Here’s Why Psychedelic Drug Therapy May Not Work for Everyone

Here's Why Psychedelic Drug Therapy May Not Work for Everyone
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  • Studies have shown that around one-third of people with mental health conditions like depression don’t respond to psychedelic treatments.
  • Scientists aren’t entirely sure why people respond to psychedelics differently, but new research suggests that genetic variations in a serotonin receptor may be a factor.
  • While genetics can play a role in many mental health conditions, some experts say that DNA is unlikely to be the sole contributing factor to how a person responds to psychedelic drugs.
  • Just as symptoms associated with various mental health conditions may present differently in different people, how people respond to psychedelics may also vary.

Many people with depression, anxiety, or post-traumatic stress disorder (PTSD) benefit from psychedelic drug treatments, clinical trials show. Psychedelic drugs affect thinking, emotion, and perception by binding to and activating the serotonin receptor in the brain.

HAS 2021 study found that psilocybin, or “magic mushrooms,” was similarly effective for treating depression as the antidepressant escitalopram (Lexapro). While the results of some trials have been promising, not everyone responds to psychedelic treatments (which is also true for antidepressants).

Scientists are not yet certain why psychedelics such as psilocybin, LSD, and mescaline don’t produce similar effects for everyone, but one possibility is that genetics may play a role.

HAS new studypublished July 27 in ACS Chemical Neuroscienceexamined the effect that different gene variants for serotonin receptor 5-HT2A have on how psychedelics bind to this receptor, noting moderate effects.

In the new study, researchers from the University of North Carolina at Chapel Hill expanded on existing research exploring the role of serotonin receptor 5-HT2A in non-psychedelic drug responses.

UNC researchers focused on seven variants caused by a change in a single DNA building block in the receptor gene, known as single nucleotide polymorphisms (SNPs). These SNPs occur in 0.003% to 7.9% of people, the authors wrote in the paper.

Working with human cells in a lab, researchers ran tests to see how different psychedelics — psilocin, mescaline, 5-MeO-DMT, and LSD — bound to these receptor variants. (Psilocin is the psychedelic active compound found in psilocybin mushrooms.)

The tests showed the receptor variants produced “statistically significant, although modest, effects” on the potency of these four psychedelics, the researchers said — at least in the lab. The effects were also dependent upon the specific drug and receptor variant combinations.

“Genetic variation in this receptor has been shown to influence the response of patients to other drugs,” Dustin HinesPhD, an assistant professor of neuroscience in the department of psychology at the University of Nevada, Las Vegas, who was not involved in the new study, told Healthline.

“While psychedelic therapies can provide rapid and sustained therapeutic benefits for multiple mental health concerns, there are a proportion of patients who fail to respond.”

According to Hines, genetic variations in this serotonin receptor may contribute to why psychedelic therapy may not work for everyone. He said two prior studies in 2020 and 2021 found that around one-third of people with depression didn’t respond to psilocybin treatment. An even smaller number of people experienced some kind of negative side effect to psychedelic treatments in general.

The UNC researchers concluded that future clinical trials may need to take into account the influence that genetics might play on how people respond to psychedelic treatments.

While genetics can play a role in many mental health conditions, a person’s DNA is unlikely to be the sole factor influencing how people respond to psychedelic treatments for depression, anxiety, or PTSD.

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Aim Rachel YehudaPhD, professor of psychiatry and neuroscience of trauma at the Icahn School of Medicine at Mount Sinai in New York, said that genetics could play a small role in people’s varied responses.

“We already know the kinds of factors that might determine response [to psychedelic treatments],” she said.

According to Hines, how a person responds to psychedelic treatment may also include their capacity for engaging in psychotherapy, their ability to be compassionate toward themselves, as well as how severe their trauma is and how early in their life it started.

Of course, these factors can affect any mental health treatment, not just psychedelic treatments. However, Yehuda noted one factor that’s specific to psychedelic treatments is how easily a person submits to the effects of a drug that alters their consciousness.

“There is a very active way that you can resist the [psychedelic] effect, and say, ‘I’m not doing this,’” she said.

Hines added that variability in mental health conditions from person to person could also contribute to how well people respond to treatments — psychedelic or otherwise.

“Some individuals with depression may have a genetic predisposition that increases the likelihood that they will experience depression in their lives,” Hines said. “Other individuals facing depression may have more situational or environmental contributions.”

Hines noted that a person living with a mental health condition such as anxiety could potentially complicate the effectiveness of the treatment.

Yehuda said that one of the challenges of determining how people benefit from a psychedelic treatment is defining what a “response” is. For instance, it could mean that after treatment, a person no longer has the condition they were being treated for, whether it’s PTSD, anxiety, or depression.

But another way to view a positive response to treatment is by noting improvements in their symptoms — maybe they’re not 100% better or “cured,” but are headed in that direction.

While most people would hope for a full recovery, even small improvements in symptoms can transform a person’s life. For some people, partial recovery might mean being able to go to a concert with a loved one. For others, it could mean feeling comfortable in a crowd or talking with a stranger at a party.

“These little behaviors make up a life,” Yehuda said. “If you can start living your life again, rejoining your family in a different kind of way, and feeling like you could take more chances and be part of the world, that’s a really good thing.”

Based on the current research, however, many people do fall into that first category of having a dramatic response to psychedelics.

“One of the things that has been impressive in the psychedelic studies is that there’s quite a large proportion of people that, by the study’s end, don’t have the condition that they had at the start,” Yehuda said. “Certainly it’s true with PTSD — there are a lot of people that flipped from having PTSD to not having PTSD, which is quite remarkable in terms of a level of response.”

Researchers like Yehuda get very excited about the large number of people who have had a clinically significant response to psychedelic treatments for mental health conditions.

And even with a proportion of people not responding, psychedelic treatments can still be valuable.

“We need to bear in mind that patients in many of the clinical trials to date are treatment-resistant and have struggled in some cases for many years before receiving psychedelic therapy,” Hines said.

Yehuda expects that as the psychedelic research field matures, clinical trials will have to be adapted to fit the reality of patient responses.

“A lot of [scientists] are interested in doing trials with psychedelics,” she said. “And hopefully these people know there is a need to consider the possibility — or to entertain the probability — that there’s going to be response variation.”

Research shows that around one-third of people with mental health conditions like depression may not receive any benefit from psychedelic-assisted treatment.

While new research shows that genetics may be one possible factor, other experts say that results from psychedelic treatments may ultimately vary depending on the individual.

Future studies could focus on figuring out who might — and might not — benefit from psychedelic-assisted treatments, as well as whether to adjust a person’s treatment when they don’t respond or try a different form of treatment altogether. Of course, this process is similar to what happens with other forms of medical treatments.

“We really don’t want to ignore or dismiss those people that don’t respond,” Yehuda said. “We need to start changing the conversation from ‘use this treatment, it will work,’ to ‘how are we going to match patients to the many treatments that are out there?’”

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