To Hallucinate or Not: The Big Questions Facing Psychedelics at FENS 2022

Psychedelics drugs are, after a near-50-year absence from research, back in vogue. There are multiple milestones by which a neutral outsider might measure the extent of psychedelics’ revival. They do have their own Netflix show (actually, they now have several) but have not yet been approved by the US Food and Drug Administration. One smaller, nonetheless significant sign that the tide around psychedelic science is changing is the decision by the organizers of the recent Federation of European Neuroscience Societies (FENS) conference, the largest such neuroscience event in Europe, to carve out a slot for this burgeoning area of research.

Previous editions of FENS had featured little mention of psychedelics. While some sessions briefly touched on the antidepressant capabilities of the non-classical psychedelic ketamine, FENS 2022 broke new ground, featuring both a mini-conference, held in conjunction with the European College of Neuropsychopharmacology, and a symposium reviewing the advent of psychedelic compounds without hallucinogenic effects.

Technology Networks attended this latter symposium, which featured talks from Maastricht University’s Dr. Kim Kuypers, Stanford University’s Dr. Lindsay Cameron, Dr. Scott Thompson of the University of Maryland and Rafael Moliner from the University of Helsinki. The symposium aimed to tackle the idea, growing in popularity among researchers, that the rollout of potential psychedelic medicines could be limited by the hallucinatory trips that these compounds induce.

Psychedelics without the trip

“If psychedelics are able to be dissociated from the therapeutic effects, then it would be useful in reducing the amount of time that a patient has to spend. In preparation, during the drug administration, with follow up – that's a lot of time on the patient's side,” explains Cameron in an interview with Technology Networks.

Cameron also hopes that making psychedelics hallucination-free could reduce cost for patients and reassure individuals who are unsure about the effects of a trip that could potentially last hours and require close supervision from a nurse or therapist throughout.  

Cameron and her mentor, University of California, Davis Professor David Olson, have made the development of non-hallucinogenic psychedelics the focus of their research. Cameron marked a significant breakthrough with the publication of a paper on a compound called tabernanthalog, an analog of the psychedelic ibogaine.

Ibogaine, a compound produced by plants in the family Apocynaceae, has shown some potential in early-stage trials for the treatment of addiction. However, its effects are long-lasting, and concerns have been raised over the compound’s toxicity and cardiac side effects.

Tabernanthalog, in comparison, is non-hallucinogenic and non-toxic. In a small study in rats, Cameron showed that the compound could reduce alcohol- and heroin-seeking behavior, raising the possibility that it might mimic ibogaine’s anti-addiction function in humans. “The idea here,” Cameron explains, “is that we have a compound that seems to be therapeutically active but would no longer be producing hallucinations. Our lab coined the term ‘psychoplastogen’ as something that is able to cause this change, to mold brains.” The speakers came back to this focus on the brain-structure altering, or neuroplastic, effect of psychedelics throughout the symposium.

A serotonin debate

While the presenters were aligned on their interest in exploring non-hallucinogenic compounds, their data didn’t always sync up. Three researchers – Thompson, Cameron and Moliner – each looked at the role of the serotonin 5-HT_2A receptor, widely thought to be essential to the hallucinatory action of psychedelics. It’s unclear right now  whether these compounds’ antidepressant effects are also derived from signaling through this receptor. Cameron’s data suggested that tabernanthalog, at least, required 5-HT_2A activation to  produce its effects. Thompson, working in rodents with psilocybin, investigated how the drug affects the brain’s reward system in the context of chronic stress – a process that his results suggested to be independent of 5-HT_2A. A final talk from Moliner highlighted why such conflicting data will be common at this early stage of our understanding of psychedelics’ molecular action: these brain processes are incredibly hard to fine-tune.

Moliner showed data suggesting that ketanserin, a compound widely used in pre-clinical research as a pharmacological tool to block 5-HT_2A receptors, might not be very selective at all, instead acting to additionally block other subtypes of 5-HT receptor. Teasing out how these different molecular actors mediate the psychedelic experience will be key not just to developing better hallucinogenic and non-hallucinogenic compounds, but to understanding how depression and other mental disorders are realized in the brain.

These differing paradigms within a field are part of what makes scientific conferences so stimulating to better research. But there are debates around psychedelics that were largely bypassed at FENS 2022. 

Leaving behind psychedelics’ taboo

Dr. Muad Abd El Hay, a postdoctoral researcher at the Ernst Strüngmann Institute in Frankfurt, went to every psychedelic talk he could at FENS; he tells Technology Networks that he has “attended specialist psychedelics conferences since 2014”. To Abd El Hay, the presence of a psychedelics slot at FENS represents a huge shift from previous years. In the past, he explains, “[psychedelics] was a taboo subject … to do it right, you basically needed to sacrifice careers in a way.”

Now the field has flipped, Abd El Hay says. As larger labs – known for breakthroughs in non-psychedelic areas of science – began to publish landmark papers, the taboo has faded away. But Abd El Hay says that the decision by FENS to focus on the non-hallucinatory effects of psychedelics was potentially a non-representative introduction to the field: “The narrative at the end was, ‘We don't need that psychedelic effect for anything to happen in mice, neuroplasticity is everything and we don’t even need the 5-HT_2A receptor.’ It was really cool data, but a lot of people would disagree with this. They weren’t represented here.”

"What I knew to be a very collaborative field is suddenly turning to a very competitive one." ~Dr. Muad Abd El Hay

There are many key questions still to be answered around psychedelics, but as they start to be recognized more widely in neuroscience, there is an undeniable sense of momentum. “We’re finally starting to make progress to get these as therapeutics,” says Cameron.

What seems less clear is whether the culture of psychedelic research will survive the field’s move to the big time. To Abd El Hay, there was a noticeably different mood among the researchers he spoke to at FENS compared to those from psychedelics-only conferences. “I feel a little bit sad, because what I knew to be a very collaborative field is suddenly turning to a very competitive one,” he says.

That change might be inevitable as psychedelic research hits the headlines more and more. The first day’s joint symposium featured a speaker from growing and aspirational psychedelic pharma company Compass Pathways, which has been criticized for its aggressing patenting of psychedelic molecules.

A non-hallucinogenic, synthetic and more corporate future for psychedelics might be required to reach more patients and help more people, but it’s hard to see how that is compatible with the field’s past mindset of sharing and collaboration. Abd El Hay, nevertheless, says he did still manage to meet some future collaborators and FENS and have fruitful discussions, even if they didn’t come as easily as at previous psychedelic meetups. “I am not giving up on this [field], but it's a bit sad to see that these problems are coming,” he says.