In 1966, U.S. senators organized hearings where doctors and government officials voiced their concerns about psychedelic use. William Frosch, a professor of psychiatry at New York University and attending doctor at Bellevue Hospital, said that LSD had “serious adverse effects with prolonged psychotic reactions even on normally stable persons.”
The president of the New York State Council on Drug Addiction, Donald Louria (who infamously said, “Gram for gram … LSD is far more dangerous than heroin”), brought up the psychedelic side effects seen at Bellevue, where “in addition to vivid, colorful hallucinations, these include many bizarre effects such as terror. … Some of the patients had developed states of anxiety so powerful that the report called them ‘panic reactions.’”
These testimonies took place in the context of the war on drugs, as pointed arguments in favor of prohibition. Four years later, in 1970, Richard Nixon introduced the Controlled Substances Act, which federally banned psychedelics, with some exceptions.
The idea of the "bad trip" has persisted culturally, even as psychedelics in the past two decades have established footholds in scientific research, academic journals, and for-profit companies. Many states have proposed or passed decriminalization laws on psychedelics, FDA approval for psilocybin for depression is inching closer, and psychedelic companies that have gone public have been valued in the billions.
Psychedelics have entered a stage of mainstreaming where those who might never have considered taking psychedelics are now curious, but could be cautious or risk-averse. They want to know, beforehand, what their experience will be like: Will it be safe, will they have a “bad trip"?
In June, I got an email pitch from a senior adviser at Bullseye Corporate, a communications firm, about the first psychedelic gene test, one that was created to meet this need. “Want to know your reaction to psychedelics before you take them? You can now—with the first ever Psychedelic Genetics Test kit… the test kit can help people considering psychedelics assisted therapy gain personalized insights into how their genetic profile may impact treatment and outcomes. In other words, it can basically predict a 'bad trip' as genetics plays a strong role in how psychedelics are received and metabolized by each user.”
Sold by HaluGen Life Sciences, a subsidiary of Entheon Biomedical Corp, the Psychedelic Genetic Test claims to help a person “understand your sensitivity to classical psychedelics,” like LSD and psilocybin, “discover your ketamine response based on genetics and format,” and “explore your short- and long-term risk factors associated with psychedelics use," according to their website.
HaluGen provided Motherboard with four test kits for $1 each plus shipping; they normally cost $89. I sent in my DNA sample from a cheek swab, as did my colleague, Tim Marchman. As a measure of quality control, Motherboard also sent in DNA samples from a pair of twins to see if their results would be the same. They were. This was a small test of only two people with identical DNA, but in this instance, HaluGen produced consistent results.
The problem with HaluGen’s test is not their DNA processing skills but what's implied from the genes they hone in on—including two genes that HaluGen claims to influence serious mental illness risk that have been scientifically discredited according to published literature. The conclusions drawn from the other genes are also overstated and misinterpreted, according to scientists Motherboard consulted who study those genes. In response to these statements, a spokesperson for Entheon told Motherboard that like other direct-to-consumer tests, the Psychedelic Genetics Test is designed to be educational, not diagnostic, and that a disclaimer on HaluGen's website clearly states that.
This may be the first psychedelics genetic test kit, but it almost certainly won’t be the last. This test exemplifies the kinds of tactics future products will likely utilize: marketing certainty based on biology (while paired with hedging disclaimers), and using scientific jargon and, sometimes, prominent research findings to justify their interpretations. Actually, though, the amount of practical insight or knowledge they can provide from a handful of genes is woefully small.
As such, tests like these create a number of risk factors all on their own. They could lead people to make decisions about drug dosage based on a simplistic reading of single gene variations, which don’t accurately predict outcomes. If a genetic test informs someone that their gene variations are "normal," it could lead them to focus less on their intentions and setting—known to be important for the experience—before a psychedelic trip. Finally, telling people based on outdated or misrepresented science that they are at risk for psychosis or schizophrenia—as I was—is both distressing and ethically fraught.
The test looks at five genes: one that is claimed to impact how fast or slow you metabolize ketamine, one that influences the density of serotonin receptors that you have, and three gene variants that HaluGen claims influence mental health risk—with the implication that those with higher risk based on those variants should be cautious of psychedelics.
In a press release, Entheon CEO Timothy Ko said, “For patients considering psychedelic-assisted psychotherapy, and providers alike, this product gives greater insight into how an individual's genetic profile could impact treatment, ultimately improving outcomes.”
The boilerplate pitch for the test I got in my inbox—that the test could "basically predict a 'bad trip'"—is predicated on a gene for a specific kind of serotonin receptor, 5HTR2A. The test said that a gene variation that led to a higher density of these receptors would make a person more sensitive to psychedelics. The suggestion here is that a higher density of these receptors is correlated with the quality of the trip that they're going to have.
Charles Nichols, a professor of pharmacology at LSU School of Medicine who researches serotonin receptors, put it plainly: "This really means nothing,” Nichols said. “The premise of trying to link one polymorphism with a behavioral predictor is just, I would say, preposterous.”
There are many other gene variations that could influence serotonin receptors outside of density, Nichols said. “It may not be the amount of serotonin receptors that you have to look at; it might be the function of the serotonin receptor: How is it signaling? How is it desensitizing?”
It doesn't mean that these receptors are unimportant. HaluGen cites 55 references on its website, and Nichols pointed out one to me: a 2019 paper from the journal Nature that showed that psychedelic effects emerge through serotonin 2A receptors. They reported that the intensity of psychedelic effects, as reported by their participants, was related to the receptor occupancy—meaning how many receptors were stimulated by psilocybin’s active metabolite, psilocin.
Nichols said this was significant research; the study showed without a doubt that these specific serotonin receptors are relevant to psychedelic intensity. But the exact relationship between gene variations, receptor density, and receptor occupancy still needs more research.
(Entheon wrote that "there is growing evidence that the HTR2A gene that governs receptor density has an influence on psychedelic sensitivity. The science is continuously improving as more studies are conducted and we’ll review and monitor new evidence as it becomes available.")
But the study found that the intensity of psilocybin experience is dependent not only upon the number of receptors that a person has in the brain but also on the occupancy of those receptors, Nichols said. "If you think about it, it could negate [HaluGen's] whole premise,” he said. “They’re trying to tell you that the number of receptors that somebody has correlates with their subjective experience. Whereas that paper is saying it’s not the number of receptors that somebody has but it's the fraction of those receptors that are occupied by the drug that govern the subjective intensity of the experience.”
Jacob Aday, an experimental psychologist at University of California San Francisco, agreed that the claim that higher density equals higher intensity doesn’t have any solid research supporting it. “In fact, it could be the complete opposite,” Aday said. “Those with a high density of serotonin receptors might need a higher dose to effectively stimulate all of the extra receptors. So they’re making an assumption that really hasn't been demonstrated anywhere.”
My test results said that my psychedelics sensitivity should be "normal," since my variation of the gene for that serotonin receptor wasn’t associated with increased or decreased receptor density. My colleague’s results said that his variant meant his psychedelics sensitivity was increased. Yet if this test was supposed to be an indication of how the actual psychedelic experience might go, it wasn’t predictive in our case. My colleague said that he has only had good psychedelic trips, and in my case, I’ve only had challenging ones.
I found the most concerning part of the results to be the mental health risk assessment. HaluGen’s test looked at three genes, DISC1, NRG1, and how many copies of the C4A gene a person had, to determine risk of different psychiatric disorders. The results say that certain variations of DISC1 and NRG1 gene have been shown to increase the risk for psychosis, bipolar, and schizophrenia.
But DISC1 and NGR1 have been thoroughly ruled out as candidate genes for schizophrenia, bipolar, or psychosis, said Steven Hyman, director of the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard. “If you apply to the [National Institute of Mental Health] with an otherwise well-written grant purporting to study DISC1 or NRG1 in schizophrenia, the grant would be automatically rejected,” he said. “It’s that straightforward.”
In a 2017 paper titled No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes, the authors re-examined 25 candidate genes previously thought to be involved with schizophrenia, including DISC1 and NRG1. “These commonly studied variants were no more associated with the disorder than would be expected by chance,” the authors wrote.
My results for DISC1 and NRG1 were "normal," as were Marchman's and the twins', but it's worth explaining how such genes were once of interest and then lost their credibility. These genes were thought to be risk factors before scientists had the statistical power of Genome Wide Association Studies (GWAS) at their disposal, Hyman explained. In the past, researchers would pick candidate genes based on guesses about what genes might be at play in a given disorder, like genes that effective drugs targeted or neurobiological pathways that seemed important.
GWAS studies don't require such a priori guesses since they look at the entire genome indiscriminately. Advances in gene sequencing made it so that scientists could look at the whole genomes of large groups of people, with and without a disease, and see what genetic variations popped up in those with the condition compared to those without it. This process eliminated several candidate genes, including DISC1 and NRG1.
Entheon's spokesperson wrote that GWAS are "just one data point that looks at the influence of NRG1 and DISC1. There are other, equally valid peer-reviewed studies, that have shown there is a potential linkage between NRG1 and DISC1 and mental health risk."
In response, Hyman said, "'Equally valid' is not nearly correct," and directed me to a 2013 editorial written by, Patrick Sullivan, the chair of the Psychiatric Genomics Consortium, who wrote that, "The published genetic evidence for an association of DISC1 with schizophrenia does not meet a high standard."
"And since then there have been large unbiased GWAS and whole exome sequencing studies of schizophrenia and bipolar disorder and neither NRG1 nor DISC 1 show association to either disorder," Hyman said. "For that matter neither emerges in other GWAS, such as for major depression."
The other gene in HaluGen's test, C4, has more rigor behind it. In fact, the relationship between C4 and schizophrenia was discovered by GWAS done by researchers at the Broad Institute, where Hyman works. The graph that showed C4's prevalence was so dramatic that it was named the Manhattan plot, for the skyscraper-like bar that was C4.
The authors of the C4 study, published in Nature, used data from more than 100,000 DNA samples from around the world. They found 100 genetic risk factors, including one very strong signal on a specific location of the genome, the gene for complement component 4 (C4), which is typically an immune molecule that helps contain infections in the rest of the body.
The researchers found that people who had particular forms of C4 had higher expressions of the gene, and higher risks for developing schizophrenia. In animal models, Harvard neurobiologist Beth Stevens determined that the C4 gene plays a role in synaptic pruning, a process that occurs during brain development where some connections between brain cells are removed.
I knew about the significance of C4 already, so I was jarred to find that I have four copies of the C4A gene. The HaluGen test said this means I have an increased risk of psychosis, bipolar, and schizophrenia. When explaining why, the test summarizes the research finding: “increased disorder synaptic pruning can be a contributing factor to a higher risk.”
Entheon's spokesperson referred me to the Nature study, writing that C4 "has one of the strongest genetic risk-associations with mental health." But the legitimacy of the science behind the C4 finding doesn’t mean that HaluGen testing me for copies of C4 is legitimate, said Hyman. C4 was an important discovery in the biology of schizophrenia, but Hyman said it’s taken out of context in this individual test result. The reason why researchers study these genes is to try to understand the underlying biology that gives rise to complex psychiatric illnesses, not for individual use.
All mental illnesses are polygenic, meaning there isn’t one gene that can be implicated in its cause. Yet even polygenic predictions are not diagnostic. That doesn’t mean they’re useless. They are a piece of a larger puzzle of mental illness—the piece that’s trying to understand mechanisms, while other pieces focus on treatment or knowledge that is more clinically useful.
From my results, Hyman said that my risk of schizophrenia has gone from a population base rate of 1% to 1.53%. And, he added, my risk of lupus may have slightly gone down. This reveals how it’s overly simplistic to pin complex illness on one or even a small handful of genes. Genes do many things, and they work in combination to produce phenotypes—the observable characteristics of a person in existence with their environment.
“The results mean, basically, absolutely nothing,” Hyman said.
Entheon responded: "While our test kits are not diagnostic in nature, results do not 'mean nothing.' They provide users with information, which within the proper context of set and setting, can be one point for discussion with a qualified medical professional about mental health."
Of the entire genetic test, Nichols said he thought the only part—conceptually—that had some promise was the ketamine metabolism section. There is a growing attempt to assess how people metabolize certain categories or types of drugs called personal pharmacogenomics.
My gene that encodes for the liver enzyme CYP2B6 has a variant that the test said means I metabolize ketamine very slowly. “‘Slow metabolizers should be more cautious when being dosed with ketamine, as they will likely experience an increased duration and intensity of effect,” the results said. It also said that I would metabolize intravenous or subcutaneous ketamine very slowly, compared to oral ketamine which was normal.
The gene HaluGen looked at was for a liver enzyme, and there are 40 or 50 different enzymes that are primarily responsible for metabolizing drugs, and different forms of the enzymes can be slow or fast metabolizers. Ketamine is known to be metabolized by a couple of major liver enzymes, and if you know which forms of enzymes you have, it could one day predict how fast or slow you metabolize, and perhaps one day inform dosage. But still, the HaluGen results fall short, Nichols said.
There are many different drugs, foods, or natural products metabolized by the enzyme they looked for, which is one of the more common ones. And there’s more than one metabolic pathway to eliminate ketamine or to change it from an active compound to a metabolite that’s not active anymore. This particular gene, “could play just a minor effect to a major effect, depending upon what fraction of ketamine would normally be metabolized by this particular pathway,” Nichols said.
In response, Entheon emphasized that, "There are a number of peer-reviewed studies that we cite that show a clear association with slow ketamine metabolism with the CYP2B6*6 genotype."
Another part of the test results was an ethnic comparison breakdown. For ketamine metabolism, for instance, it showed me how I compared to Caucasians, East Asians, and Africans. Some of the genes included different ethnic comparisons, like Indian.
These breakdowns are a reflection of what we know about the frequency of certain genetic variation in people of certain ancestries, and are often based on research that looked at specific parts of the world. "That's really the basis of tests like 23andMe," Nichols said. But since this test wasn't targeted at revealing my ancestry, it's hard to see how this summary is useful. The test kit did not ask for my background (I am biracial), so Nichols said that ancestral overviews wouldn't be predictive in most cases, and certainly not mine. Entheon wrote that "The ethnic breakdowns are for informational purposes only and are not designed to make a specific prediction."
How can we tell what a person’s psychedelic experience be like? Will it be good or bad, healing or unsettling? “There’s been quite the spectrum of reactions to psychedelics, everything from angelic to hell,” Aday said. "And so a natural question is how can you predict if you're going to have the hellish experience or the angelic experience.”
It's still a pressing question, especially when considering psychedelics in a therapeutic context. In a review from this year co-written by Aday and his colleagues, they summarized predictors for individual psychedelic experiences and concluded that we’re only starting to be able to name and verify what can actually forecast what kind of experience a person will have.
Notably, these predictors are dynamic, not fixed, as evidenced by the fact that the same person might have a “bad” trip at one point in their life and a “good” trip at another. (Also, calling a trip “bad” is subjective in and of itself; the word researchers and clinicians use today is “challenging.” While some psychedelic experiences can be challenging, and they certainly will be in the treatment of mental illness, if users are able to integrate the experience, they can often still find ways to make it meaningful.)
Aday and his colleagues went through all the literature published on predicting psychedelic trips in the last 20 years and found that, broadly, the most reliable predictors could be grouped into two categories: traits and states.
States are how someone is feeling in the moment before they’re about to take the drug. Traits are more stable variables, like personality. People who are more open to experiences, for example, or more willing to think in different ways before they took psychedelics have been shown to be more likely to have positive experiences. Those low in openness or with rigid thinking styles are more likely to have challenging experiences.
Traits are hard to alter, so thinking about how to modify people’s states and moods can be an approach to encouraging good experiences and outcomes, Aday said. Making sure people aren’t confused, that they’re focused on their intentions, and have a safe environment to take the drug in.
“You can't control personality traits necessarily, but you can control the setting of the drug that is administered and the preparation that's done beforehand,” Aday said. People who take psychedelics in research trials also have thorough interviews where they’re asked questions about their physical and mental health history.
This is all somewhat intuitive. But a trait like "openness" is mushier than a definitive-seeming genetic result—which is why a test like HaluGen's will have market appeal. (Entheon wrote to Motherboard that, "The presence of genetic risk factors is not a guarantee of developing a mental illness and is just one of many factors that can impact someone’s mental health, which HaluGen clearly states.The test kit is meant to provide users with additional information to help them make informed decisions about potential treatment, but only within the context of the very important set, setting, and subjective psychological predictors and other conversations that should be taking place with a medical professional or genetic counsellor.")
But since tests like these rely on genetic jargon, its results could unduly influence people, according to Woo-kyoung Ahn, a psychology professor at Yale University. Part of Ahn’s research is exploring how people’s expectations of their symptoms are influenced when they learn about genetic predispositions.
In an experiment, Ahn and her colleagues gave people a fake saliva test, which they were told could detect genetic susceptibility to depression. People who were told that they tested positive on the test felt there wasn’t as much that could be done about their depression. “That is, genetic attributions make them feel that they have less control,” Ahn said.
Using the same saliva test framework, they measured people’s memory of their depression over the previous two weeks. People who were told they had elevated genetic risks for depression reported being more depressed.
Even those put into study groups that are told they aren’t genetically susceptible to a condition can experience negative consequences. People told that they weren’t genetically susceptible to obesity “felt more invincible; they discounted the significance of a healthy diet and regular exercise, and when presented with a menu for a hypothetical lunch, they were also more likely to select unhealthy food,” Ahn said. “We call this the genetic invincibility effect.”
While Entheon told Motherboard "We are fully transparent with the 55 peer-reviewed studies that we cite," and that "anyone that buys our psychedelics genetic test also has full access to these scientific references with our whitepaper and can review for themselves," that leaves it up to members of the public to interpret complicated genetic studies and apply them to their results.
When it comes to psychedelics, a sense of "invincibility" could have serious ramifications. Take the ketamine metabolism result: Nichols said that telling someone they’re a slow or fast metabolizer, and prompting them to modify their dose, might backfire if they’re metabolizing it through other routes. “This is a potentially dangerous product, not only misinformative,” Nichols said.
Many groups in the psychedelic field are working on optimizing the amount of a particular drug to give an individual, but it's not always intuitive. A recent study from Johns Hopkins University found that there was no significant difference in experience between groups that got psilocybin doses adjusted to their weight, for instance—despite this being common practice.
“There are people putting millions of dollars into trying to develop these kinds of tests and assays,” Nichols said. “I think this kind of product is really taking advantage, and almost predatory, of people who want this kind of information but don't understand how complex the question is that they're trying to answer.”
Telling a person that they have reduced, normal, or heightened sensitivity doesn’t guarantee they’ll avoid a challenging experience. “Some people might become overly confident or think they can take the drug in a more dangerous location or more uncertain setting,” Aday said. “They might make riskier decisions because they've been told ‘I’m going to be fine’ beforehand.”
In the future, there might be a more biological approach to customizing doses or predicting with more certainty the kinds of experiences people will have. "But even right now, I think that’s kind of a big leap to make," Aday said. "I wouldn’t spend my own money on this."
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