14 December 2021

In ‘Esketamine: uncertain safety and efficacy data in depression’, Horowitz and Moncrieff maintain their concerns about the uncertain effects associated with esketamine.^{Reference Horowitz and Moncrieff1} We agree with the authors that several clinical questions deserve ongoing exploration. However, we challenge their criticism of the pleasurable ‘highs’ associated with esketamine intoxication.

The clinical relevance of acute subjective effects has been central to healthcare's growing fascination with medical hallucinogens^{Reference Yaden and Griffiths2} – drugs that puzzlingly carry both potential for abuse and therapeutic benefit. Here, we use the term ‘medical hallucinogen’ to represent substances such as ketamine, psilocybin and MDMA, which differ meaningfully in chemical structure and activity but induce qualitatively similar and dose-dependent alterations in perception, mood and cognition. When considering these agents, it is worth recognising (a) the potential for a ‘therapeutic intoxication', in which a short-term, positively experienced drug state mediates clinical effect; and (b) that the associated risks of the acute ‘high’, particularly the risk of misuse or abuse, might be safely contained within an adequately supportive treatment setting.

The possibility of a therapeutic intoxication is consistent with current research into medical hallucinogens. Subjective ‘happiness’ during ketamine infusions, for example, appears to predict antidepressant response over time.^{Reference Chen, Lin, Wu, Bai, Li and Tsai3} Crucially, this acute effect predicts responses at follow-up assessment points beyond the mere ‘hours’ mentioned by Horowitz and Moncrieff, and rather extends to 2 weeks post-administration. These and other data suggest that positively experienced drug intoxication in carefully screened, well-controlled and psychologically informed treatment contexts can occur safely^{Reference Johnson, Richards and Griffiths4} and mediate subsequent benefits that persist well beyond the day of administration.

These treatment ‘highs’ can then be examined through a lens that considers addiction but not exclusively so. We propose that there is value to a broader perspective on the emotional and subjective qualities associated with intoxication – one which acknowledges risk and the prospect of a conceptually novel approach to the varieties of suffering that compel individuals to seek psychiatric care. Psilocybin and MDMA, but not cocaine, seem to support enduring and complex possibilities for self-learning that can be harnessed with psychological interventions.^{Reference Lepow, Morishita and Yehuda5} Such data indicate granularity and suggest that positively experienced intoxication is not alone sufficient for therapeutic growth. Similarly, ketamine and its derivatives are not routinely administered in contexts that include psychotherapy, but the combination may facilitate new insights and ways of being for people.^{Reference Dore, Turnipseed, Dwyer, Turnipseed, Andries and Ascani6} Although biological psychiatry has not always concerned itself with these aims, the field is uniquely positioned to help.

The ongoing study of medical hallucinogens may at times overestimate their benefits and underestimate their risks, and, for this, scientific integrity is essential. Moreover, not every ‘high’ is therapeutic, and models for hallucinogen use that contribute to experiential avoidance, medication dependence and a diminished sense of agency for patients should be scrutinised. However, a nuanced evaluation of risk and appropriate mitigation strategies can support the development of a new kind of psychiatry. Emerging psychiatric interventions, in our view, should not be condemned merely on the basis that some patients report enjoying the associated subjective effects – an intervention is not ‘bad' just because it feels ‘good’.