Key Insights

• Psychedelics are evaluated under standard regulatory frameworks like other drugs, but their unique psychoactive properties require tailored safety protocols, such as addressing 5-HT2B receptor interactions and incorporating specific cardiac evaluations to minimize risks.
• Psychedelic trials face methodological challenges, including functional unblinding and small sample sizes due to cost and labour-intensive processes. Innovative placebo designs and dose-response planning are advancing study reliability and regulatory compliance.
• Despite a history of stigmatization and classification as Schedule I substances, modern research highlights psychedelics’ physiological safety, low addiction potential, and promising therapeutic applications, with efforts underway to align their classification with their clinical value.

Author: This page has been made possible with the help of Chiara Corpetti, PhD in Pharmacology and Toxicology.

Regulatory Frameworks and Safety in Drug Development

Safety is a primary objective and critical consideration in developing new therapeutic drugs. Several procedures are in place to assess the safety and efficacy of drugs. Drug development typically begins with an Investigational New Drug (IND) application, which includes preclinical data, manufacturing details, and proposed clinical study protocols. This application, reviewed by the FDA or EMA (Europe), allows clinical trials to proceed only if protocols meet strict safety standards. These steps address basic information regarding adverse and suspected adverse reactions. Clinical trials involving humans may commence if the review confirms that the proposed clinical trial protocols are satisfactory. Researchers must specify the drug under investigation, the dose to be administered, and the target of people, among other things.

After pre-clinical studies, clinical trials progress through three phases:

• Phase I assesses toxicity, metabolism, and side effects in healthy volunteers.
• Phase II evaluates the drug’s effectiveness and safety in affected individuals.
• Phase III further confirms safety and efficacy in larger, diverse populations.

If Phase III results are favourable, a New Drug Application (NDA) is submitted for final approval, often alongside long-term studies to monitor side effects in broader populations. Despite the complexity and expense of drug development, numerous psychedelic drugs are now advancing through these clinical stages, showing potential for safe and effective therapeutic applications [1].

Unique Challenges in Psychedelic Research

Psychedelics maintain a distinct societal relationship, unlike any other pharmacological agent. Policies of the 1960s hindered the development and evaluation of psychedelic molecules for therapeutic purposes, delaying scientific progress and the assessment of their efficacy and safety. Subsequently, media portrayals depicted psychedelics as extremely dangerous drugs.

However, recent years have seen an increase in interest and investments in psychedelics research, presenting new views on their promising therapeutic potential (Nichols, 2016; Hall, 2022). The evaluation of psychedelic drugs in development programs follows the same regulatory standards as other drugs seeking approval from regulatory bodies. Nevertheless, the assessment of psychedelics for safety and efficacy as potential therapies requires tailored approaches and specific considerations. These adjustments allow for equitable evaluation within the standard drug development framework while accommodating the unique therapeutic and psychoactive properties of psychedelics [2].

Researchers must contend with the fallout from this era of research to prove that these drugs are both effective and safe. Regulatory agencies continue to question the therapeutic potential of psychedelics as compared with other medications, highlighting unique safety challenges and controversies. In the preliminary evaluation phase of an IND, adequate pharmacological and toxicological data must be provided to establish the safety of clinical investigations. Despite many chronic target conditions, current research primarily focuses on single-dose or intermittent dosing regimens. Thus, developing chronic or chronic-intermittent dosing protocols in preclinical studies is essential when a single dose effect is not long-lasting and requires repeated administration. In this regard, determining the optimal dosing regimen for each animal species through repeat-dose toxicity studies is crucial to ensure safety that supports progression to human clinical trials [2]. 

For instance, recent studies have studied the interaction of psychedelics with the 5-HT2B receptor, which has been linked to cardiac valvulopathy (those diseases that affect one or more valves of the heart, because they either do not open or close properly, which influences the proper functioning of the heart) in several studies. The FDA emphasizes the importance of considering this potential risk in preclinical safety assessments. For repeat-dose preclinical studies, it is advisable to include specific cardiac valve evaluations to ensure patient safety and avoid potentially serious adverse effects. By implementing these measures, future studies could enhance the safety profile of psychedelics and minimize cardiac risks through targeted protocols and continuous monitoring with echocardiograms to support heart health ([2]; EMA, 2024; Rouaud et al., 2024). 

After identifying all potential safety effects and gathering preliminary data, psychedelic compounds can proceed to clinical evaluations, although these still face certain limitations and biases.

Advances in Study Design and Therapeutic Potential

Psychedelics undergo the gold-standard testing procedures of drug development, randomized-controlled trials (RCTs). In RCTs, the study population is carefully selected and then randomly assigned to either a treatment or control group. The treatment group receives the drug being studied, and the control group receives a placebo, with randomization minimizing the likelihood of biased results [3]. However, treatment models using psychedelics do not fully align with this gold standard and present different challenges. Specifically, RCTs do not account for how extra pharmacological variables influence the drug experience, yet these extra pharmacological variables have been deemed essential to facilitating the psychedelic experience (Carhart-Harris et al., 2018).

The effects of psychedelics on functional disorders appear promising, often leading to symptom improvement, in contrast with inactive placebo treatments, which may worsen symptoms due to negative expectations. Consequently, researchers are exploring alternatives to inactive placebos, such as sub-perceptual doses of psychedelics or psychoactive drugs that partly mimic the psychedelic experience. These alternatives could enhance future study designs by ensuring a more accurate measurement of psychedelic impact on efficacy and safety (Muthukumaraswamy et al., 2021). In psychedelic trials, patients may be able to identify that they’ve received the active drug due to its potent effects, creating a risk of bias. To mitigate this, researchers are employing specific questionnaires or strategies to manage functional unblinding better, thus improving study reliability.

The FDA recommends careful planning of plan dose-response relationships when designing studies with psychedelics, aiming to confirm safety and efficacy before progressing through the development pipeline [2]. However, regulatory bodies also tend to require large sample sizes to prove a drug’s efficacy and safety. Still, at present, sample sizes in trials using psychedelics tend to be relatively low. Reasons for this could relate to psychedelics being expensive and difficult to procure, as well as psychedelic-assisted psychotherapy being a labour-intensive process given the time required for preparation, integration and the experience itself.

Based on a wide range of research, psychedelics are considered physiologically safe and do not lead to dependence or addiction (Nichols, 2016). The EMA has recognized that the available data does not indicate a potential for addiction with classical serotonergic psychedelics (EMA, 2024). This evidence stands in contrast with psychedelics’ current position as Schedule I substances, which – by definition – have no accepted medical value and also possess high abuse potential.

Collaborative Efforts for Safe Psychedelic Therapies

Interestingly, Matthew Johnson and his colleagues at Johns Hopkins used the very same factors of the Control Substance Act, which classifies psychedelics as Schedule I substances, to assess the abuse potential of psilocybin. Johnson and his colleagues found that although potential harms exist for unprepared, unsupervised users, and in those with or predisposed to psychotic disorders, modern research addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility (Johnson et al., 2018). Moreover, these researches suggest that psilocybin would be more appropriately classed as a Schedule IV substance, given its therapeutic potential and safety.

What makes psychedelics all the more interesting is the ability of extra pharmacological factors to influence the experience, be it positively or negatively. As a result, therapy rooms in which psychedelics are administered are manipulated to ensure patients have a safe and positive experience. Again, Johnson and his colleagues at John Hopkins are accredited with writing the go-to guidelines for conducting psychedelic research in humans (Johnson et al., 2008). In their seminal paper, Johnson and FDA guidance for industry emphasize that the physical environment be free of extraneous medical or research equipment, in combination with careful volunteer screening, volunteer preparation and interpersonal support from two or more trained monitors, may help to minimize the probability of acute psychological distress during psychedelic studies and ensure the safety of patients.

Overall, adverse physiological reactions to classic psychedelics are rare. Nonetheless, psychedelics can create severe psychological distress and should be approached with caution. As psychedelic research is progressing, researchers and regulators are working together to realize the potential of psychedelic drugs in a manner that is safe for all those involved.

External references for Safety and Psychedelics

All resources available on Blossom are directly linked on this topic page. Find even more background about this topic with these external references.

1. FDA. (2017). The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective. Food and Drug Administration. Retrieved from https://www.fda.gov/drugs/information-consumers-and-patients-drugs/fdas-drug-review-process-ensuring-drugs-are-safe-and-effective
2. FDA. (2023). Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for Industry. June, 2023. Retrieved from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations
3. Hariton, E., & Locascio, J. J. (2018). Randomised controlled trials—the gold standard for effectiveness research. BJOG: an international journal of obstetrics and gynaecology, 125(13), 1716. https://pmc.ncbi.nlm.nih.gov/articles/PMC6235704/pdf/nihms966617.pdf