With psychedelic-assisted psychotherapy on the cusp of broad clinical approval in the United States, there is a new pressing need to understand exactly which patients may be best suited to this novel treatment and which patients are most at risk of adverse reactions.
Vancouver-based company Halugen has recently launched a genetic test that purportedly screens for genetic variants influencing how a person may respond to certain psychedelic drugs. But some researchers are skeptical there is any evidence to suggest genetic screening can predict how a person will response to psychedelics.
Set and setting
Back in the 1950s, before LSD crossed over into mainstream recreational circles, a small but dedicated volume of researchers were investigating the therapeutic applications of these weird new drugs called psychedelics. It quickly became apparent to any psychedelic researcher at the time that LSD can generate a huge variety of responses in any given patient. And this was a problem …
Most therapeutic drugs have a consistent and quantifiable effect. Even more intoxicating drugs such as opiates can be dosed with relative predictability. But psychedelics are fundamentally different. Sometimes one could experience a sublime transcendent trip, while other times they could undergo a traumatic hallucinatory nightmare.
If these drugs were going to become effective therapeutic agents it was crucial to understand what factors determine good and bad trips. Those early researchers couldn’t identify any particular physiological factors that seemed to correlate with the quality of a psychedelic experience. By the end of the 1950s most in the field had determined environmental, or extra-pharmacological factors, were the key elements influencing a person's psychedelic trip.
Even a 1958 World Health Organization report on hallucinogens in psychiatry grappled with this problem. Ultimately the WHO report noted how unique these drugs were in the way external factors so fundamentally influence their effects.
“Perhaps their outstanding characteristic is the fluctuating course of their effects, and the striking dependance of these effects on the precise constellation of environmental factors,” the report stated.
All of this coalesced in what is now regarded as the concept of "set and setting". Popularized by Timothy Leary in the 1960s, this hypothesis posits an individual’s response to a psychedelic drug is primarily shaped by, “set (personality, preparation, expectation, and intention of the person having the experience) and setting (the physical, social, and cultural environment in which the experience takes place).”
Fast forward to 2021, psychedelic-assisted psychotherapy is finally back in the mainstream and on the verge of being rolled out in thousands of clinics across North America. And the same questions that were raised over 60 years ago are again being asked.
So what factors can be used to minimize the risk of a negative psychedelic experience in a therapeutic context?
"Our ability to predict is almost none at all”
In a recent 60 Minutes profile on the modern renaissance of psychedelic science, Anderson Cooper asked pioneering researcher Roland Griffiths if there is any way to predict which patients could have a bad psychedelic experience. Griffiths swiftly responded, “Our ability to predict that is almost none at all.”
Over the last decade hundreds of people have been administered psilocybin as part of clinical trials exploring psychedelic-assisted psychotherapy. A number of safety guidelines have been clearly established to help inform participant selection in trials. And so far, these measures have worked pretty well with nearly no serious adverse events reported in trials testing psychedelic therapies.
Most current screening measures for psychedelic clinical trials look to exclude individuals with either a personal, or familial, history of psychiatric illness (primarily schizophrenia, psychosis or bipolar disorder). Subjects with hypertension can also sometimes be excluded, as well as those on certain kinds of antidepressants.
That's about it. Psychedelics have proven to be extraordinarily safe drugs when administered in controlled conditions. But a few thousand patients dosed in clinical trials is one thing, potentially millions of people dosed once the treatments become widely available is a whole different game.
The psychedelic genetic test
Vancouver-based start-up HaluGen Life Sciences is pursuing a way to use modern genetic technology to help offer clinicians a quantifiable way to evaluate how a patient could respond to psychedelic drugs. Early in 2021 the company released the first iteration of its novel psychedelic genetic test.
For CAD$89 HaluGen offers a personalized psychedelic report incorporating a number of surveys and questionnaires with genetic test tracking five specific gene variants. The report is supplied through, of course, a custom-made smartphone app.
“The HaluGen psychedelic pre-screening platform offers a comprehensive solution to identify inter-individual variations to psychedelic drug effects, highlight short- and long-term genetic risk profiles as well as categorize personal and familial risk,” the company states. “By combining a simple, non-invasive cheek swab DNA sample with comprehensive pre- and post-psychedelic usage questionnaires, HaluGen offers a simple and effective method for users, researchers and clinicians to gain further insights into their psychedelic experience.”
Out of the five gene variants screened in HaluGen’s test, three target one’s propensity for developing mental health disorders including schizophrenia and psychosis, one tracks a gene variant claimed to influence ketamine metabolism, and another looks for a gene variant thought to influence serotonin receptor density.
It is this last genetic target that forms the company’s "Classical Psychedelic Report", predicting a “person’s sensitivity to serotonergic psychedelics such as LSD, DMT and psilocybin.”
So what evidence is there that specific genetic variants in the serotonin-2A receptor gene can influence a person’s sensitivity to psychedelics? Little scientific data is presented on the company’s website and in response to a query from New Atlas HaluGen cited this specific 2019 study.
The study is a small but robust and influential brain imaging study investigating exactly how psilocybin could be exerting its hallucinogenic effects on the brain. Building on prior research suggesting “serotonergic psychedelics exert their psychoactive effects through the serotonin 2A receptor,” the study offers strong evidence that psilocybin does indeed exert its subjective psychedelic effect by stimulating serotonin 2A receptors.
However, the study offers no direct evidence of certain genetic variants influencing subjective psychedelic responses.
Jacob Aday, a researcher from Central Michigan University, recently published a systematic review of the current literature on the factors that can predict a response to psychedelic drugs. In a statement to New Atlas, Aday expresses skepticism that a genetic test such as this could offer any robust prediction of psychedelic responses.
“To date, there has been no peer-reviewed research identifying genes that can be used to predict how individuals will react to psychedelics,” Aday tells New Atlas. “Our team just completed a rigorous systematic search of the psychedelic literature and no such study has been published. Therefore, I am skeptical about claims that genetics can be used to robustly predict psychedelic effects.”
In a White Paper supplied to New Atlas by HaluGen, the company describes individuals with a particular HTR2A gene variant as likely having high serotonin 2A receptor density.
“Therefore, HTR2A TT (AA) carriers with higher 5-HTR2A receptor density, could be more susceptible to stronger hallucinogenic effects through increased receptor activity and may wish to consider a lower starting dose when undergoing potential psychedelic therapy,” states HaluGen.
In direct response to this quote Aday says, “…there are no studies showing this to be the case and it could in fact be the complete opposite—that those with high 5-HT2A receptor density would need a higher dosage to effectively stimulate their high number of receptors.”
Somewhat recalling the older "set and setting" hypothesis, Aday’s recent review article on the subject homed in on certain personality traits that seem to best predict an individual’s acute response to psychedelic drugs. The review article, co-authored with Alan Davis from The Ohio State University and colleagues from Central Michigan University, found absorption, openness, and acceptance to be the three traits most likely to lead to a positive psychedelic experience.
The article found individuals low in those specific traits were more likely to suffer adverse or negative psychedelic experiences. Those in apprehensive, preoccupied or confused states also displayed greater adverse responses to psychedelics.
"There was also tentative evidence that increased experience with psychedelics and increased age were associated with slightly less intense effects with the drugs," notes Aday. "And there weren't any differences according to sex. Men and women responded similarly."
Ultimately it is unclear exactly how robust genetic screening for psychedelic effects is right now. Aday says there isn’t enough direct evidence to show genetics can predict an individual’s reaction to psychedelics. He does suggest, on the other hand, is that there is enough evidence to establish how baseline personality traits can influence a psychedelic experience.
To date, there has been no peer-reviewed research identifying genes that can be used to predict how individuals will react to psychedelics
Just like we have decades of strong research investigating how set and setting influences a psychedelic experience, we have good evidence pointing to specific personality traits that can be associated with beneficial psychedelic effects.
And … we can screen for those traits using conventional pre-existing techniques, including interviewing subjects before dosage sessions and closely tracking family histories of schizophrenia or psychosis. While the HaluGen test includes surveys and questionnaires that may lend themselves towards this approach, a lack of evidence at this stage raises doubts over the veracity of genetic testing.
Speaking recently to Forbes Albert Garcia-Romeu, a researcher from Johns Hopkins who has worked with patients on early psychedelic clinical trials, agrees it may be more useful right now to screen for familial mental health conditions.
“I don't think we know enough yet to use that in a way that would work properly,” says Garcia-Romeu. “You can, I think, get the same type of information just by looking at a person's mental health and family mental health history. And it's probably more relevant to do that than the genetic work.”
In the future there certainly may be stronger evidence of genetic characteristics that influence the acute effects of psychedelic drugs. But right now Aday says we should focus more on what we actually have good evidence for.
"The genes [HaluGen] selected to screen for they chose because they are associated with traits that are thought to be predictive of acute effects,” says Aday. “However, it would be much more efficient to just screen for those traits in the first place rather than for genes that are weakly linked to those traits. They are essentially diluting their predictive power by examining variables that are indirectly linked to psychedelic effects.”
