The age of psychedelics.

The 21st century has seen a dramatic flow and ebb in the fortunes of clinical psychopharmacology particularly with regard to antidepressants. For about 20 years, perhaps from about 1985 onwards, the tide flowed in with many ‘new’ drugs being made available to clinicians. In mood and psychotic disorders, these were essentially incremental advances from old drugs such as amitriptyline and clozapine albeit often treatments with very real extra clinical benefits such as improved toxicity. Some of these, such as the SSRIs (selective serotonin re-uptake inhibitors), were even celebrated as ‘wonder drugs’ in popular culture. Inevitably, the tide turned. Many large pharmaceutical companies reoriented their strategic directions away from psychopharmacology causing much consternation from researchers in the field despite a flowering of experimental approaches which significantly enhanced our capacity for research (Dawson et al., 2011). The tide also turned in popular culture probably due to, now discredited, secondary analyses suggesting that SSRIs were not significantly better than placebo. Although, it has now been recognised that antidepressants ‘do work after all’ (Young and Moulton, 2020), it remains a concern that this further re-evaluation has not changed popular opinion which may be even influencing policy decisions and may likely reflect stigma and biases (Nutt et al., 2014). Controversy also continues with regard to antidepressants and withdrawal. Much of the recent debate here has focused on the prevalence and length of withdrawal, and some continue to state that withdrawal symptoms from these medicines constitute ‘addiction’. In an editorial in this Journal, experts helpfully reviewed the evidence underlying these recent debates, acknowledged gaps in knowledge and made suggestions for how the field can progress (Jauhar et al., 2019). Then came ketamine; metaanalyses indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes and this treatment seems to be practicable in a routine clinical setting (Conley et al., 2021; Diamond et al., 2014). Although much remains to be understood about the psychopharmacology of ketamine (Jelen et al., 2021), it is clear that new therapies targeting glutamate, and indeed gamma-aminobutyric acid (GABA), are emerging (Gordon, 2019) and may become useful clinical treatments. In parallel with these exciting new therapeutic developments, the whole field of psychedelic psychopharmacology has also emerged from the shadows cast a generation ago by the ‘war on drugs’ (Carhart-Harris et al., 2013). Ironically, given the recent emphasis on novel neurotransmitter-based approaches, these are essentially serotonergic drugs all having in common the property of 5-HT2A agonism (Dos Santos et al., 2021). The emerging novel treatment for treatment-resistant post-traumatic stress disorder (PTSD), 3,4-methylenedioxymethamphetamine (MDMA), which has beneficially augmented psychotherapy in several small clinical trials is also a serotonergic agent (Illingworth et al., 2021). Although psychedelic treatments face a testing route to gain credibility, supportive evidence is now accumulating, at least for psilocybin, for the treatment of depression (Carhart-Harris et al., 2021a; Rucker and Young, 2021). Interestingly, these treatments are being considered as ‘psychopharmacological’ in a complete sense in that it is both the drug and the attendant psychological support which may be necessary for full therapeutic benefit. Indeed, such an approach might also pertain to other novel treatments (Sumner et al., 2021). It is within this context that we must consider this present edition of the Journal which contains reports from many leading groups in the field and focuses on many different aspects of psychedelic therapy. Carhart-Harris et al. (2021b) ask if pragmatic research, realworld data and digital technologies can aid the development of psychedelic medicine. They note that positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. They suggest supplementing such traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations may help support the development of safe, effective and cost-efficient psychedelic therapy. Teixeira et al. (2022) explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. They note that therapeutic models including psychedelic experiences and common behaviour change methods are being tested for addiction and eating disorders. They further note that this research could be extended to help promote improved diet, The age of psychedelics