Unlocking the potential of psychedelic compounds in psychiatry

‘We’ve further expanded our experience with ketamine and gained new experience studying DMT,’ says Dr Gabriel Jacobs, Research Director in Psychiatry. ‘Although psychedelics have been around for a long time, there is still much we don’t know about their human pharmacology. At CHDR, we have an array of methods to systematically characterise the pharmacodynamic effects of psychedelic compounds, such as the NeuroCart®, quantitative EEG with or without event-related potentials, and TMS-EEG. We use both subjective and neurocircuitry-based CNS biomarkers, and relate the effects to the compounds’ pharmacokinetics.’

DMT

Jacobs and his team are currently conducting a study with DMT in a group of volunteers who are experienced in the recreational use of psychedelics. DMT is a short-acting drug that, like other classic psychedelics, acts via the 5-HT2A receptor in the brain. In this study, the team is investigating the relationship between pharmacokinetics, subjective effects and various CNS-based biomarkers. Jacobs: ‘We carefully select and prepare the participants for the study. We then guide them through the psychedelic experience, and debrief them afterwards. In this regard, we’ve benefited greatly from the expertise of Chris Timmermann of Imperial College London, who is an expert in the field of DMT research.’

Cybin, the sponsor of this study, is planning to characterise a DMT derivative (CYB004) in future studies, which will be developed for people suffering from generalised anxiety disorder. A key challenge is that DMT is rapidly broken down by the enzyme monoamine oxidase both centrally in the brain and peripherally in plasma. This leads to significant variability between individuals, both in plasma levels of DMT and in the corresponding psychedelic effects.

Jacobs: ‘There is a lack of published data regarding the pharmacokinetics of DMT, which are quite variable. Moreover, there is no “standard” dosing approach for the drug, and other research groups have previously employed different dosing paradigms and formulations, which makes it difficult to draw appropriate comparisons. Therefore, in this study we aim to identify an optimum dose and dosing approach that results in pharmacodynamic effects which are expected to translate into therapeutic benefits in patients with mental health disorders.’

Non-psychedelic alternatives

Psychedelic substances can be remarkably safe and effective in the treatment of several psychiatric disorders. However, the therapeutic application of psychedelics is very demanding compared to regular pharmacotherapy. ‘Not only do patients need to be screened for various risk factors, they must also be given careful guidance before, during and after a psychedelic session,’ says Jacobs. ‘The session itself can also be quite an intense experience for the patient.’

Currently, there are efforts underway to develop compounds that have the same therapeutic effect but with fewer or no ‘psychedelic’ effects such as loss of psychological integrity or hallucinations. ‘This is down to molecular changes that render such compounds more selective for receptor subtypes or different populations of 5-HT and NMDA receptors,’ explains Jacobs.

‘We’re currently performing a number of studies for Gilgamesh Pharmaceuticals, who are at the forefront of developing such compounds. For us, this is a new challenge. The aim of these studies is to demonstrate pharmacological effects in healthy volunteers. This should enable us to characterise the clinical differences and similarities of such compounds compared to drugs we’ve already characterised, such as ketamine and DMT.’ The team will combine established methodologies with more experimental new ones, such as measures of reward based on the Research Domain Criteria of the US National Institute of Mental Health. ‘This is really exciting because it’s still uncharted territory. However, we’ve already invested quite a lot of work in identifying and validating reliable assessments of this kind, and we’re keen to see how they shed light on the effects of these compounds.’