At Clinica Synaptica, we believe that understanding the history of therapeutic tools is as important as knowing their mechanism of action. The history of ketamine has unfolded over more than 60 years thanks to a combination of serendipity, the rediscovery of early research, and the growing clinical need for innovative treatments. In this post, we offer a brief overview of its evolution.
Ketamine as an anesthetic in military contexts
Ketamine was first tested in humans more than 60 years ago as an alternative anesthetic to phencyclidine (PCP) (Corssen & Domino, 1966). It was soon incorporated into military medicine during the Vietnam War due to its powerful analgesic effect, rapid onset of action, and wide margin of safety against respiratory depression. These pharmacological characteristics made it particularly valuable in combat situations, where it could be administered even by non-medical personnel in extreme trauma conditions. Since 1985, ketamine has been included in the World Health Organization’s List of Essential Medicines (WHO, 2023).
Ketamine as a therapeutic tool in mental health
Many of the most transformative advances in mental health did not originate in large laboratories, but rather in the clinical intuition of professionals who dared to look beyond established uses.
This was the case in the 1970s with Mexican psychiatrist Salvador Roquet, who began using ketamine in “psychosynthesis” sessions for a purpose very different from its anesthetic use: to facilitate deep emotional processes, promote personal growth, and increase self-awareness (Kolp et al., 2014; Walsh et al., 2022). At a time when these ideas were almost heretical, Roquet observed surprising clinical improvements in patients with neurosis, psychosis, and personality disorders, reporting success rates of close to 85%. Today, this perspective is integrated into the approach of neuroscience and psychotherapy, allowing us to continue exploring the therapeutic potential of psychedelic-assisted therapy.
A decade later, in the former Soviet Union, psychiatrist Evgeny Krupitsky began developing one of the first structured models for the therapeutic use of ketamine in the treatment of alcohol dependence. The results were as striking as they were unexpected: 66% abstinence after one year compared to only 24% in the control group (Krupitsky & Grinenko, 1997; Krupitsky et al., 2002). However, his work was abruptly interrupted in 2002 when, following the collapse of the Soviet bloc, ketamine was withdrawn from medical use, silencing his research for years.
Meanwhile, in another setting seemingly far removed from psychotherapy, operating rooms were also beginning to tell a different story. Research conducted by anesthesiologists such as Garry S. Sklar (Sklar et al., 1981) and Danish psychiatrist Karl Hansen demonstrated something that we now consider fundamental: the experience with ketamine did not depend solely on the dose, but also on the context and intention with which it was administered. Music, therapeutic accompaniment, psychological preparation for the experience… everything we now know as set and setting began to emerge as a decisive factor in therapeutic outcomes. These conditions facilitated experiences of high psychological value and clinical potential at sub-anesthetic doses.
The neurobiological key: NMDA receptors
However, the major neurobiological breakthrough came in the 1980s, when it was discovered that ketamine acts as an antagonist of glutamate NMDA receptors (Lodge et al., 1982). These receptors play a key role in synaptic plasticity, memory, and emotional regulation, which helps explain ketamine’s unique psychopharmacological effects. This neurobiological discovery explained why ketamine promotes therapeutic effects in mental health, why it does not behave like a classic antidepressant, and why its effects appear so quickly.
Ketamine as a tool for treatment-resistant depression
As early as 1975, preclinical studies in animals suggested that ketamine might have antidepressant properties in rats (Sofia & Harakal, 1975). However, it was not until decades later that this finding began to be transferred to the human clinical setting, driven by the interest of a group at Yale in understanding the function of glutamate receptors.
In a first controlled trial, Berman et al. (2000) studied 14 patients with major depression, randomly assigning them to receive a single dose of ketamine (0.5 mg/kg IV) or placebo. Surprisingly, on the third day, those treated with ketamine showed significant reductions in depressive symptoms, marking a turning point in research on fast-acting antidepressants.
Subsequent studies confirmed the rapidity and robustness of its antidepressant effect: significant clinical improvements observable in just 2 hours (Zarate et al., 2006). In addition, ketamine was shown to reduce suicidal ideation in patients with treatment-resistant depression who did not respond to other treatments and to improve depressive symptoms in people with bipolar disorder (Diaz-Granados et al., 2010a; 2010b; Zarate et al., 2012).
Since then, ketamine has been evaluated in more than 25 studies focusing on major depression and treatment-resistant depression, showing consistent results, especially in patients who had undergone multiple previous failed treatments (Price et al., 2022). This line of research opened a new door: the possibility of a fast, effective treatment that is different from traditional antidepressants, transforming the way we approach depression in clinical practice.
Ketamine-assisted psychotherapy
It has been barely five years since ketamine began to be integrated into the model of psychedelic-assisted therapy, showing success in the treatment of both addiction and depression (Walsh et al., 2022). Ketamine induces an entropic state that interrupts the rumination patterns characteristic of depression (Carhart-Harris & Nutt, 2017). In addition, both ketamine (Kopelman et al., 2023) and serotonergic psychedelics (Aleksandrova & Phillips, 2021) promote neuroplasticity, facilitating the consolidation of new positive learning generated during psychotherapy.
In this way, ketamine, rather than an isolated drug, becomes a therapeutic tool capable of prolonging the clinical effects of psychological intervention, overcoming the limited duration of infusions alone (Dakwar et al., 2014, 2017).
Acknowledgements
At Clinica Synaptica, we specialize in ketamine-assisted therapy for people who have not found relief with conventional treatments. It is a powerful clinical tool that, when integrated with rigorous psychiatric evaluation, psychological support, and ethical follow-up, can transform deeply stagnant therapeutic processes.
To date, we have witnessed hundreds of processes in which this model has shown great potential. At Clinica Synaptica, we would like to acknowledge the visionary researchers and pioneers whose work and dedication have enabled us to offer this service today to those who need it most.
Bibliography
Aleksandrova LR, Phillips AG (2021) Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends in Pharmacological Sciences 42(11): 929–942.
Berman RM, Cappiello A, Anand A, et al. (2000) Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47(4): 351–354.
Carhart-Harris RL, Nutt DJ (2017) Serotonin and brain function: A tale of two receptors. Journal of Psychopharmacology 31(9): 1091–1120.
Corssen G, Domino EF (1966) Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesthesia and Analgesia 45(1): 29–40.
Dakwar E, Levin F, Foltin RW, et al. (2014) The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biological Psychiatry 76(1): 40–46.
Dakwar E, Hart C, Levin F, et al. (2017) Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: A randomized, crossover trial. Molecular Psychiatry 22(1): 76–81.
DiazGranados N, Ibrahim LA, Brutsche NE, et al. (2010a) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Journal of Clinical Psychiatry 71(12): 1605–1611
Price RB, Kissel N, Baumeister A, et al. (2022) International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators. Molecular Psychiatry 27(12): 5096–5112.
Kolp E, Friedman HL, Krupitsky E, et al. (2014) Ketamine psychedelic psychotherapy: Focus on its pharmacology, phenomenology, and clinical applications. International Journal of Transpersonal Studies 33(2): 84–140
Krupitsky E, Grinenko A (1997) Ketamine psychedelic therapy (KPT): A review of the results of ten years of research. Journal of Psychoactive Drugs 29(2): 165–183.
Krupitsky E, Burakov A, Romanova T, et al. (2002) Ketamine psychotherapy for heroin addiction: Immediate effects and two-year follow-up. Journal of Substance Abuse Treatment 23(4): 273–283.
Lodge D, Anis NA, Burton NR (1982) Effects of optical isomers of ketamine on excitation of cat and rat spinal neurones by amino acids and acetylcholine. Neuroscience Letters 29(3): 281–286.
Sofia RD, Harakal JJ (1975) Evaluation of ketamine HCl for anti-depressant activity. Archives Internationales de Pharmacodynamie et de Thérapie 214(1): 68–74.
Sklar GS, Zukin SR, Reilly TA (1981) Adverse reactions to ketamine anaesthesia: Abolition by a psychological technique. Anaesthesia 36(2): 183–187.
Walsh Z, Mollaahmetoglu OM, Rootman J, et al. (2022) Ketamine for the treatment of mental health and substance use disorders: Comprehensive systematic review. BJPsych Open 8(1), e19.
Zarate CA Jr, Singh JB, Carlson PJ, et al. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63(8): 856–864.
Zarate CA Jr, Brutsche N, Laje G, et al. (2012) Relationship of ketamine’s plasma metabolites with response, diagnosis, and side effects in major depression. Biological Psychiatry 72(4): 331–338.
