The neurobiological mechanisms underlying psychedelic therapy are multi-modal, crossing molecular, cellular, and network systems. The primary initial pharmacological target appears to be activation of 5-HT2A receptors particularly in cortical layer 5 pyramidal cells [16–25], though 5-HT2A independent mechanisms may also be important [26]. Psychedelics promote structural and functional neural plasticity [27–31] and both preclinical [29] and clinical neuroimaging data suggests that psychedelics lead to 5-HT2A receptor- mediated glutamate release in the medial prefrontal cortex [32]. Psychedelics induce changes in global brain connectivity [33, 34], including default mode network (DMN) integrity [35] and amygdala reactivity [36, 37].

However, psychedelic compounds induce a wide range of complex subjective experiences with marked individual variation, even in the therapeutic setting and are contraindicated in psychosis spectrum disorders and mania [38, 39]. Furthermore, caution is required for those with a family history of psychosis. The individual variation and divergence between potential therapeutic utility for some disorders and contra-indication in others demands meticulous, high-quality research that incorporates a precise-personalized-psychedelic therapy paradigm [40, 41]

There are marked differences between recreational and therapeutic uses of psychedelics [42–44]. Psilocybin therapy data from John Hopkins University, over a 16-year period, encompassing 250 volunteers and 380 sessions, reported no major psychological issues, with 0.9% of volunteers experi- encing minor and transient psychological issues [42]. This contrasts with a survey of 1993 recreational psilocybin users, of which 7.6% reported seeking treatment for psychological symptoms they attributed to their challenging psilocybin experience [42]. This included three self-reported cases of incipient and enduring psychotic symptoms (at least one year) and three cases of attempted suicide [42].

In parallel to the “Psychedelic Revolution in Psychiatry” [45], recreational use appears to be increasing [46–51]. A recent survey conducted from March to May 2020 by the European Monitoring Centre for Drugs and Drug Addic- tion with 10,000 respondents from across Europe (average age 29 years, 58% male) showed that 10% used lysergic acid diethylamide (LSD) in the last 30 days [52]. Nation- ally representative data from the Crime Survey for England and Wales (2018/2019) reported that 0.5% of 16–59 years used magic mushrooms in the last 12 months, whereas in young adults (16–24 years), the rate was 1.6% [53]. A decade ago, Irish data from a representative number of people aged between 15 and 64 years (n = 7669 respondents) indicated that 7% had previously used magic mushrooms in their lifetime (6.5% of men and 4% of women) and 0.5% had used magic mushrooms in the previous year [54]. A recent survey of American university students (n = 3525) showed that 11% had previously used psychedelics [55].

Notwithstanding the self-selection bias inherent in the Global Drugs Surveys (GDS), the most recent GDS of 26,000 people, of whom 72% were males and approxi- mately 1% were Irish, revealed some interesting trends [49]. This survey demonstrated increasing psychedelic use and reported that 55% of respondents used magic mushrooms in the last 12 months, mostly for “well-being,” but also for “self-medication” [49]. Worryingly, 40% of those who reported using psychedelics did not undergo any preparatory or integration sessions [49]. In addition, almost a quarter of respondents self-reported psychedelic microdosing over the last 12 months [49]. Furthermore, 4.2% of those using rec- reational psychedelics for emotional distress or psychiatric conditions sought emergency medical treatment over the last 12 months, including people with self-reported psychotic (0.2%) and bipolar (2.1%) disorders [49].

In terms of acceptability of psychedelic therapy, 35% of American college students (n = 124) agreed that psych- edelics can be a therapeutic tool for those with depression and 39% for anxiety [56], with a much higher proportion (84%) supporting further research [56]. Interestingly, these attitudes were approximately in line with an online survey of American psychiatrists (n = 324), in which 42% reported that psychedelics show promise in treating some psychiatric dis- orders, with a quarter thinking psychedelics are unsafe even under medical supervision [57]. Echoing the college stu- dents, approximately 80% agreed that psychedelics deserve further research, with males and early career stage trainees (< 40 years) having more favourable attitudes towards the therapeutic use of psychedelics [57].

Results from the previous GDS (2019) of 85,000 people showed that 59% of people who previously used psychedelics said they would accept it as treatment for depression or PTSD, compared to only 18% of those surveyed who had never used psychedelics [58]. Of the respondents who would not accept PT, concerns related to “brain damage and bad trips” [58].

Society’s relationship and attitude towards psychedelics are complex, but if we are to consider using these com- pounds in clinical practice, it is essential to look beyond past mistakes of over-exuberance and non-scientific ideol- ogy, towards a shared transparent scientific understanding of the risks and benefits of psychedelic therapy [59]. This is all the more important in the context of increasing rates of recreational psychedelic use, the potential of psychedelics to exacerbate underlying pre-dispositions to psychosis and mania, together with psilocybin therapy being on the verge of translating into the psychiatric clinic for a range of non- psychotic psychiatric disorders [4].