Ketamine was first synthesised in 1962. Its key properties were discovered immediately because it is a profoundly psychoactive drug. As an anaesthetic, its advantage is that appropriate doses produce a markedly dissociated state with full analgesia and amnesia for operative procedures and no depression of respiration. Indeed, it is classed among the world’s ‘essential medicines’ by the World Health Organization for just these properties. It was originally approved for medical use as an anaesthetic in 1970, and it is still widely used in emergency settings.

The parallel story of ketamine is what happens after the acute drug effect wears off. Ketamine’s synthesis was the result of a systematic search for molecules that might have the properties of another drug, phencyclidine, but without the latter’s disadvantages. Phencyclidine also produces dissociative anaesthesia, but at high doses there is a risk of excitation and seizures as the drug clears. From the beginning with ketamine there were also reports of activation, but of emotional effects rather than seizures – elevation of mood, even a sense of awe, panic, fear. It turned out that phencyclidine and ketamine had effects that made them attractive to recreational drug users. The synthesis of phencyclidine was relatively simple, that of ketamine more difficult. Ketamine appeared as a recreational drug with the diversion of medical or veterinary supplies (ketamine was unregulated until 1999 in the USA). Since then, ketamine’s popularity as a recreational drug has waxed and waned at different times, in different social groups and in different geographies. Its image has reflected the customary changes in emphasis balancing social attitudes and public health messages. But it was always about the potential for misuse.

The eventual kindling of interest in ketamine for psychiatry lay in its pharmacology. Glutamate is the main excitatory neurotransmitter in the brain. Its receptor mechanisms were worked out from the 1980s on, and the N-methyl-D-aspartate receptor proved to be the probable target for ketamine. Initially, the rather phoney hypothesis was that ketamine’s subjective and cognitive effects were a good model for schizophrenia. However, this ushered in a methodology for studying ketamine in the emerging field of experimental psychopharmacology. My friend the late great Ian Reid deserves a mention here: he was convinced that ketamine would be an antidepressant because his own work on electroconvulsive shock in rats suggested the key involvement of glutamate receptors. I have an abiding sense of responsibility for not jumping on his idea to do the necessary clinical study with him. Instead, John Krystal’s group at Yale grabbed the glory. Since then, ketamine itself and its enantiomer, esketamine, have been widely studied, and esketamine was eventually approved by the US Food and Drug Administration for treatment-resistant depression in 2019 – so it took anaesthesiologists 8 years and psychiatrists 57 years to work out the use case fully.

Keith Rasmussen does full justice to the details of the ketamine story. His bibliography is extensive, and he is diligent in describing the many studies that have contributed to our current understanding. The book provides an exhaustive qualitative review of the field. It’s all there, but I am afraid it is not a page turner. Indeed, the sheer number of individual studies illustrates the abiding problem of inadequate power in so many academic clinical trials. How to synthesise the resulting mass (or mess) of results defeats the best of us.