Psychedelics, substances that produce non-ordinary states of consciousness, are currently being heralded as the therapeutic saviours for our long-standing mental health crisis, with preliminary studies showing promising results for psilocybin, MDMA and Ketamine-assisted therapy for depression, PTSD and addiction. 

However, whatever way you dress it up, the psychedelic trip and all it entails (insert here rubbing up against the darker recesses of your unconscious mind, uncontrollable vomiting and intense mystical experiences), is not for everyone. Nor is the current psychedelic-assisted therapy model, which requires weeks of therapy before and after treatment, a financially viable proposition for the biotech and pharma companies jostling for position in the psychedelic space.  

For a while now researchers have been trying to unpick what happens in our brains after ingesting psychedelics. From a biological point of view, scientists know that by activating the 5-HT2A serotonin receptor, compounds like psilocybin appear to cause the hallucinatory effects associated with psychedelics. Other changes in the brain include a shutting down of the default mode network, increased neuroplasticity, and improved connectivity between different parts of the brain. 

What is not clear is whether any one particular change or indeed all of them together are responsible for the impressive therapeutic outcomes experienced by patients receiving them in clinical trials and in other settings. 

Indeed is it even possible at all to reduce the effects of psychedelics to purely biological mechanisms of action?  

Psychedelics Without The Trip

This is very much the hope for researchers racing to develop psychedelic drugs without the trip that will create neurobiological changes like neuroplasticity without any altered state in consciousness, while ideally still having some therapeutic benefit for depression, PTSD, and addiction.    

“They are kind of chemical analogues of psychedelic agents,” says Dr David Luke, Associate Professor of Psychology at the University of Greenwich and Honorary Senior Lecturer at the Centre for Psychedelic Research, Imperial College London, “which are hoped will work the same way as psychedelics to help with mental health problems… without giving people any kind of psychedelic subjective experience based on the principle that the entire effect of psychedelics is on a non-psychological, biological level.”

This is a big assumption according to Luke, who in this interview coined the term ‘pseudodelics’, and he is not alone in his thinking.

“It’s trying to approach psychological issues in a purely biological way,” he says, “which hasn’t worked very well for psychiatry so far in the last 100 years… Psychiatry has been in crisis; the treatments haven’t improved in decades.”

In contrast, psychedelics are arguably so effective because they are much more than a sum of their ‘biological mechanism of action’ parts. Commonly reported occurrences under the effects of psychedelics include spiritual or mystical experiences, the healing of traumatic past events, deep psychological insights, greater feelings of connection, and the much hallowed ‘ego death.’ Indeed, studies even show the greater the mystical experience, the better the therapeutic outcome. 

However, while there is a correlation between these subjective experiences and psychedelics’ antidepressant effects, causation has not been proven, leading to a flurry of activity in labs around the world, including the DARPA (Defense Advanced Research Project Agency), to tweak existing psychedelic molecules or create new ones without the hallucinogenic effect. 

So far, front runners include an analogue of ibogaine called tabernanthalog. Ibogaine, an alkaloid found in Iboga root, has shown anecdotal success in treating heroin addiction, however, its hallucinatory effects and coronary risks have limited its clinical application. In opiate-addicted mice at least, tabernanthalog has shown promising results in reducing alcohol and heroin-seeking behaviour, while producing antidepressant-like effects.   

Another molecule, AAZ-A-154, has been found to activate the 5-HT2A serotonin receptor without making its furry subjects hallucinate, and appears to make them happier in the process. 

To Twitch or Not to Twitch

Testing molecules for psychedelic effects on animal models is far from an exact science, with head twitching being the standard sign that the mice or rats are tripping.

“Rodents aren’t little people with furry coats on, you know,” says Dr Luke. “Translational medicine doesn’t always work. Rats don’t communicate psychological experiences. There’s limitations to animal models, and also you can’t second guess how effective it is going to be.

“So it might be that some of these analogue psychedelics do have beneficial effects in reducing symptoms and some of it maybe is on a purely biological level. But my guess as a psychologist is that the psychological experience probably has an important role to play.”

Ultimately, we will only know whether these compounds have any significant therapeutic benefit for conditions when these animal studies are translated to humans. But if their efficacy is proven, this could have significant implications for the existing psychedelic-assisted therapy model. 

“In principle,” admits Luke, “the whole bottom could drop out of the psychedelic medicine approach if these drugs are found to be as effective as psychedelics with therapy. The research into the mystical experience would probably just die a death as well because all the funding would probably dry up and no one would be interested in psychedelic-psychedelics anymore; which could happen. So it’s really important… to see how they work in humans. I’m guessing they’ll be useful, but probably not as effective.”

“It is going to be really interesting,” he goes on. “It’s going to be like the ultimate, ‘let’s get materialist reductionism in the ring with somehow thinking being human is anything more than just being a meat sack’ and see who comes away with a bloody nose?”

Where will you be betting your money?

Mary Biles is a plant medicine advocate, author of The CBD Book, medical cannabis writer and podcast host who loves to unpack the science behind medicinal plants and psychedelics. Tweets @Mary_Biles






 

 

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