Creating a ketamine epidemic?

Ketamine has been claimed to be the first truly new pharmacological approach for treating depression in the past 50 years and promoted as the first of a new generation of rapid acting antidepressants (eg. see BMJ news report). US clinics increasingly offer IV infusions of ketamine off label. In March, esketamine, a nasal ketamine-based drug, was approved by the US Food and Drug Administration (FDA) for treatment-resistant depression. This is despite it performing better than placebo only in one out of three studies (see my tweet).

Concern about potential approval of esketamine by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK has led to discussion through responses to a BMJ article. The latest response by Mark Horowitz and Joanna Moncrieff expresses concern that "history is repeating: a known drug of abuse, associated with significant harm, with scant evidence of efficacy, is being submitted for licensing, without adequate long-term safety studies".

It's important not to forget the epidemic of amphetamine use that peaked round the end of the 1960s (see article). Ketamine has the ability to induce an acutely altered state of consciousness, reminiscent of indigenous medicines such as ayahuasca, peyote, and ibogaine, which have been used for centuries across many cultures (see another article). Amphetamines in general were prescribed readily and with insufficient thought in the past (see yet another article). Amphetamine was said to adjust hormonal balance in the central nervous system by creating or amplifying adrenergic stimulation so as to promote activity and extraversion. It was even said that true addiction to amphetamine probably did not occur.

However, evidence emerged after 1960 that amphetamine is truly addictive, instead of merely habituating. The introduction of monoamine oxidase inhibitor and tricyclic antidepressants from the end of the 1950s did not immediately lead to a significant decline in prescribing of amphetamines, but eventually the claim that the newer drugs were superior to amphetamines held sway. Amphetamines and barbituates had nonetheless seemed better to doctors than the bromides and nerve tonics that had been prescribed up to the 1950s. Psychiatrists used to complain that GPs, when they did use the newer tricyclic antidepressants, did not use them in sufficiently high enough therapeutic doses. This complaint was heard less when the SSRIs were introduced in the 1980s, perhaps partly because fluoxetine, maybe the most successful SSRI, was initially introduced at a single dose.

50 years may seem a long time not to have had any new pharmacological treatment for depression but it's important history isn't repeated. It actually wasn't that long ago that the epidemic of amphetamines was created by doctors. Do they really want to do the same with ketamine?