Skip the trip – does the world need non-hallucinogenic psychedelics?

July 20, 2022

Psychedelics are on the cusp of going mainstream. With the recent progressions in psychedelic medicine and lavish praise from the media, scientists and activists alike are only a stone’s throw away from bringing psychedelic therapy to the forefront of psychiatry. 

Despite the withstanding obstacles – both legal and clinical – more and more people are beginning to recognise the value of a psychedelic trip. But sceptics worry these psychoactive drugs may do more harm than good. 

Some scientists now believe that the impressive mental health benefits of psychedelics could be teased apart from all the mysticism and the trippy visuals. Is there such a thing as magic mushrooms, without the magic? Yes – and they could be game-changers for the field of psychedelic medicine. 

Psychedelics as the future of psychiatry

Research into psychedelic drugs is experiencing a renaissance. “Magic mushrooms”, LSD, ketamine, and MDMD – all substances that have fallen victim to the enduring war on drugs – are now proving to be invaluable tools for our mental health. As it evolves into a flourishing field of psychiatry, psychedelic-assisted therapy holds the potential to banish depression for up to a year, undo psychological trauma, and yield permanent shifts in mood and behaviour. 

Evidence of its clinical potential might be piling high, but do researchers actually know how it works? Although the exact mechanisms underlying psychedelic therapy are still being investigated, studies have shown that they are able to switch off the brain network responsible for sustained negative thoughts called the default mode network (DMN), whilst simultaneously increasing connectivity between other parts of the brain. 

These substances have also been shown to enhance neuroplasticity, the brain’s ability to modify its own structure and function. Lastly, but certainly not least, classic psychedelics are known to activate serotonin 5-HT2A receptors, which is what triggers the hallucinations that are characteristic of the psychedelic experience. 

It is believed that the amalgamation of these biological mechanisms is able to halt negative thinking, permitting profound personal revelations that result in lasting shifts in perspective and mood. But now, some researchers believe that the intense, mystical, “trippy” part of the trip is just smoke and mirrors.

It’s a bold claim to suggest that hallucinations are redundant – and one that has certainly sparked considerable debate in the community. But if it could be possible to yield the same therapeutic benefits of psychedelics, without patients having to go through this often life-changing – and often challenging – experience, this could completely turn psychedelic medicine as we know it on its head.

Skipping the trip – how and why?

Psychonauts among us, or those who have ever used psychedelics in pursuit of enjoyment or spiritual advancement, may be questioning why you would even want to bypass the trip. There are actually two key reasons why non-hallucinogenic psychedelics could be therapeutically useful.

Firstly, money. Some would argue that the existing framework for psychedelic therapy isn’t hugely feasible on a large scale. With preparation and integration sessions, as well as the lengthy trip itself, just one patient requires hours of personal treatment. Non-hallucinogenic drugs, however, would require less supervision and, thus, would be more scalable and profitable. 

those who have ever used psychedelics in pursuit of enjoyment or spiritual advancement may be questioning why you would even want to bypass the trip

The second, and perhaps the most important point, is that psychedelics aren’t for everyone. As any users will know, psychedelics send you down a hallucinogenic rabbit hole. You have access to the deeper territories of your subconscious which, for anyone living with anxiety,  trauma, or depression, could bring some pretty nasty stuff to the surface. What’s more, with the small risk of psychosis for those with a family history of schizophrenia, psychedelic therapy isn’t accessible to every patient.

Despite studies showing that psychedelic-induced feelings of mysticism correlate with improved therapeutic outcomes, whether or not the trip is necessary for psychological healing is yet to be determined. Psychedelics both produce profound experiences and have an antidepressant effect, says Chuck Raison, a professor of psychiatry at the University of Wisconsin-Madison. “They do both at the same time, so they get mythically linked, because the human brain works like that. It sees causation where there’s association.”

What some researchers have set out to address is whether the conscious experience of psychedelics plays a part in their therapeutic effectiveness. If scientists were then able to isolate their antidepressant effects in a drug that has no psychoactive properties, this could transform the future of mental health. 

The potential of “pseudodelics”

Is it even possible to skip the trip? New research suggests so. In the last few years, several non-hallucinogenic chemical compounds have been identified that mimic the biological effects of psychedelics, but without the hallucinations. 

In a 2022 interview with Volteface, Dr David Luke, a Psychology Professor at the University of Greenwich and Lecturer at the Imperial College London Centre for Psychedelic Research, coined the term “pseudodelics” to describe these non-hallucinogenic psychedelics – or, more specifically, “chemical analogues of psychedelic agents”. This is pretty much the science-lingo for “the same but slightly different”. 

As chemical cousins of psychedelics, they activate the same receptors, induce the same brain changes, and perhaps the same mental health improvements as psychedelics, but without the hallucinations.

In theory, if these drugs were proven to be safe and effective, this could allow for medicines to be self-administered, whereas the current model requires the guidance of trained clinicians in multiple, separate sessions. And unlike existing antidepressant drugs, such as SSRIs, it looks as though “pseudodelics” would not require daily administration. Just one or two doses could yield long-term mental health improvements. 

Could they really work?

It certainly sounds too good to be true – and even the existing evidence isn’t hugely robust, but there are some promising findings.

Chemical analogues of interest include AAZ-A-154 and tabernanthalog (TBG), both identified by a team of researchers at the University of California led by Prof David Olson. Animal studies of both compounds suggest that they, too, can produce rapid and long-lasting antidepressant and anti-anxiety effects, as well as promote neuroplasticity. 

But the evidence is far from conclusive. Not only are animals pretty unreliable models when it comes to investigating hallucinations and psychological experiences, but whether their antidepressant effects would translate into humans remains unclear. Many psychedelic researchers also find it hard to believe that these drugs would be effective when stripped down to their pure biological level. “My guess as a psychologist,” says Dr Luke, “is that the psychological experience probably has an important role to play.”

My guess as a psychologist is that the psychological experience probably has an important role to play

Dr Luke isn’t the only researcher to argue that the trip is essential for psychological healing. Dr Carhart-Harris, former Head of the Centre for Psychedelic Research, has implied that it is the extreme change in brain plasticity that can lead to extraordinary emotional changes. “They might create something akin to psychedelic tofu…or something that isn’t that trippy, that does a little bit of plasticity but it’s not really transformative,” he tells The New York Times.

Carhart-Harris also warns that simply increasing neuroplasticity in the brain “could shape someone in a bad direction,” and that the existing framework – where patients are guided by a psychotherapist – is what helps to push psychedelic therapy patients into a more positive mindset. 

For argument’s sake, however, let’s say these non-hallucinogenic psychedelic work – that their efficacy is proven. What would this mean for the future of psychedelic medicine?

Dr Luke claims that “research into the mystical experience would probably just die a death as well because all the funding would probably dry up.” For researchers who have endeavoured to understand the mystical element of psychedelics, this is understandably hugely concerning. 

Entheogenix Biosciences, a new AI-enabled biotech company, are instead investigating how they could “improve” the current model, rather than break it down. Its CEO, Srini Rao, told Vice that its team of researchers aren’t necessarily looking to skip the trip, but rather condense it. A therapy session that would typically last for 6-8 hours could then, in theory, be shortened to only 45 minutes. 

Entheogenix also hopes to “fix” other issues associated with existing psychedelics. Since serotonergic psychedelics come with a risk of damage to the heart muscle, this could improve the safety profile of psychedelic therapy and, in turn, advance the progression of its clinical study. 

The concept of non-hallucinogenic psychedelics is certainly a divisive one. The key takeaway here, however, is that researchers don’t yet know whether the hallucinogenic bit of the trip is crucial to its therapeutic effectiveness. There’s evidence to back up both sides of the argument, so we’re a long way from knowing for sure. 

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