Lifting depression: Are hallucinations compulsory?

Is it necessary to trip the same light fantastic as recreational users of magic mushrooms, or is there a way to make psilocybin more of a daily drive?

With psilocybin having entered the medical sphere in Australia for the first time last month, scientists are divided over whether the hallucinations are the reason why it’s effective for treatment-resistant depression, or whether we can get away with psilocybin-lite.

For people self-medicating migraines or to stop smoking – both are emerging indications for psilocybin – being able to take a pill and go about their day without falling deeply in sync with ants crossing a footpath or sunlight playing on leaves, is likely to be very useful.

The same can be said for people with a family or personal predisposition to psychosis, or a history of trauma, or who lack the funds for the estimated $20,000 it will cost to buy the medication and hire two clinical psychologists for a six to eight hour session.

Is the full ticket just for fun or essential

Psilocybin is known to be very good at lifting the symptoms of depression and anxiety with only a few doses, which is why the Australian Therapeutics Goods Administration earlier this year (TGA) approved its limited use for treatment resistant depression with the rule taking effect on 1 July.

Does that mean to fix migraines, sufferers really do need to commune with the ants?

But attempting to ‘sliver off’ only the physiological benefits of psilocybin is opening up new ground in our understanding of how the brain works, says Martin Williams, president of psychedelics research not-for-profit Prism, and a Monash University MDMA and psilocybin researcher.

He says we know neural network connections deteriorate in the course of some mental illness, so the question is whether restoration of those connections could be all that’s required to resolve those conditions – or whether the hallucinations are also part of the cure.

Psilocybin, DMT and LSD work by inducing neuroplasticity, or creating an opportunity for the pathways in the brain to change, says Associate Professor Daniel Perkins, co-founder of University of Melbourne’s Medicinal Psychedelics Research Network and Executive Director of the Psychae Institute, a not-for-profit medicinal psychedelics research institute.

“The question will really be whether you can still get the efficacy if you have a similar drug, which doesn’t cause the hallucinations,” he told Cosmos.

“When you actually look at the clinical studies, the strongest predictor of clinical outcomes is the psychotherapeutic effects. And so that would be this sort of intense emotional processing and people gaining all these profound personal insights about themselves.”

Then there is the well-studied association of depression with inflammation, which also reduces with psilocybin. Does that mean to fix migraines – for which anti-inflammatories have long been the mainstay drug – sufferers really do need to commune with the ants?

Maybe, Perkins says, as we won’t know until the new edition of psilocybin emerges from the lab.

Team Psychoplastogens

Psilocybin’s effect is due to binding with several of the same 14 receptors that serotonin also attaches to, the 5-HTs.

These are the protein newswires that receive and report information to the body.

After a decade of closely watching the brain on LSD, scientists are sure it’s receptor 2A which is behind hallucinations.

Why, however, is still unknown.

How do scientists know whether their mouse is tripping or just feeling nice?

Yet researchers like David Olson, director of the UC Davis Institute for Psychedelics and Neurotherapeutics and leader of the scientists heading down this particular rabbit hole, believe that it’s the drug itself that provides the benefit, not the trip.

He has led several studies in mice and rats that suggest by adjusting the psilocybin molecule, it is possible to prevent the hallucination.

How do scientists know whether their mouse is tripping or just feeling nice? They watch for a characteristic rapid head twitch.

“The advent of psychoplastogens – compounds with the abilities to rapidly rewire neural circuitry by engaging plasticity mechanisms – represents a new era in the development of neurotherapeutics focused on fixing neural circuits rather than rectifying chemical imbalances,” Olson wrote in a 2020 paper.

He says “mystical-type effects, such as spiritual experiences, feelings of unity, and disembodiment” may simply indicate the 5-HT2A receptor is in play, rather than other changes in neural circuitry.

On a more practical level, future drugs could simply be more accessible without the hallucinogenic effect and the time required to undergo a monitored treatment, says Sam Banister, chief scientific officer Psylo, a company investigating just that proposition.

This is a brand new field, one that only really kicked off two years ago, yet a swathe of biotechs are dropping in, from Psilera and Compass Inc in the US to April 19 Discovery in the UK and Psylo in Australia.

“We’ve moved pretty quickly. And we’ve been very, very strategic,” says Banister.

“We’ve got a library of about 350 compounds that spans 13 different chemotypes… We’re doing what’s called lead optimization. So it’s taking natural psychedelics and making sensible modifications to them that can do things like remove some of the hallucinogenic properties, but keep a lot of the antidepressant profile.”

Psylo hopes to have a clinical candidate by the end of 2023 to take into preclinical testing, before animal trials and then, all going well, have the data and a drug ready to be tested on people by the end of 2024.

Anyone who is anyone is microdosing

The argument against spending incredible sums on developing drugs that don’t make patients see different dimensions (the rule of thumb spend for developing a new drug is about $1 billion dollars, from lab research to commercialisation) is to simply microdose.

People from Silicon Valley tech bros to working mums have sworn by a daily dose to lift their mood and enhance creativity without hallucinations.

And then there is the kicker: microdosing might give you heart disease.

But research is patchy on how much of this is placebo effect: it appears to work in rats and definitely in people who expected a boost, but gold standard trials are yet to be conducted.

A planned double-blind, randomised, placebo-controlled trial by Canadian psychedelics company Optimi Health Corporation was withdrawn in March with the reason cited on the US ClinicalTrials.gov registry as being “the sponsor no longer wishes to pursue the methods outlined in the protocol”.

Dr Mike Musker from the University of South Australia says microdosing is one way that psilocybin is being used, but evidence comes from the experience of individuals expecting a result.

“They’ve taken a dose that doesn’t provide a hallucinatory experience, it lowers the cognisant threshold, but the daily dose of that over a long period of time, has helped them in their depression, has lifted their mood, changed their views on the world, so there’s certainly been some evidence there,” he said during a webinar on the topic this month.

And then there is the kicker: microdosing might give you heart disease.

Psilocin, which is what psilocybin turns into in the body, interacts strongly with the 2B serotonin receptor.

So did fenfluramine, the active ingredient in 1990s weight loss miracle drug Fen-Phen. Just a few months using the drug left people with valvular heart disease, because of that potent interaction with the serotonergic receptor.

The overall effect of psilocybin and other drugs in the tryptamine family are increasingly well known – they can alleviate depression and anxiety, aid substance abuse, fix migraines, increase creativity among others – and if the optimistic hopes of industry figures are a measure, one day we may even see them stacked next to the Panadol.