Non-hallucinogenic psychedelic analogues
A panacea for mental health?
There has been growing research and investor interest in the potential use of psychedelic drugs in the treatment of depression, most notably LSD and psilocybin derived from “magic mushrooms”. However, the hallucinogenic side effects of these compounds hamper their use as effective therapies. Now – in what could be a potential breakthrough – scientists in China have designed psychedelic-like molecules (analogues) that appear to alleviate depressive symptoms, without the hallucinogenic side effects.
Lysergic acid diethylamide (LSD) is a member of a large class of molecules called ergolines, which have been used as therapeutics for conditions such as migraine headaches, post-partum haemorrhage, and Parkinson’s disease. LSD affects neurons via the interaction with a specific type of receptor on the cell surface, called a G-protein-coupled receptor (GPCR). More specifically, LSD interacts with the 5-HT2-family of serotonin receptors, in particular the 5-HT2A receptor (5-HT2AR). Serotonin is a neurotransmitter that can affect a number of behavioural conditions, including mood, appetite, sleep, and cognition, amongst others. In other words, LSD and other psychedelic compounds mimic the role of serotonin to elicit their hallucinogenic and other effects (i.e. an agonist).
Although ergolines have a similar chemical structure, they can elicit a wide range of effects in vivo, from anti-pain to hallucinations. One of the ways these compounds can achieve this is by forming distinct structural interactions with GPCRs. Agonists can then activate different signalling pathways in the cell, depending on this interaction, and elicit a specific effect on the cell. Endogenous agonists of GPCRs, such as serotonin, activate both G-protein and β-arrestin signalling pathways in cells, while other compounds elicit selective pathways. This “selective agonism” provides a potentially useful approach to develop novel therapies to treat neurological conditions.
In a recent paper published in Science, Cao et al. looked at the structural interactions of a range of psychedelic compounds with the 5-HT2AR cell surface receptor. The scientists used psilocin (the active metabolite of psilocybin), LSD, as well as the endogenous neurotransmitter serotonin and Bayer’s non-hallucinogenic psychedelic analogue drug Dopergin (lisuride). Studies have shown that β-arrestin signalling is associated with responses in mice that are analogous with non-hallucinogenic anti-depressive behaviour in humans. Consequently, the scientists designed β-arrestin-biased compounds, a number of which were shown to elicit these responses in mice.
Although these are very early results, it does suggest that novel psychedelic analogues and their interaction with the 5-HT2AR cell surface receptor could lead to new therapies that retain antidepressant effects, without causing hallucinations.
Despite their significant side effects, a number of companies have demonstrated some promising results with psychedelic compounds. For example, Compass Pathways showed that a 25mg dose of its psilocybin candidate, COMP360, significantly lowered depressive symptoms in patients with treatment-resistant depression, compared with a control group. Meanwhile, a team at the University of California, Davis, showed promising results with a non-hallucinogenic version of the psychedelic drug ibogaine (tabernanthalog).
Although psychedelics have certainly piqued the interest of both the scientific and investor community in the past few years, there are many unknowns that need to be addressed before any viable product could come to the market. In addition, more research needs to be done into the log-term effects of using psychedelic compounds, particularly in patients with pre-existing neurochemical dysfunction. But if these initial results are anything to go by, novel psychedelic compounds may well be one of the best candidate solutions for the ever burgeoning demand for better mental health.