LSD analogue synthesised by swapping just two atoms less likely to cause hallucinations | Research

An analogue of the psychedelic drug LSD has been found to offer the same therapeutic effects as LSD but is less likely to cause the hallucinogenic trips associated with the drug. The researchers say that their work highlights the potential of rationally designed, non-hallucinogenic psychedelic analogues in the treatment of neuropsychiatric diseases such as schizophrenia, where the use of psychedelics is not recommended.

‘A lot of neuropsychiatric diseases are characterised by physical changes in the structure of the brain, and one particular change that is very relevant is the atrophy of neurons in a part of the brain called the prefrontal cortex – the conductor of the brain,’ explains David Olson, a chemist and neuroscientist based at the University of California, Davis, in the US, whose lab carried out the study. ‘In 2018 we found that psychedelics from a variety of different chemical classes were very good at promoting the growth of those key cortical neurons. [But] what we’re really interested in is could these neuroplasticity-promoting agents be used for conditions like schizophrenia?’

Olson says the idea to convert LSD into a potent therapeutic agent that promotes neural plasticity but with reduced hallucinogenic potential, stemmed from a combination of traditional medicinal chemistry and structure-based design. ‘We noticed in the literature that if you [take tryptamine] and just switch the carbon and nitrogen on the indole ring and turn it into an isotryptamine, it tended to be much less hallucinogenic,’ explains Olson. ‘So we wondered if we could play this atom swapping game on the ergoline framework [that features in many alkaloids and LSD too], and if we did, would we have a very potent but non hallucinogenic analogue of LSD?’

They carried out chemical transposition of a carbon and a nitrogen within the ergoline core of LSD, with the goal of selectively disrupting the hydrogen bonding interaction between the indole N–H and specific parts of the 5-HT_2A serotonin receptor, while maintaining the other interaction sites. The result was an LSD analogue which they named ‘JRT’ after the lead author of the study. Olsen described the process as like rotating the tyres on a car – the parts may have moved but the compound’s shape stays the same.

Same but different

‘There are many non-hallucinogenic analogues of LSD, but the fundamental difference is that all of those compounds are very different in structure [to LSD]. JRT has the exact same overall shape as LSD and the exact same molecular weight,’ he says. ‘I don’t care how good of a chemist you are … you couldn’t tell them apart.’

After conducting a series of assays in vitro and in mouse models they found that JRT was very potent and highly selective for binding serotonin receptors, specifically 5-HT_2A receptors – the activation of which are key to promoting cortical neuron growth. They also found it had powerful neuroplastic effects, increasing the density of neural branching in the prefrontal cortex, and improved measures relevant to the negative and cognitive symptoms of schizophrenia, without exacerbating hallucinations and gene expression associated with psychosis.

‘We have very effective medicines for blocking the positive symptoms, the hallucinations,’ says Olson. ‘We don’t really have anything for the cognitive and the negative symptoms – that’s really what prevents people from holding a job and entering society.’

Using tests, such as the mouse head twitch response assay, which, Olson says, correlates well with human hallucinogenic potency, they found that JRT did not produce hallucinogenic-like behaviours in mice dosed with LSD. They thought that the reason for this could lie in the fact that, in contrast to LSD, JRT does not bind the 5-HT_2A receptor for very long.

‘If you block that receptor in humans, you block the hallucinogenic effects,’ Olson explains. ‘If you knock that out in mice, you block the characteristic behavioural effects of psychedelics in mice. What we found was that JRT doesn’t activate the receptor as strongly as LSD, which indicated that it was likely to be non-hallucinogenic.’

The researchers said their work highlighted the potential for modifying the chemical structures of psychedelics to produce analogues with improved efficacy and safety profiles. Although Olson says that, for JRT to make it into a schizophrenia patient population, a few more ‘molecular tweaks’ will be needed. ‘We’re hopeful that we’ll have an even better compound than JRT for schizophrenia, but I think JRT, right now, is incredibly promising for a lot of other indications,’ he adds.

Argel Aguilar-Valles, a neuroscientist at Carleton University, Canada, describes JRT as ‘an interesting compound’ but says it remains to be seen whether it serves any therapeutic potential for schizophrenia in the clinic. ‘Schizophrenia is complex. If anything, their work indicates that maybe some negative symptoms and perhaps cognitive inflexibility that characterises schizophrenia, can be treated with some of these compounds without the worry of the potential side effects. But the positive symptoms, they don’t seem to show – they don’t see any worsening, but they don’t see any improvement either.’

In addition, he explains that it is difficult to properly assess hallucinogenic potential in mice models. ‘Some of these compounds we don’t really know if they’re truly nonpsychedelic derivatives. Obviously, the in vitro and animal model assays are not fully going to recapitulate the experience that humans have, at least not in a way that we can measure it. So they will need to be tested [on humans].’