The field of psychedelic therapeutics is moving fast; there are now hundreds of clinical trials spanning early to late stages, led by small biotechs and Big Pharma companies alike. This Monday, Compass Therapeutics announced they submitted a New Drug Application (NDA) to the FDA for COMP360, a synthetic form of psilocybin, for treatment-resistant depression.
Yet, these trials are rapidly progressing against a backdrop of inconsistent results in the foundational science investigating these drugs. Animal behavior experiments do not always show positive effects from psychedelic therapies, and discrepancies can arise from differences in the dose, experimental conditions, and behavioral tests used.
Given that animal models are commonly used to understand the mechanistic neuronal and circuit-level effects of psychedelics in the brain, a team of researchers from five different labs at UC Berkeley, UC San Fransico, and Stanford University, set out to discover which effects from psilocybin are actually durable in mice. Their results were recently published in Nature Neuroscience.
“In doing so, we hoped to guide future mechanistic research of psilocybin’s effects to focus on what is replicable, rather than what is not,” Odilia Lu, a neuroscience PhD student in Stephan Lammel’s lab at UC Berkeley, and co-first author on the paper, told DDN.
They found that psilocybin did not lead to replicable long-lasting decreases in anxiety or depressive-like behaviors — instead, all five labs found increased anxiety soon after the therapy was given. They did find that expressions of fear were reduced, on the other hand.
“The large number of null results at persistent timepoints did surprise me, personally,” Lu said. “Therapeutic-like effects of psilocybin are being published at a high rate, and the media often portrays psychedelics as potential ‘cure-alls’ and the next-generation of psychiatric treatments. I carried some of that expectation with me.”
The team now hopes their study will inspire other labs to also seek out the most robust effects. “It's an urgent call to the field,” Lammel said in the press release. “It means, hey, we understand the excitement about psychedelic drugs and we have seen their therapeutic effects in humans, but let's all work together as a group, not individually, to solve this and really leverage the potential these drugs might have.”
Identifying the most replicable effects
To find the most robust effects of psilocybin in mice, the five research labs followed identical protocols. Pooling all the data together revealed that the most reproducible effects were increased anxiety and decreased fear expression at the acute timepoint. Null effects for the more well-known and expected long-lasting reductions in depression or anxiety-like behaviors were not observed.
While some labs found statistically significant effects and some didn’t, the labs attribute this to a small underlying effect size. Methodological variables, such as the sex of the handler, purchase companies that sold the mice, and the number of weeks mice were housed in the laboratory before experimentation did not impact the effects of the drug.
But the researchers are not suggesting that the study means all prior findings are false positives in mice, or that pursuing psychedelic therapy for anxiety and depression and humans is not still worthwhile. “I would caution against overinterpreting our null results in mice as evidence that psychedelics lack therapeutic potential for depression or anxiety in humans,” said Lu. “There are important limitations to translating preclinical behavioral findings, ranging from the validity of the methods used to induce depression-related phenotypes in mice to the extent to which behavioral assays capture the complexity of human depression and anxiety.”
She added that the subjective effects of psychedelics could interact with pharmacological effects in humans, and it’s not known and difficult to measure whether mice experience anything similar. Lu noted it’s also possible that psychedelics are more efficacious in humans more generally. “Psychedelic treatment in humans often involves psychological preparation, therapy and continued support,” she said.
At the same time, given their findings related to decreased fear expression in the mice, Lu said that she would be interested in whether that result translates to humans. “Could this effect be leveraged during exposure therapy for PTSD to facilitate extinction of conditioned fear responses? I think this is an interesting potential therapeutic application that warrants further investigation,” she said.
Continuing the search for what works and what doesn’t
With their new combined data in hand, Lu said that the team is still interested in psilocybin’s reported effects for depression. Instead of abandoning this direction because of the null results in their study, they are now interested in investigating exactly which experimental conditions, including the dose, leads to reliable replication for depressive symptoms.
The multi-institutional study also generated new questions to answer, said Lu, such as: how generalizable therapeutic benefits are across patient demographics and differing administration settings, what contributes to the therapeutic effects in terms of things like expectations and psychotherapy, and whether these therapies do acutely increase anxiety in humans as they do in mice.
Lu also hopes their study will encourage similar studies in the future. ”When an effect replicates across laboratories, we can have greater confidence in its robustness and begin investigating the underlying mechanisms. When it doesn't, we can work to understand which experimental conditions might explain the differences,” she said. “Both outcomes are valuable for moving the field forward.”
