Mind-altering medicines

With a post-Covid mental health crisis looming, Maria Burke reports on research into the use of psychedelics-based medicines

Many researchers are predicting a massive mental health crisis exacerbated by the Covid pandemic and associated lockdown measures. With depression and anxiety rates increasing rapidly around the world, companies developing psychedelics-based medicines as novel mental health therapies are gaining increasing attention.

In a research note in April 2020, Amma Shah, an analyst at Eight Capital, a Canadian investment bank, estimated the potential market for psychedelics-based mental health treatments to be around $100bn. The first company in the psychedelics industry to trade publicly launched on Canada’s NEO stock exchange in early March, 2020. Mind Medicine raised over $30m from investors.

Companies are looking to exploit the recent surge in research. Researchers around the world report promising results from compounds such as psilocybin, the active ingredient in magic mushrooms, LSD and ibogaine found in a West African shrub.

‘Psychedelic medicine can provide an effective therapy for many hard to treat conditions, such as PTSD, treatment-resistant depression, addiction and potentially many other disorders,’ says Jo Neill, professor of psychopharmacology at the University of Manchester, UK: ‘More research is urgently required to enable our understanding of how these drugs work and how they can best be used for patient benefit.’

To accelerate R&D efforts, researchers would like these recreational drugs to be re-scheduled as Schedule 2 drugs. At present, they are listed as Schedule 1 drugs in the UK and the rest of the world, meaning they can only be studied under licence from regulators.

In July 2020, Neill joined her voice to many others in a report calling on the UK government to relax drug scheduling restrictions for psilocybin. ‘They hinder research, creating time delays, significant costs, and unnecessary bureaucracy,’ says the report from the Adam Smith Institute and written by teams from King’s College London (KCL) and the University of Manchester.¹ It argues that psilocybin is not dangerous and not addictive when compared with other drugs.

First synthesis

Albert Hofmann, a chemist working for Sandoz, first isolated synthesised psilocybin in 1958; he was also the first to synthesise and investigate the psychedelic effects of LSD in the 1930s and 1940s. Sandoz backed investigations into the therapeutic potential of psilocybin as it was much easier to study than LSD.

Psilocybin is a psychedelic alkaloid of the tryptamine family found naturally in over 100 species of fungi. Like LSD, it induces temporary changes in mood, perception and cognition. When taken orally, the effects come on in 20-40 minutes and last around three to four hours, compared with LSD, which can produce effects that last for 12 hours.

However, research into LSD, psilocybin and psilocin, its pharmacologically active metabolite, was curtailed in the 1970s when they were listed as Schedule 1 drugs under the UN 1971 Convention on Psychotropic Substances. It wasn’t until the 2000s that research picked up again as scientists searched for new ways to treat mental health conditions amid rapidly increasing numbers of sufferers.

A significant step forward came in 2016, when a team at Imperial College London led by Robin Carhart-Harris, published a proof-of-concept study of psilocybin for treatment-resistant depression in 12 patients. Administered in a clinical setting with psychological support, the treatment appeared to be safe and warranted further research. All patients showed some clinical improvements for at least three weeks after treatment.²

Two further landmark US studies that year – one from the Center for Psychedelic and Consciousness Research (CPCR) at Johns Hopkins University³ and one from New York University (NYU)⁴ – backed up these findings. These looked at cancer patients with anxiety and depression. They showed that a single psychedelic experience in a clinical setting could produce profound and enduring mental health benefits.

NYU recently reported a long-term follow-up of its 2016 study in a subset of original participants. Its study found sustained reductions in anxiety, depression, hopelessness, demoralisation and death anxiety at 4.5 and 6.5 years later.⁵ ‘These results may shed light on how the positive effects of a single dose of psilocybin persist for so long,’ says lead author Gabby Agin-Liebes. ‘The drug seems to facilitate a deep, meaningful experience that stays with a person and can fundamentally change his or her mindset and outlook.’

Mechanism of action

Psilocybin appears to directly increase activity and change patterns of connectivity in brain regions strongly associated with ongoing depression and anxiety. Scientists believe that it does this by activating receptors for serotonin. Through working on the serotonin system, psilocybin ‘relaxes’ the brain mechanisms that mediate thought and behaviour, loosening the habitual patterns of thinking and behaviour underpinning many mental health conditions. As old patterns ‘dissolve’, a therapeutic ‘window of opportunity’ is introduced.

Patients receiving psilocybin describe a ‘waking dream’, with new insights and understanding emerging about why they are suffering. Researchers think that these experiences may be enough to reset the brain. Afterwards, therapists work with patients to discuss new perspectives on their difficulties, including planning for the future.

In May 2020, researchers at the CPCR at Johns Hopkins University compared the brain scans of people after they took psilocybin with scans of people taking a placebo. They found that the claustrum region was 15-30% less active in patients taking psilocybin.⁶ This region is believed to be responsible for focusing attention and switching tasks. The researchers say this could explain why people taking psychedelic drugs often report feeling connected to everything and a reduced sense of ‘self’. They also found that psilocybin changed the way that the claustrum communicated with brain regions involved in hearing, attention, decision-making and memory.

‘Our findings move us one step closer to understanding mechanisms underlying how psilocybin works in the brain,’ says Frederick Barrett, assistant professor of psychiatry and behavioral sciences at the CPCR. ‘This will hopefully enable us to better understand why it’s an effective therapy for certain psychiatric disorders, which might help us tailor therapies to help people more.’

Meanwhile, Robin Carhart-Harris’ team at Imperial is currently reviewing data from a trial comparing psilocybin-assisted therapy with a six-week course of a conventional antidepressant drug. Carhart-Harris theorises that psychedelics boost plasticity in the brain and this surge leads to a psychedelic experience that makes lasting therapeutic change possible. The same dramatic effect might happen in extreme trauma, but with psychedelic therapy, the experience is carefully prepared for and controlled.

From his experience, patients report feeling clear-sighted, emotionally and physically recalibrated, and sometimes as if they have released pent-up mental pain. This is different to conventional anti-depressants, which can make people feel vague and muddled. Preliminary analyses of their data indicate ‘game-changing results’, he says.

Development apace

Several companies are now developing psychoactive compounds for depression, anxiety and addiction. In 2019, Compass Pathways completed the largest ever randomised study of psilocybin at KCL. It involved 89 healthy volunteers who were given COMP360, the company’s patented synthetic psilocybin formulation. Doses were administered simultaneously to up to six participants, who then received one-to-one psychological support.

‘The results of the study are clinically reassuring and support further development of psilocybin as a treatment for patients with mental health problems that haven’t improved with conventional therapy,’ says James Rucker, Consultant Psychiatrist at KCL’s Institute of Psychiatry, Psychology & Neuroscience. ‘About a third of people suffering with major depression don’t get better with standard drug and psychological treatments. Good quality, small-scale clinical trials have indicated that psilocybin therapy is an effective new treatment for those people.’ 

Compass, which received a FDA Breakthrough Therapy Designation for its psilocybin therapy in October 2018, is now beginning Phase 2b trials of COMP360 after an $80m funding round in April 2020. It will be the largest clinical trial of a psilocybin formulation to date, recruiting 216 patients across Europe and North America.

Compass is keen to stress that psilocybin therapy is very different from taking recreational drugs. ‘Patients are given the psilocybin dose in a carefully prepared setting, with psychological support from specially trained therapists who are present throughout the experience,’ a spokesperson points out. ‘The psilocybin session is preceded by preparation sessions and followed up with integration sessions [talking through experiences] with the same therapist. This is not a drug being taken alone at home.’

In November 2019, the US-based Usona Institute, a not-for-profit research organisation, also received a FDA breakthrough designation for its psilocybin treatment PSIL201, the first for Major Depressive Disorder. Phase 2 trials are under way involving 80 patients.

Usona recently published a ‘breakthrough’ technique in kg-scale synthesis of pharmaceutical grade psilocybin.⁷ The synthesis was designed to address several challenges encountered by previous attempts at scale-up, which struggled to provide consistent yield and purity of products, and weren’t suitable for pilot plant-scale reactors.

The company claims that ‘the scalability, controllability, and reproducibility in this newly developed procedure demonstrate that a classic reaction can produce pharmaceutical-grade psilocybin at a large scale in fewer steps’. It involves Speeter–Anthony tryptamine synthesis to produce the intermediate psilocin, which is then phosphorylated directly with phosphorus oxychloride. ‘The combination of simplicity, stability and quality from this process is elegant,’ says Gary Tarpley, Chairman of the Scientific Advisory Board at Usona. This work is now available to current Good Manufacturing Practices (cGMP) manufacturing labs and qualified researchers.

Psychedelic medicine can provide an effective therapy for many hard to treat conditions, such as PTSD, treatment-resistant depression, addiction and potentially many other disorders.
Jo Neill professor of psychopharmacology, University of Manchester

LSD and ibogaine

Interest is also growing in LSD and ibogaine. Mind Medicine recently entered a 10-year exclusive collaboration with Matthias Liechti, a researcher in psychedelics pharmacology at University Hospital Basel (UHB) in Switzerland. Jamon ‘JR’ Rahn, co-CEO of Mind Medicine, says the Liechti lab’s impressive list of clinical trials and human safety studies on LSD represent pivotal work in understanding how LSD interacts with the human body.

The company has acquired five Phase 1 clinical trials and three Phase 2 clinical trials from UHB. It is currently focused on the Phase 2 trials, particularly a LSD therapy to treat anxiety. The other two are to test LSD as a treatment for severe cluster headaches (suicide headaches), and proof-of-concept trials to evaluate microdoses of LSD in adult ADHD.

Rahn says: ‘While there is more to learn about the mechanism of LSD in relation to anxiety, it is understood to increase brain communication and support talk-therapy by expanding the mind and minimising inhibitions. LSD works by influencing a diverse set of neurotransmitter systems but its psychosensory effects are mostly mediated by activation of [serotonin] receptors.’

Additionally, with the UHB collaboration, Mind Medicine is working on two other drugs, MDMA (ecstasy) and DMT (N,N-Dimethyltryptamine), as well as a personalised medicine dose optimiser and an LSD neutraliser, which functions as an ‘off switch’ in the event of a negative experience.

Mind Medicine is also exploring a derivative of ibogaine, a natural indole alkaloid, to treat opioid addiction. Ibogaine is derived from the West African iboga plant where it was used in healing ceremonies and initiation rituals. 18-MC, which was invented by the company’s Scientific Advisory Board Chair, Stanley Glick, is designed to be a safer version. Ibogaine has been linked to heart side-effects and may be unsuitable for people with cardiovascular issues.

‘Addiction is a brain disease, driven by a single disease process: the dysregulation of dopamine, a potent neurotransmitter, in the brain’s reward/pleasure centre located in the midbrain,’ explains Rahn. ‘We are developing 18-MC to treat the cause of the brain disease that is addiction, rather than merely substituting one addictive substance for another less harmful one.’ In April 2020, Mind Medicine began human safety trials for 18-MC in Australia and aims to begin Phase 2 trials later in 2020. The company intends to apply for US FDA Breakthrough Therapy Designation for its Addiction Program.

Another company developing ibogaine for treatment of opioid addition is Miami-based DemeRx. The company received a boost in January 2020 when the global biotech platform ATAI Life Sciences announced a $22bn investment in two separate joint ventures (JV). The first JV involving its ibogaine therapy DMX-IB1 is looking to start Phase 2 studies in opioid-dependent patients.

Deborah Mash, CEO of DemeRx, led a large study of ibogaine involving 102 opioid dependent and 89 cocaine dependent subjects in the West Indies in 2000. It found that a single oral dose of ibogaine significantly reduced opioid withdrawal scores thirty-six hours after treatment, while also reducing the severity of cravings and depression in both groups. Importantly, these positive effects persisted at a one-month follow up.⁸

‘Not only were patients able to safely and successfully transition into sobriety, we found no evidence of additional abuse potential,’ says Mash. ‘Given the limitation in currently available treatments, ibogaine represents an enormous leap forward for sufferers.’

As ibogaine therapy is contraindicated for those with cardiovascular issues, the ibogaine JV will involve developing a treatment protocol that includes proper screening procedures, dosing guidelines, and administration best practices.

Researchers believe ibogaine affects multiple neurotransmitter systems, including serotonin and NMDA receptors found in nerve cells, although its exact mechanism is unclear. By producing a visual experience and dream-like state, ibogaine appears to help some people receive insights into their destructive behaviour. Mash describes ibogaine as ‘an addiction interrupter’ or a transition to sobriety. She says it gives the patient a ‘neurochemical reset’ providing a window of opportunity to end drug addiction when they don’t experience cravings, making them more ready to accept treatment such as rehabilitative therapy.

The second JV will evaluate noribogaine (DMX-NB1), a metabolite of ibogaine, as a possible follow-up or maintenance therapy. Noribogaine is an indole alkaloid with an unusual opioid pharmacology. The company plans to develop it as an adjunct therapy to support patients after ibogaine detoxification who are in early recovery. It says noribogaine has pharmacologic properties that distinguish it from methadone, buprenorphine and the major opioid analgesics in clinical use today.

References

1 adamsmith.org/research/medicinal-use-of-psilocybin/
2 R. L. Carhart-Harris et al; Lancet Psychiatry, 2016, 3 (7), 619
3 R. R. Griffiths et al; J. Psychopharmacol., 2016, 30 (12), 1181
4 S. Ross et al, J. Psychopharmacol., 2016, 30 (12), 1165
5 G. I. Agin-Liebes et al; J. Psychopharmacol., 2020, 34 (2), 155
6 F. S. Barrett et al; NeuroImage, 2020, 218, 116980
7 R. B. Kargbo; ACS Omega, 2020, 5, (27), 16959
8 D. C. Mash et al, Ann. N. Y. Acad. Sci., 2000, 914, 394