The therapy of psychiatric disorders still faces significant challenges related to high rates of treatment resistance and, in many instances, a delayed onset of action. These problems emphasize the need to develop novel treatment options for psychiatric disorders. Psychedelic drugs are promising candidates, with positive data from ketamine, psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), and lysergic acid diethylamide (LSD) Clinical studies. However, psychedelic clinical trials come with unique challenges, and collaboration with an experienced psychedelics contract research organization (CRO) may significantly contribute to their success.

Classes of Psychedelic Compounds

The term psychedelics encompasses a number of different compounds that can cause perceptional disturbances, hallucinations, and apparent consciousness expansion. It has been hypothesized that a facilitatory effect of psychedelics on brain plasticity is implicated in these actions. Psychedelics are generally divided into four classes based on their chemical and pharmacological characteristics. These classes include:

1. Classic psychedelics, such as LSD, psilocybin, and ayahuasca, include agonists of the serotonin 2A (5-HT2A) receptor.
2. Empathogens or entactogens, including MDMA (also known as ecstasy), encompass mixed serotonin and dopamine reuptake inhibitors and releasers.
3. Dissociative anesthetic agents, such as ketamine, are N-methyl-D-aspartate (NMDA) antagonists.
4. Atypical hallucinogens, such as ibogaine, affect multiple systems of neurotransmitters.

Research on the Therapeutic Potential of Psychedelics for Psychiatric Disorders

Some psychedelics derived from plants or mushrooms, such as psilocybin, mescaline, and DMT, have been used for centuries in religious ceremonies in some cultures. But it wasn’t until 1938 the psychedelic LSD was first synthesized by the Swiss chemist Albert Hofmann with further LSD clinical studies. During the 1950s and 1960s, psychedelics were actively investigated for their therapeutic potential in psychiatric disorders. This research was eventually halted primarily because of concerns related to drug abuse potential. Nevertheless, since the 2000s, it has undergone a new surge.

The therapeutic potential of psychedelics for psychiatric disorders

The need to search for new therapeutic alternatives for psychiatric disorders is emphasized by the fact that currently approved therapeutics still have limitations. Thus, treatment resistance is reported in a large subset of patients, and many therapeutic agents, especially antidepressants, have a delayed onset of action. These challenges are associated with serious consequences for individual patients, whose functional status and quality of life are affected negatively, and for public health with increased healthcare costs.

Recent studies on psychedelic substances, including the LSD clinical studies, have delivered promising data regarding their potential for treating psychiatric disorders. The mechanisms of action of psychedelics differ from those of currently approved therapeutics, which may inform the development of novel classes of therapeutics in the future.

Moreover, psychedelics reportedly have a rapid onset of their effects, which may be an advantage in instances in which a rapid-effect onset is critical. In addition, psychedelics can be integrated with other, already established, evidence-based treatment modalities, such as psychotherapy and pharmacotherapy.

Further rigorous clinical trials conducted in controlled settings must confirm current findings, address potential risks, determine the appropriate dosing schedules, and further elucidate the underlying mechanisms. In June 2023, the United States Food and Drug Administration (US FDA) released guidance to sponsors with general considerations for developing psychedelic drugs to treat medical conditions.

 Recent advances in the field of psychedelic research include:

• A combination of an oral antidepressant and an esketamine nasal spray has been approved by the US FDA for treatment-resistant depression.
• MDMA and psilocybin have been granted “breakthrough therapy” designations by the US FDA for treating posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively.
• Clinical trials with psychedelic-supported psychotherapy have demonstrated symptom alleviation in psychiatric disorders but should still be followed up by further randomized, controlled clinical trials.
• LSD clinical studies have also shown positive results, indicating the need for further investigations.

 Challenges Associated With Psychedelic Clinical Trials

There are several challenges associated with psychedelic clinical trials, including the following:  

The risk of human abuse potential (HAP) – HAP is probably the most serious concern faced by research on psychedelic compounds. According to the U.S. Drug Enforcement Administration (DEA), LSD, psilocybin, and MDMA are classified as Schedule I substances under the Controlled Substances Act, indicating a high abuse potential, no currently accepted medical treatment use in the United States, and a lack of accepted safety for use under medical supervision. Ketamine, however, is classified as a Schedule III substance under the Controlled Substances Act, indicating an accepted medical use (e.g., anesthesia) and a lower abuse potential.

Challenges with blinding study volunteers and raters – Psychedelic clinical trials  volunteers who receive psychedelic compounds may experience functional unblinding from the development of perceptual disturbances. This poses challenges with using an inert placebo and with the blinding of study volunteers and raters.

Difficulties discerning between the effects of psychedelic compounds and psychotherapy – In many instances, psychedelic clinical trials may include the administration of psychedelic compounds and psychotherapy or psychological support, which might impede the assessment of the effectiveness of the psychedelic compound itself.

Recruitment challenges – Depending on the study specifics and the dose of the psychedelic drug candidate, both normal healthy volunteers (NHVs) and patients may be recruited. However, there may be self-selection of individuals expecting to experience benefits from psychedelic compounds for participation in psychedelic clinical trials, raising concerns that these volunteers may not always be representative of the general population.

Safety Considerations When Conducting Psychedelic Clinical Trials

Psychedelic compounds may be administered as high-dose psychedelics or microdosed. These different administration paradigms have distinct implications regarding safety monitoring.

High-Dose Psychedelics

Administration of high-dose psychedelics may lead to hallucinations, changes in consciousness, and sensory-perceptual alterations. As such, it requires the presence of a highly qualified and specifically trained facilitator during the psychedelic clinical trial  who should be involved in a preparatory, treatment, and integration session. Additionally, studies using high-dose psychedelics require psychological support or supportive psychotherapy for patients and a risk mitigation strategy. In all cases, study volunteers’ safety should be the number one priority, and assessments should be designed in the least disruptive manner, especially when dealing with trials like LSD clinical studies.

Microdosing

When microdosing is performed, many of the mentioned challenges are not present. In microdosing, sub-perceptual psychedelic doses are administered that are below the threshold, inducing observable perceptual alterations. Thus, no psychedelic effects, which some study volunteers may experience as too intense or intimidating, are observed. 

Microdosing psychedelic studies can be performed at typical Phase 1 clinical facilities, and their safety monitoring can be carried out by the principal investigator (PI) and specifically trained safety staff but without the need to involve specialized facilitators. After the optimal dose and formulation of a psychedelic drug candidate are selected, microdosing may be performed in the context of outpatient studies.

What to Look for When Selecting a Psychedelics CRO

When selecting a CRO to conduct a psychedelic clinical trial, it’s essential to ensure the CRO, at minimum, meets the following criteria:

Expertise in clinical trials involving CNS compounds and drug candidates with HAP – The HAP and effects on consciousness and perception of psychedelic drug candidates pose serious challenges in their drug development programs. Therefore, it is essential to work with a clinical partner with extensive clinical trial design expertise for CNS compounds and drug candidates with HAP.

The ability to design complex clinical trials. Psychedelics CROs should have experience with all aspects of clinical trial design, including single ascending dose studies and pharmacodynamic assessments. They should also have the know-how to address challenges related to placebo and nocebo effects and masking. If the application of an inert placebo is not feasible, alternative strategies —  including subperceptual doses of a psychedelic drug or other psychoactive drugs —  mimicking certain aspects of the psychedelic experience may be implemented. In addition, video or central raters blinded to the visit number and treatment allocation may be considered.

Experience with recruitment for clinical trials. Expertise in recruiting study volunteers for psychedelic clinical trials involving CNS compounds and drug candidates with HAP is critical to ensure that the recruited individuals are representative of the overall population.

Bioanalytical capabilities for psychedelic compounds and metabolites. A psychedelics CRO should have extensive bioanalytical know-how and state-of-the-art bioanalytical facilities to quantify psychedelic drug candidates and their metabolites accurately and reliably.

Partner With the Right CRO for Your Next Psychedelic Drug Clinical Study

BioPharma Services is an innovative, full-service CRO with expertise in early-phase clinical trials, including clinical studies on psychedelic drug candidates. Our expert multidisciplinary team, bioanalytical expertise, state-of-the-art facilities, and niche expertise in CNS and HAP studies enable us to successfully design and conduct even the most complex clinical trials on psychedelic drug candidates, including LSD clinical studies.

Our strengths in psychedelic clinical trials and overall research on psychedelic drug development include:

• Expertise in studies on compounds with CNS activity and HAP, which enables us to effectively design and conduct clinical trials on psychedelic compounds
• A state-of-the-art, in-house bioanalytical laboratory equipped with a platform for liquid chromatography with tandem mass spectrometry that has validated a wide range of psychedelic compound assays
• An extensive database of study volunteers, including over 18,000 NHVs and individuals from special populations
• State-of-the-art clinical facility, including our Phase 1 clinic with extensive safety monitoring and controlled substance licenses, in Toronto, Canada.

If you are looking for a psychedelic CRO with extensive expertise and an innovative mindset to advance your clinical trial program with psychedelic drug candidates, complete the form below to schedule a discovery call with a BioPharma Services medical team member.