What are the risks and benefits of the use of psychedelics for treatment of mental health disorders?Photo credit: Pawel Czerwinski via Unsplash
On 9August, the US Food and Drugs Administration (FDA) rejected a New Drug Application (NDA) for the use of MDMA-assisted psychotherapy to treat Post-Traumatic Stress Disorder (PTSD). The NDA was submitted by Lykos Therapeutics. This was the first time the FDA had considered a psychedelic for medical use — patients had hoped this decision would grant approval for the first new PTSD treatment in over two decades. There is a high unmet need for PTSD treatments, and for psychiatric disorders more generally. Many biotechnology companies have pinned their hopes for novel treatments on psychedelics. Clinical trial data looked promising, so why did the FDA make this decision, and what implications will this have on the nascent field of psychedelic therapeutics?
This was the first time the FDA had considered a psychedelic for medical use…
PTSD is a psychiatric disorder that can develop after a distressing event, affecting many veterans and survivors of abuse. Symptoms of the disorder include intrusive flashbacks, hypervigilance (state of increased alertness), negative alterations in cognition, and dissociative symptoms. PTSD symptoms are mediated by an overactive amygdala, a small part of your brain with the main purpose of processing emotions, creating a dysregulated fear response. No medications have been developed to treat PTSD specifically; antidepressants can be prescribed, but they often fail to address all symptoms. Current treatment options primarily rely on psychological approaches like exposure therapy. In these sessions, patients recount their traumatic experience and therapists guide the extinction or reframing of the negative memories. MDMA was used to supplement talking therapies in the 70s (before it was made illegal) and recent evidence supports such use. MDMA reduces activity in the amygdala, making it easier for patients to process their trauma.
No medications have been developed to treat PTSD specifically; antidepressants can be prescribed, but they often fail to address all symptoms.
Despite mounting political pressure for FDA approval and lobbying from veteran patient groups, insiders were unsurprised by the verdict. A meeting in June saw the FDA’s independent advisory board express overwhelming doubts towards Lykos’ clinical trial data. The board had concerns over issues like functional unblinding, addiction liability, and the overall safety profile of the drug. The FDA issued a Complete Response Letter detailing the reasons for the rejection and calling for a further clinical trial (known as a phase 3 study). Whilst this document is confidential, Lykos have since reported that it echoed the concerns of the advisory board.
An additional phase 3 clinical trial will be costly and is expected to delay the approval process by 5 years…
For Lykos, the outcome is a drastic setback; The company has cut 75% of staff and founder Dr Rick Doblin has left the board. Having initially resisted the request for another trial, a Lykos press release on 18th October suggested that they had resigned to the FDA’s demands. An additional phase 3 clinical trial will be costly and is expected to delay the approval process by 5 years, severely limiting Lykos’ chance to be the first company to get an MDMA treatment to market. To rub salt in the wound, a day after the FDA’s announcement, the journal Psychopharmacology retracted three papers from Lykos over allegations of unethical conduct. Investors may also be rattled by the FDA’s decision and their concerns may have been compounded by the recent announcement from Compass Pathways about the delays to the COMP360 trial (a clinical trial investigating psilocybin as a treatment for major depression).
The FDA’s response is not a death sentence for psychedelic treatments. Instead of an outright rejection, it is a call for more evidence. This requirement may help the field by encouraging more rigorous research standards. Lykos’ downfall could be the sacrificial lamb of psychedelics research, laying out a clearer roadmap for others by highlighting the FDA’s pain points.
Lykos’ downfall could be the sacrificial lamb of psychedelics research…
Atai Life Sciences and Compass Pathways are among the companies distancing themselves from Lykos, by focusing solely on drug treatments without involving psychotherapy in their trials. Many believe this to be one of Lykos’ mistakes, as the FDA is unable to regulate psychotherapy. Theoretically, Lykos’ inclusion of psychotherapy is justifiable. Evidence shows that psychedelics work by increasing patients’ openness to therapy. However, this approach is incompatible with the current regulatory system, raising questions over the FDA’s preparedness for the anticipated psychedelic drug revolution. Furthermore, the Lykos trial used an internally formulated, ‘personalised’ therapy approach, which is difficult to validate. For biotechnology companies unwilling to neglect the psychotherapy component, it remains clear that they must use standardised approaches that are supported by existing literature.
Future trials can also learn from Lykos by targeting functional unblinding. Due to the potent and recognisable effects of psychedelics, patients are often aware that they have been given the drug or a placebo – in Lykos’ trials, 94% of participants correctly identified that they had received the drug. This unblinding is problematic for two reasons. It can cause bias in the patient’s opinion of treatment, but can also be detected by therapists who may act differently with patients depending on their treatment. The solution moving forward lies in the use of active placebos – compounds which mimic the physiological effects of psychedelics without the therapeutic benefit.
…in Lykos’ trials, 94% of participants correctly identified that they had received the drug.
In addition, companies will be scrabbling to prove the safety of the psychedelic drugs they are trialling. Research teams are exploring multiple approaches: optimising dosages to reduce side effects and enhancing psychological support during treatment sessions. Some are attempting to engineer out the hallucinogenic effects entirely. Again, this demonstrates that the FDA’s decision should ultimately benefit patients in the long-term.
Overall, it seems industry experts have interpreted the FDA’s decision in August as specific to Lykos and remain optimistic about the future of psychedelics. However, the process has highlighted overarching concerns. While many are incredibly passionate about getting these drugs approved, it is vital that such passion compromise objective evaluation in clinical trials, especially when the disorders involved rely heavily on self-reported symptoms. Neutrality, ethical stringency, and scientific rigour will be key in securing future FDA approval.
