequence variations in its gene that affected the hallucinogenic signaling of four commonly used psychedelic drugs.
It was discovered that there were statistically significant effects on the efficacy and potency of the four therapeutically relevant psychedelics— psilocin, mescaline, 5-MeO-DMT and LSD.
The gene variants that a team of researchers from the Department of Pharmacology at the University of North Carolina (UNC) identified coded for different variants of the serotonin 5-HT2A receptor. This is the key receptor that psychedelics bind to—psilocin, the active metabolite that makes magic mushrooms “magic”, is chemically near-identical to serotonin.
Working in vitro with human cells, the team used various investigative procedures to assess how the different gene forms of the 5-HT2A receptor behaved when binding to the four relevant psychedelics. “Once 5-HT2A is activated by a drug, it has several options on what to do next,” said UNC researcher Gavin Schmitz. “Two procedures were used to test those pathways independently, which means that we can see how much the 5-HT2A prefers one pathway over another and how that balance changes with different drugs over time.”
The team found that, with certain combinations of drug and receptor type, there were significant differences in the drug’s potency—for example, one particular receptor showed a nine-fold increase in potency in response to mescaline.
“Clinical studies have found a wide variety of responses to psychedelic drugs, with some patients seeing huge benefits after treatment and some seeing no benefits at all. Our study suggests that genes matter in determining how sensitive we are to the effects of psychedelics,” said Schmitz. “We chose to start with the 5HT2A receptor due to research showing it to be crucial in mediating the psychoactive effects of psychedelics. As other important receptor targets are identified, I would be greatly interested in exploring them too.”
Could the set of genes we are born with also affect how psychedelic hallucinations alter our reality? “I think this is absolutely possible,” concludes Schmitz. “We are all a little bit different from each other and those differences matter especially when it comes to deeply personal experiences.”
UNC study lead researcher Bryan Roth, who also leads the National Institutes of Health (NIH) Psychotropic Drug Screening Program, said that, based on the study, they expected patients with different genetic variations to react differently to psychedelic-assisted treatments. “We think physicians should consider the genetics of a patient’s serotonin receptors to identify which psychedelic compound is likely to be the most effective treatment in future clinical trials,” Roth said. “This is another piece of the puzzle we must know when deciding to prescribe any therapeutic with such dramatic effect aside from the therapeutic effect. Further research will help us continue to find the best ways to help individual patients.”