In 1967, when the United Nations Convention on Drugs classified psychedelics as Schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.
Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.
Before they were classified as Schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.
Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico School of Medicine, Albuquerque, New Mexico.
Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zurich in Switzerland began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, in Baltimore, Maryland, that is widely cited as a catalyst for the current renaissance in psychedelic research.
To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, Medscape Medical News spoke to nine expert researchers from around the globe.
Global Legal Status
In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.
In the United States, classic psychedelics remain Schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the US Food and Drug Administration under licensure from the Drug Enforcement Administration.
France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.
In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.
Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.
“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the Department of Mental Health, National Autonomous University of Mexico, Mexico City, told Medscape Medical News.
Psychedelics are also illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.
Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.
However, like other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. However, it is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
Potential Indications
Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.
In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, in Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.
In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression and are currently exploring their use in the treatment of anorexia and various pain syndromes.
In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.
Researcher Helen Dolengevich, MD, a psychiatrist at the Hospital Universitario del Henares, in Madrid, Spain, noted that although research on esketamine for the treatment for severe depressive disorder with suicidal thoughts is currently underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.
Mexico’s Velásquez notes that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
Environment Is Key
Most psychedelic researchers agree that in order to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.
Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said ongoing US psilocybin research — primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache — generally include one or two treatment sessions, each of which lasts 6 to 8 hours.
Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”
For Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.
“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.
Gründer agreed.
“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dolengevich and Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.
Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of the Instituto Phaneros in São Paulo, Brazil, believe more research is needed to determine the optimal therapeutic environment for individual agents.
“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
Risks, Abuse Potential
The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of the experts Medscape spoke with is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.
It is recreational use that presents an abuse concern, said Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”
Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.
“Functionally, psychedelics are antiaddictive,” Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”
Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.
“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”
Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, in Italy. Pani explained that with low doses and micro-doses of psychedelics, the potential for abuse is eliminated.
Nutt, Pani, and Ferreri also noted the importance of medical supervision. For instance, said Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters ― heart rate and blood pressure, in particular ― because the drug can have hypertensive effects.
Schenberg also noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.
Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.
“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
Psychologically Challenging
Experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.
Gründer and Dolengevich emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.
For Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.
Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.
The situation is similar in Spain, where Dolengevich noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.
Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
Patient Education
Preparing and educating patients about the therapy are critical, said Gründer, especially given the intense response psychedelic treatment often invokes.
Echoing Gründer, Tófoli said explaining the nature of psychedelic treatment to potential patientshelps ease anxiety.
Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.
There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patient’s experience with psychedelics to help them gain insight into the underlying cause of their depression.
Schenberg also noted that at his institution in São Paulo, they have developed online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
Working Out Treatment Protocols
Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Pani noted that current psychedelic research in Italy predominantly focuses more on micro-dosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 μg, in contrast to low dosing or full dosing.
Therapeutic regimens in Brazil, said Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.
In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.
For Mexico’s Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.
With ketamine therapy, Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.
The question of the duration of treatment effect is important. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.
“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Griffiths.
Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three quarters of patients treated with psychedelics for major depression relapse within 3 to 9 months.
“Most get better,” he said, “but the majority of depression comes back over a period of months.”
Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.
“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”
All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.
“We can look forward to continued growth and expansion of this research,” said Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”
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