In brief
- Ketamine was synthesized in 1962 as a safer anesthetic and was later added to the WHO Model List of Essential Medicines.
- Since 2000, its rapid antidepressant effects have been studied; in 2019, the FDA and EMA approved esketamine for treatment-resistant depression.
- It is a molecule with a broad trajectory: anesthetic, psychiatric medication, and recreational substance. Understanding how it works helps in making informed decisions and managing the context to mitigate risks such as dependence or bladder damage.
Few molecules have traveled as long a road as ketamine: from an operating room and battlefield anesthetic to one of the most discussed breakthroughs in recent psychiatry. We review its history with rigor and without sensationalism.
An anesthetic born in 1962
Ketamine was synthesized in 1962 by chemist Calvin Stevens, who was collaborating with the American pharmaceutical company Parke-Davis. The search was driven by a specific problem: phencyclidine (PCP), a previous anesthetic, caused states of agitation and prolonged psychiatric disturbances. The goal was to find a related compound that was more manageable and shorter-acting. The new candidate, identified in the laboratory as CI-581, fulfilled that promise. The first human trials began in 1964, led by researchers Edward Domino and Guenter Corssen. They described a peculiar state in which the patient appeared disconnected from their surroundings without losing consciousness or breathing entirely; they called it “dissociative anesthesia,” a term that remains in use today.
From the operating room to the battlefield
In 1970, ketamine received authorization from the US Food and Drug Administration (FDA) as an anesthetic for human use, marketed as Ketalar. Its advantage over other anesthetics of the time was notable: at surgical doses, it tends to preserve respiratory drive and maintain blood pressure, and it can be administered intramuscularly when venous access is unavailable. These properties made it especially useful in resource-limited settings, from pediatric surgery to emergency medicine and war zones. For this reason, the World Health Organization includes it on its List of Essential Medicines as a general anesthetic. Decades later, it remains a standard tool in anesthesia and pain management.
From recreational use to regulation
The same dissociative effect that made it valuable in the operating room explains its arrival in recreational spaces. Since the 1980s, and especially the 1990s, ketamine became a presence in nightlife under names like “Special K” or simply “K.” This growing use led US authorities to include it in 1999 in Schedule III of the Controlled Substances Act, a category that recognizes its therapeutic value while regulating its access. In Spain and the European Union, it is a prescription medication; that is its current legal framework, which we include here as context.
The psychiatric turn
The most recent chapter began in 2000, when Robert Berman’s team published the first randomized, double-blind, placebo-controlled trial in Biological Psychiatry suggesting an antidepressant effect. In a small group of patients with depression, a single sub-anesthetic intravenous dose was associated with mood improvements within hours—a pace very different from that of classic antidepressants, which take weeks. That finding opened two decades of research into the role of the glutamate system and the NMDA receptor in depression. The most visible result arrived in 2019: the FDA (in March) and the European EMA (on December 18) authorized esketamine, one of the components of ketamine, as a nasal spray. Its indication is specific: adults with treatment-resistant major depressive disorder, in combination with another antidepressant (SSRI or SNRI) and administered under medical supervision due to sedation and dissociation effects. Much of the research into other applications remains preliminary or experimental, an open field that is worth following with interest and caution.
Harm reduction
Anyone who decides to explore ketamine outside of a medical setting can reduce risks by understanding how it works. Dissociation affects perception and coordination, so it helps to choose a safe and quiet environment, pay attention to set and setting, avoid driving or operating machinery, and have a trusted person nearby. Combining it with alcohol or other depressants can affect breathing, so spacing out or avoiding those mixtures is the most cautious approach. Frequent use is associated with dependence and a characteristic condition of the bladder (so-called ketamine-induced cystitis); evidence suggests that reducing frequency and, above all, taking breaks or stopping usually improves these symptoms. In the event of persistent urinary discomfort, abdominal pain, or psychological distress, consulting a healthcare professional is a good way to take care of yourself. And if you are going through a difficult time or having thoughts of self-harm, asking for help is also a form of self-care: in Spain, you can call 024, the suicide prevention hotline.
Sources
- European Medicines Agency (EMA). Spravato (esketamine): EPAR summary. European Medicines Agency, authorization of December 18, 2019.
- Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000.
- Drug Enforcement Administration. Placement of Ketamine into Schedule III. Federal Register, July 13, 1999.
Educational content written from a harm reduction perspective and with respect for individual freedom. It is not a substitute for advice from a healthcare professional and is not intended to encourage or condemn any drug use.
