31 January 2022

We agree that a drug is not necessarily bad just because it feels good – drugs that produce generally pleasant effects (e.g. benzodiazepines) are useful in some situations.

The trouble is that when a drug makes you feel euphoric, ‘high’ or just pleasantly ‘merry’, it is difficult to distinguish these drug-induced alterations from long-lasting and clinically relevant effects on mood. Depression scores will be lower than they would otherwise be, but this does not indicate that anything has happened to the individual's underlying mood, and evidence for long-term benefits is weak and confounded by the problems we described in our original article. The same effects would occur with alcohol or cocaine. But even unpleasurable or neutral drug-induced experiences may reduce feelings of depression by virtue of distracting people from their underlying feelings.

A further problem is the difficulty – if not impossibility – of doing double-blind studies with drugs that induce psychoactive effects, especially those that produce as unique effects as psychedelics. Many of the people coming forward for research are young men who have used psychedelics before, so know what to expect,^{Reference Carhart-Harris, Giribaldi, Watts, Baker-Jones, Murphy-Beiner and Murphy1} and we know that expectations exert a strong influence on outcome across numerous conditions.^{Reference Chen, Papakostas, Youn, Baer, Clain and Fava2}

Some of the esketamine studies show how profound the placebo effects associated with the administration of psychedelics can be. In the only positive trial of esketamine, people allocated to placebo improved by a huge 17.0 points on the Montgomery–Åsberg Depression Rating Scale over 4 weeks.^{Reference Popova, Daly, Trivedi, Cooper, Lane and Lim3} Having said this, we accept that people may occasionally gain insights through the use of psychoactive substances, though this is not necessarily restricted to psychedelics, and there are safer routes to personal development – such as exercise, art, exposure to nature and psychotherapy.

Furthermore, the opioid crisis has shown just how short-sighted it is to think that the risks of misuse and dependence can be safely contained by ‘an adequately supportive treatment setting’, with a recent report on esketamine finding evidence of intoxication, tolerance, dependence and abuse from pharmacovigilance data and patient reports,^{Reference Baudot, Soeiro, Tambon, Navarro, Veyrac and Mezaache4} also present in clinical practice.^{Reference Taillefer de Laportalière, Yrondi, Jullien, Cestac and Montastruc5} This is only one subset of the harms produced by esketamine, which include bladder damage,^{Reference Castellani, Pirola, Gubbiotti, Rubilotta, Gudaru and Gregori6} cerebrovascular and cardiovascular consequences,^{Reference Taillefer de Laportalière, Yrondi, Jullien, Cestac and Montastruc5,Reference Horowitz and Moncrieff7} and concerns over connection to increased suicides.^{Reference Gastaldon, Raschi, Kane, Barbui and Schoretsanitis8} ‘Bad trips’ are also an issue.^{Reference Baudot, Soeiro, Tambon, Navarro, Veyrac and Mezaache4}

We are particularly concerned by the commercialisation of psychedelic ‘treatments’. Ketamine clinics have become an industry in the USA, and venture capitalists are also funding psychedelic research centres, waiting for the go ahead for medical use.^{Reference Osgood9} Like any business, there is an imperative to expand the market and to keep people coming back; hence, treatment indications are often elastic and include feeling ‘blocked’, ‘lacking purpose’ or experiencing stress.^{Reference Osgood9} Similarly, despite being presented and evaluated as a one-off or short-term intervention, there is a tendency toward long-term use as witnessed in the US ketamine clinic industry.^{Reference Thielking10} It is likely that these people include many who have become physically or psychologically dependent, as well as those who are desperate for a cure, all of whom make profitable customers.

People have used psychoactive drugs to change and expand their consciousness for centuries, including to block out painful emotions and thoughts; this may have short-term benefits but is rarely an effective strategy in the long run. How these substances are regulated is an important debate and should not be replaced by a process of medicalisation that may end up harming and exploiting vulnerable people.