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Although the long-awaited use of psychedelics in the treatment of mental health disorders failed to receive approval in 2024, the research community is actively working to demonstrate the significant potential of these unconventional substances.
In August, the FDA rejected Lykos Therapeutics' application to use MDMA (3,4-methylenedioxymethamphetamine, commonly known as ecstasy or molly) in combination with therapy to treat resistant post-traumatic stress disorder (PTSD). If approved, the drug would have been the first psychedelic to receive FDA approval, but the agency requested additional studies to confirm the safety and efficacy of the treatment. Although the FDA's letter to Lykos has not been published, the advisory committee has previously expressed concerns about the complexity of evaluating therapeutic effects and the difficulty in setting up a truly «blind» experiment. The committee noted that mind-altering effects may make participants more able to predict whether they received the drug or a placebo, which could skew the results.
At the September 2024 Congressional Roundtable on Psychedelic Therapy, American Psychiatric Association (APA) leaders emphasized the importance of high-quality, unbiased research and the need to incorporate a psychotherapy component into models of care. The APA is also working to update the 2017 Clinical Practice Guidelines for the treatment of PTSD in adults.
While more research is needed, scientists are optimistic about the prospects for approval of MDMA, psilocybin, LSD (lysergic acid diethylamide) and other psychedelic substances in the coming years. «The FDA's decision on MDMA involved only one drug, one sponsor, and one application» — said Fred Barrett, PhD and director of the Center for Psychedelics and Consciousness Research at Johns Hopkins University. «This is just the beginning. It will likely take studies with different designs to confirm the safety and efficacy of these drugs for the FDA to gain confidence».
Scientists involved in clinical trials of psychedelics emphasize that problems with blindness often occur in other studies of treatments for mental disorders, such as antidepressants.
While federal regulators await additional data from clinical trials, new research is helping to understand how psychedelics affect the brain to promote long-term improvements in substance use disorders, PTSD, depression, anxiety and other conditions. Recent findings show that these drugs affect neural connections related to self-identity and memory, helping people overcome maladaptive behaviors.
As interest in psychedelic therapy grows and understanding of the neurobiological mechanisms involved increases, psychologists are playing a key role in the development of the field. «The potential is enormous, but many people mistakenly believe it's a magic drug that can solve their problems» — says Mia Sarno, Ph.D., a psychologist and licensed clinical psychologist involved in clinical trials of psychedelics. «Psychologists are in a unique position to provide guidance because we are experts in assessment, research, ethics and the study of consciousness». Sarno believes that the field of psychology has an obligation to ensure that psychedelic therapy is used safely for people with mental disorders.
Activation of hippocampal mechanisms
Recent research reveals the mechanisms by which psychedelics enhance synaptic connections in the brain, and shows how medical professionals can use this neuroplasticity to treat therapy-resistant mental disorders. In one experiment, scientists scanned the brains of healthy adult participants before, during, and three weeks after administering a high dose of psilocybin, and again six to 12 months later. The control group used methylphenidate, a drug used to treat attention deficit hyperactivity disorder (ADHD). During the psychedelic session, scans showed that neural pathways associated with the default mode network (responsible for the sense of identity) were «desynchronized» or disrupted (Siegel, JS et al., Nature, vol. 632, 2024).
After the psychedelic experience, much of the brain activity returned to normal, but there were long-term changes in the connections between the hippocampus — the memory center — and the passive mode network.
«The shift of these brain regions to a more plastic and adaptive state seems to contribute to behavioral change in humans» — noted Joshua Siegel, MD, PhD, a neuroscientist and first author of the study based at New York University's Center for Psychedelic Medicine. «When therapy is delivered in this context, it allows people to use this increased flexibility to overcome maladaptive behaviors».
The role of psychedelics in memory formation has also been studied. A recent study covering a variety of drugs such as sedatives, cannabinoids, and stimulants found that psychedelics impaired the formation of episodic memories in the hippocampus — memories of events related to time and emotion (Psychological Review, vol. 131, no. 2, 2024). At the same time, cortical memory for familiar objects improved with high doses of psychedelics. This is related to memories without specific details, such as when a person seems familiar but cannot be identified. «Shutting down the hippocampus may be a useful way to generate new cortical learning and redefine behaviors that have been formed over time» — explained Manoj Doss, Ph.D., lead author of the study and a researcher at the University of Texas Center for Psychedelic Research and Therapy at the Austin Dell Medical School.
Although the long-awaited use of psychedelics in the treatment of mental health disorders failed to receive approval in 2024, the research community is actively working to demonstrate the significant potential of these unconventional substances.
In August, the FDA rejected Lykos Therapeutics' application to use MDMA (3,4-methylenedioxymethamphetamine, commonly known as ecstasy or molly) in combination with therapy to treat resistant post-traumatic stress disorder (PTSD). If approved, the drug would have been the first psychedelic to receive FDA approval, but the agency requested additional studies to confirm the safety and efficacy of the treatment. Although the FDA's letter to Lykos has not been published, the advisory committee has previously expressed concerns about the complexity of evaluating therapeutic effects and the difficulty in setting up a truly «blind» experiment. The committee noted that mind-altering effects may make participants more able to predict whether they received the drug or a placebo, which could skew the results.
At the September 2024 Congressional Roundtable on Psychedelic Therapy, American Psychiatric Association (APA) leaders emphasized the importance of high-quality, unbiased research and the need to incorporate a psychotherapy component into models of care. The APA is also working to update the 2017 Clinical Practice Guidelines for the treatment of PTSD in adults.
While more research is needed, scientists are optimistic about the prospects for approval of MDMA, psilocybin, LSD (lysergic acid diethylamide) and other psychedelic substances in the coming years. «The FDA's decision on MDMA involved only one drug, one sponsor, and one application» — said Fred Barrett, PhD and director of the Center for Psychedelics and Consciousness Research at Johns Hopkins University. «This is just the beginning. It will likely take studies with different designs to confirm the safety and efficacy of these drugs for the FDA to gain confidence».
Scientists involved in clinical trials of psychedelics emphasize that problems with blindness often occur in other studies of treatments for mental disorders, such as antidepressants.
While federal regulators await additional data from clinical trials, new research is helping to understand how psychedelics affect the brain to promote long-term improvements in substance use disorders, PTSD, depression, anxiety and other conditions. Recent findings show that these drugs affect neural connections related to self-identity and memory, helping people overcome maladaptive behaviors.
As interest in psychedelic therapy grows and understanding of the neurobiological mechanisms involved increases, psychologists are playing a key role in the development of the field. «The potential is enormous, but many people mistakenly believe it's a magic drug that can solve their problems» — says Mia Sarno, Ph.D., a psychologist and licensed clinical psychologist involved in clinical trials of psychedelics. «Psychologists are in a unique position to provide guidance because we are experts in assessment, research, ethics and the study of consciousness». Sarno believes that the field of psychology has an obligation to ensure that psychedelic therapy is used safely for people with mental disorders.
Activation of hippocampal mechanisms
Recent research reveals the mechanisms by which psychedelics enhance synaptic connections in the brain, and shows how medical professionals can use this neuroplasticity to treat therapy-resistant mental disorders. In one experiment, scientists scanned the brains of healthy adult participants before, during, and three weeks after administering a high dose of psilocybin, and again six to 12 months later. The control group used methylphenidate, a drug used to treat attention deficit hyperactivity disorder (ADHD). During the psychedelic session, scans showed that neural pathways associated with the default mode network (responsible for the sense of identity) were «desynchronized» or disrupted (Siegel, JS et al., Nature, vol. 632, 2024).
After the psychedelic experience, much of the brain activity returned to normal, but there were long-term changes in the connections between the hippocampus — the memory center — and the passive mode network.
«The shift of these brain regions to a more plastic and adaptive state seems to contribute to behavioral change in humans» — noted Joshua Siegel, MD, PhD, a neuroscientist and first author of the study based at New York University's Center for Psychedelic Medicine. «When therapy is delivered in this context, it allows people to use this increased flexibility to overcome maladaptive behaviors».
The role of psychedelics in memory formation has also been studied. A recent study covering a variety of drugs such as sedatives, cannabinoids, and stimulants found that psychedelics impaired the formation of episodic memories in the hippocampus — memories of events related to time and emotion (Psychological Review, vol. 131, no. 2, 2024). At the same time, cortical memory for familiar objects improved with high doses of psychedelics. This is related to memories without specific details, such as when a person seems familiar but cannot be identified. «Shutting down the hippocampus may be a useful way to generate new cortical learning and redefine behaviors that have been formed over time» — explained Manoj Doss, Ph.D., lead author of the study and a researcher at the University of Texas Center for Psychedelic Research and Therapy at the Austin Dell Medical School.
While training the brain to learn new healthy behaviors can help patients, the results underscore the need for therapeutic guidance when using this treatment method. «We must guide the learning process to some extent to avoid the formation of false beliefs» — Doss noted.
Challenges in the study
Despite the increasing number of psychedelics studies, scientists have noted the need to address the challenges of identifying the right patient population for the study. In late 2022, a team from the Center for Psychedelics Neuroscience at Massachusetts General Hospital began selecting potential participants for a study designed to evaluate the effects of a single dose of psilocybin on rumination and brain activity. They were looking for people suffering from treatment-resistant depression, which is defined as a lack of response to two or more antidepressant regimens given an adequate dose and duration of treatment. Many candidates were excluded due to the lack of two successful trials with antidepressants. In addition, the study required participants to abstain from cannabis use for 18 weeks, and many potential participants did not meet this criterion because they were regular cannabis users. A total of 700 people were screened and none of them met the inclusion criteria.
Researchers will also need to conduct studies on more diverse groups of participants. Most of the evidence on psychedelics is based on studies that are dominated by affluent, educated white people. In one review of 39 studies conducted between 1994 and 2024, more than 85% of participants identified as non-Hispanic whites, with only 3.1% black, 6.8% Hispanic/Latino/Hispanic, 3.6% Asian, and 1.2% indigenous (The Lancet: eClinicalMedicine, vol. 74, 2024). «We can't say with certainty that members of other communities will respond in the same way» — said study co-author Albert Garcia-Romeu, PhD and deputy director of the Center for Psychedelics and Consciousness Research at Johns Hopkins University.
To increase diversity in clinical trials of psychedelics, Garcia-Romeu encourages researchers to partner with community organizations, religious institutions and other groups to actively involve community members in research projects.
Patient and provider education
Although federal approval of psychedelics is still pending, there has been a growing patient interest in these therapies. According to a recent survey of more than 200 mental health professionals in California, nearly half of them noted that patients seek information about psychedelics from them (Clinical Psychology and Psychotherapy, Vol. 30, No. 6, 2023). Most of the professionals interviewed were generally supportive of the use of psychedelics in psychotherapy and the treatment of mental disorders. However, almost half of them do not feel confident answering patients' questions about the effects of psychedelics.
There are many educational programs in the United States that teach mental health professionals about the history of psychedelics, the various substances available, safety issues, contraindications, and how to integrate therapy into treatment. To support psychologists in working with patients, a group of experts from six divisions of the American Psychological Association (APA) plans to release a free toolkit and webinar series in 2025 covering current research, key elements, ethical considerations, and patient care models for this type of treatment, Sarno said. She added that psychologists can participate in psychedelic therapy through ketamine clinics, FDA clinical trials, or by offering psychedelic integration therapy to those patients who are dosed in other settings.
Educated clinicians can also help develop treatment standards as psychedelics become more common in medical practice.
Patients may be more susceptible to transference and countertransference, as well as become more vulnerable to power dynamics in their relationships with therapists. Providers, in turn, must create a bias-free space for patients' experiences, which may be unusual, Sarno noted. They may observe patients shaking, moving erratically or making sounds that resemble screaming. Hallucinations are also possible, including visions of people, non-human beings or geometric shapes and colors.
Psychologists have an opportunity to establish safe practices by advocating for informed and informed consent processes in the context of psychedelic therapy, Haug added. For example, physical touch, not typically used in psychotherapy, can be used to create a sense of reassurance during a session. This may include holding hands or touching the patient's shoulder. The consent process should provide patients with the opportunity to practice choice, such as refusing to be touched by the therapist.
Although psychedelic therapy still faces federal barriers, patients continue to seek out these treatments. For people suffering from therapy-resistant conditions, getting guidance from a knowledgeable and unbiased medical professional about psychedelics can help them make informed decisions.