LAUSR

This special edition of the Journal of Psychopharmacology continues a reflection of psychopharmacology’s vogue to breathe new life into old drugs. The shimmer of psychedelia is back from the grave of legal prohibition, seemingly to tempt society (and psychiatry) again. It is generally unknown by whole generations of psychiatrists that the classical psychedelics d-lysergic acid diethylamide (LSD) and psilocybin were prescribable medicines in psychiatry throughout the USA and Europe until prohibition was effectively imposed on routine clinical use and most scientific research around 1970. Hundreds of papers were published on their clinical use, which we have synthesised in systematic reviews (Butler et al., 2020; Rucker et al., 2016; Weston et al., 2020) and narrative (Rucker et al., 2018). Since 1970, the law has not changed, despite our pleas (Nutt et al., 2013; Rucker, 2015). So, why is this resurgence of interest happening now (and is it wise)? Repurposing old drugs (e.g. ketamine) is on trend, yes, but the main driving forces behind psychedelia’s contemporary dance with clinical science is perhaps more reflective of a general softening of societal attitudes towards ‘bad’ drugs, large investment in clinical trials of psilocybin (and MDMA), along with a rather heady sense of ‘general enthusiasm’ that wisdom suggests might benefit from a note of caution. Can modern paradigms of trial design and neurobiological research, coupled with strict legal regulations on the use of psychedelics, be reconciled to ‘make psychedelics medicines again’? We will see. Not dissimilar to a psychedelic ‘trip’ itself (and not dissimilar to the pivotal mental states (PiMS) that Brouwer and CarhartHarris (2021) propose in this edition’s first piece), it is hard to see where the field is going to end up. Indeed, PiMS are conceptualised as critical brain states that serve to allow psychological processes of reorganisation, but only when the brain is sufficiently ‘stressed’. Could psychedelics, via their action at 5-HT2A receptors, elicit this state in a stressed mind, prompting a salutary reorganisation if the context is safe and supportive? Perhaps. Stenbaek et al. (2021) present a characterisation of the relevance of the 5-HT2A receptor to the psychedelic state, establishing that neocortical 5-HT2A receptor binding is negatively correlated with the duration of peak effects and positively correlated with the time to return to normal consciousness. No neocortical 5-HT2A (it seems) means little capacity for a PiMS (or whatever term you might choose in preference). What happens downstream of 5-HT2A? Using electroencephalography, Pallavicini et al. (2021) describe the neural and subjective effects of a short acting psychedelic, N,N-dimethyltryptamine (DMT). Similar to previous studies, DMT suppressed 8–12 Hz (alpha) oscillations, whilst changes in the gamma range of oscillations correlated with some features of the reported ‘mystical’ experience. Further downstream, Jefsen et al. (2021) investigate the acute effects of psilocybin on the expression of 46 neuroplasticity related genes in the prefrontal cortex and hippocampi of rats, showing rapid expression in plasticity promoting genes, more so in the prefrontal cortex (where 5-HT2A is densely expressed). Yet, 5-HT2A is but one modulator, and Inserra et al. (2021) show that LSD modulates neuronal activity in both the reticular and mediodorsal thalamus in part due to its action as a type 2 dopamine receptor agonist. Psilocybin and LSD are clinically indistinguishable in terms of subjective effects, so the relevance of D2 remains unclear. However, an overarching effect may be a functionally selective overall modulation of thalamocortical gating to open Huxley’s ‘reducing valves’ of the psyche into a therapeutic ‘window of opportunity’. Back from the meta-physical rabbit hole, what dose of psilocybin is best (and how do you work it out)? Garcia Romeu et al. (2021) consider whether a weight-adjusted or fixed-dose strategy should be employed for psilocybin. In 288 participants given psilocybin, they found no evidence to support a weight-adjusted or sex-informed dosing regimen, suggesting a fixed dose (probably of 25 mg) is optimal for most people. However, if so, then what mediates a ‘bad’ or a ‘good’ trip (and could we ever predict this if Brouwer and Carhart-Harris (2021) are right)? Hirschfeld and Schmidt (2021) present a dose–response relationship estimate using questionnaire ratings of the psychedelic experience under different doses of psilocybin given in a trial setting. Whilst positive experiences were correlated with dose, negative experiences were much less so. The authors contrast this speculatively Psychedelics: Old drugs, new trips