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Real-World Challenges of Psychedelic Therapies

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Real-World Challenges of Psychedelic Therapies

Psychedelic-assisted therapies are on the cusp of mainstream acceptance, with promising results from clinical trials paving the way for potential FDA approval. However, the potential benefits of these treatments are intertwined with real-world concerns about their safety and efficacy.

To address this critical issue, I have reached out to Dr. Rick Dart, a leading expert in toxicology and emergency medicine. Dr. Dart has dedicated his career to understanding the benefits and risks of various medications. In a recent commentary, Dr. Dart and his colleagues emphasize the urgent need for post-market surveillance programs to ensure the safe and effective implementation of psychedelic therapies.

In this interview, Dr. Dart delves into the complexities of this emerging field, discussing the potential risks associated with the widespread use of psychedelics like MDMA and ketamine, the role of REMS (Risk Evaluation and Mitigation Strategies) in mitigating those risks, and the crucial need for a comprehensive approach to data collection and analysis.

Dr. Dart, who has witnessed firsthand the challenges of drug regulation, particularly during the opioid epidemic, shares his insights on the FDA’s approval process, the potential for drug withdrawal, and the importance of understanding patient perspectives on the effectiveness of psychedelic treatments. 

You’ve been at the Rocky Mountain Poison and Drug Center for nearly 32 years. Why did you decide to focus on psychedelics now, and how does it connect to your previous experience?

Dr. Dart: The principle of medicine is to use tools where the benefits outweigh the risks. Throughout my career, I’ve been examining this balance with various medications. Since the early 2000s, we’ve been studying opioid analgesics, which genuinely tested this balance. 

With the growing momentum and increased use of psychedelics, along with their proposed therapeutic potential, examining them was a natural transition. We’ve already studied opioids, stimulants, and muscle relaxants—psychedelics are the next logical step in understanding medication benefits and risks.

With MDMA on the cusp of FDA approval, what were your initial thoughts on the advisory committee’s strong opposition, and do you have any perspective on the likelihood of approval?

Dr. Dart: I’ve seen this scenario with at least a dozen drugs over the past 30 years. While the FDA generally follows the advisory committee’s advice, they don’t always adhere strictly to it. 

Despite the committee’s concerns, the FDA might still approve MDMA, though I’d estimate the chances are less than 50/50. There’s substantial experience with psychedelics and MDMA, but safety concerns remain significant. 

There is substantial experience with psychedelics and specifically with MDMA. While there are valid concerns about the research design, many believe that MDMA works. The real question is whether it is safe enough for use. Unfortunately, we don’t have a definitive answer yet. The FDA could potentially approve it with restrictions to limit its availability.

If I had to bet, I’d lean towards it not being approved. However, I’ve seen drugs with similarly negative votes still get approved. We’ll have to wait until August to see the outcome.

Lessons From Ketamine

With the rise of ketamine clinics, what risks are associated with its widespread availability?

Dr. Dart: Ketamine has been around for a long time and is generally safe when used in a controlled setting, like an emergency department, with medical supervision. Its effects are short-lived, which adds to its safety profile compared to longer-lasting psychedelics like MDMA.

However, the effectiveness data for ketamine is less clear. Esketamine, a derivative of ketamine, has shown promising effectiveness through rigorous FDA trials. For ketamine, many studies are observational and non-blinded, lacking comparison groups, which makes it hard to determine if improvements are due to the drug or other factors like counseling.

A significant regulatory issue is that ketamine was initially approved for anesthesia, not for its current uses. Prescribing laws allow physicians to prescribe approved drugs for any use, creating a gap in scrutiny for ketamine’s new indications.

This regulatory flexibility has led to varied practices. Some clinics follow a medical model with supervised sessions, while others offer less supervision, even allowing at-home use monitored via camera or not at all. This looser supervision increases risks. There have been incidents requiring emergency department visits, though no deaths have been reported that I am aware of. The risk increases with less stringent oversight.

Risk Evaluation and Mitigation Strategies (REMS)

Can you explain what REMS means and how it could apply to MDMA, psilocybin, and other psychedelic treatments?

Dr. Dart: REMS, which is the abbreviation for Risk Evaluation and Mitigation Strategy, became emphasized during the prescription opioid epidemic in the 2000s. Traditionally, the FDA would approve a drug and leave it to doctors to use it appropriately. However, with powerful and addictive drugs, the FDA realized some providers weren’t as responsible. REMS is a structure put in place to reduce the risk of adverse events from drug use.

REMS can include educational materials for patients on drug use and adverse events and special qualifications for providers, such as board-certified psychiatrists with experience in specific conditions. It can also involve direct-to-clinic drug delivery, where the drug is administered in a clinic, and the patient is observed before going home. For example, doctors administer Spravato (esketamine) in a clinic and monitor the patient for two hours before leaving. This procedure ensures proper use under medical supervision.

However, REMS doesn’t guarantee safe use. Therefore, evaluation of the REMS is needed. Real-world data programs like RADARS® (Researched Abuse, Diversion, and Addiction-Related Surveillance) System assess outcomes by looking at adverse events and their rates post-treatment. 

How do REMS for psychedelics differ from those for opioids or other drugs? Is it due to the therapy component, abuse potential, or something else?

Dr. Dart: Psychedelics differ significantly from opioids and stimulants, primarily due to the lower craving associated with them. Unlike opioids, which cause severe withdrawal and a desperate craving, psychedelics don’t lead to such intense or immediate needs. People don’t typically commit crimes to get psychedelics; their use is typically periodic.

Lower craving results in fewer severe issues like those seen with opioids. Psychedelics, when used correctly, are generally safe, and the adverse events we monitor for are different from those with opioids. For instance, we watch for relational issues between providers and patients, such as abuse as well as persistent perceptual disorders. These unique risks require tailored mitigation strategies.

We use mosaic surveillance, examining problems from multiple angles to avoid biases from single data sets. This approach for psychedelics differs from that for opioids or stimulants, requiring adapted tools to gather relevant data. It’s also crucial to differentiate between users—whether they are part of structured state programs, using recreationally, or involved in spiritual groups, as these contexts influence safety and efficacy.

Are measures for psychedelics developed after approval, or are sponsors involved early on? Are there lessons to learn from ketamine?

Dr. Dart: We’ve learned much from monitoring Spravato and are in ongoing dialogue with state programs like Colorado and Oregon. Our initial, small-scale programs have provided valuable insights. For example, focus groups with psychedelic users and providers in Denver revealed crucial usage and monitoring practices. These insights help shape our data collection with patient consent.

We see two main paradigms: the FDA and state programs. The FDA requires sponsors to monitor drug safety, typically starting post-approval. Sponsors may develop safety programs in advance, but active monitoring begins once the drug is on the market. State programs, driven by legislation, operate differently and more slowly, often needing more specific product identification than federally approved drugs.

State-level monitoring faces challenges due to product variety and unclear identification, making data collection harder. Historically, state programs encounter predictable issues post-approval, like cannabis-related accidents. Public perception often blames state programs without considering broader contexts.

We aim to demonstrate that state programs offer safer alternatives through structured supervision, reducing risks better than unregulated environments. This data-driven approach helps policymakers defend these programs and highlights the benefits of regulated use.

Bridging the Gap Between Clinical Trials and Real-World Monitoring

What are some potential issues to monitor in real-world data that aren’t evident in clinical trials?

Dr. Dart: Clinical trials involve controlled groups, often excluding patients with comorbidities or other complications. For instance, MDMA trials exclude those with heart conditions due to cardiovascular risks. However, once approved, the drug is used by a broader patient population, necessitating post-marketing surveillance. 

Cardiovascular effects are a primary concern for all psychedelics, especially MDMA. Agitated delirium or psychosis is another issue. Trials usually focus on single-issue patients, but real-world usage involves complex, overlapping mental health conditions. For example, someone with both PTSD and manic depressive disorder might have different outcomes. 

This is why patient registries that track long-term data on conditions and adverse events are crucial. Understanding cardiovascular health and comorbidities in a broader population will be vital.

How can we track and monitor real-world usage of psychedelics, and what impact does unregulated use have on data quality?

Dr. Dart: Tracking real-world usage is challenging. Studying an FDA-approved drug is easier due to defined documentation and treatment periods. In state programs, usage can be sporadic and less structured, with patients possibly viewing it as personal use.

Collecting longitudinal data is essential to track drug usage over time and identify factors contributing to adverse events. For instance, if a patient initially does well on FDA-approved MDMA but later uses unregulated psychedelics, it’s crucial to distinguish the causes of any adverse events. Accurate data collection helps make these distinctions clear. 

Our program aims to follow patients over time, monitoring their drug use and health outcomes. There’s a risk of patients seeking cheaper, unregulated alternatives, which can lead to potential abuse and health risks. Detecting these patterns is vital, as street MDMA often contains methamphetamine, posing different risks. Thorough data collection is more important than ever to ensure safety.

Before the rise of psychedelics, cannabis became widely available through state-level programs. Are there lessons from monitoring cannabis that we can apply to psychedelics as they become more widely available?

Dr. Dart: With cannabis, the movement was almost political, leading to minimal initial research as it was assumed safe. This time, we’re trying to get ahead. If the state designs thoughtful metrics and incorporates them into rule-making, it would provide the data researchers like us need to analyze the program’s effects on the population, like Colorado.

The FDA operates broadly nationally, but we need a customized approach for Colorado. We hope to implement these measures soon after the program launches. Oregon didn’t do this initially, leading to current challenges. We’re trying to learn from them and act proactively.

What challenges do you foresee with diverse psychedelic user populations in real-world settings?

Dr. Dart: A significant challenge is the diversity of psychedelic user populations. Some individuals use psychedelics for self-improvement, aligning with the FDA-approved drug population. However, others use psychedelics in less supervised, polydrug environments. The safety and effectiveness for these users will be different.

These users might not be seeking self-improvement, but rather the experiences psychedelics produce, sometimes with other substances. This distinction is crucial as we move forward and requires significant effort to address appropriately. Understanding these different user groups and their varied contexts is essential for effective monitoring and safety measures.

Preventing Drug Withdrawal Based on Post-Marketing Surveillance

Are there circumstances you foresee through post-marketing surveillance that might trigger FDA withdrawal of MDMA or other psychedelic treatments?

Dr. Dart: Yes, adverse events linked to subsequent use of illicit substances could be a significant trigger. For instance, a patient might have a positive experience with legally prescribed MDMA but later use an illicit version, leading to severe reactions. This can complicate the safety profile of the original drug.

The FDA has withdrawn drugs when post-marketing data revealed significant safety concerns. Robust data collection is crucial. Suppose a manufacturer doesn’t adequately monitor adverse events. In that case, it becomes difficult to distinguish between the effects of the approved drug and other variables, which might lead to withdrawal or ‘black box’ warnings.

For example, if there’s a spike in cardiovascular incidents among MDMA patients, thorough data collection is essential to determine if these are related to MDMA or other substances like methamphetamine. Understanding these nuances can prevent unwarranted blame on MDMA and ensure patient safety.

Comprehensive surveillance involves tracking all substances a patient uses and changes in their health status. Detailed records help pinpoint the exact cause of adverse events, whether it’s the approved drug or another factor.

The safety of MDMA and other psychedelic treatments hinges on meticulous post-marketing surveillance, tracking patient outcomes and behaviors, and distinguishing between controlled and illicit substance effects. This ensures these treatments remain safe and effective for the broader patient population.

How do you plan to evaluate the effectiveness of psychedelic treatments?

Dr. Dart: Evaluating effectiveness also involves gathering patient-reported outcomes, which the FDA and sponsors often overlook. We want to know if the drug helped the patient, how it continues to help, and in what ways.

Having this information is crucial for making informed decisions. Patient-reported outcomes are invaluable if the FDA needs to consider withdrawing a drug or if the state needs to discipline a provider. This data can also help tailor safety requirements without removing a beneficial drug from the market.

It’s exciting to collect this kind of information, which we’ve never had before. By combining effectiveness data with safety monitoring, we can ensure these treatments remain both safe and beneficial for patients.

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