History of Ketamine's Use in Psychiatric Conditions

Ketamine was first synthesized in 1962 by Dr. Calvin Stevens, a chemist at Parke-Davis Laboratories, as part of a search for a safer anesthetic alternative to phencyclidine (PCP), which was known for its severe psychoactive effects. By 1970, ketamine had been approved for use as an anesthetic in humans and animals. Its dissociative properties, which provide a sense of detachment from the environment and self, made it particularly useful in medical settings. However, these same properties also led to its exploration in psychiatric contexts, albeit somewhat inadvertently.

In the early 1970s, ketamine’s psychoactive effects caught the attention of researchers interested in its potential for treating mental health conditions. Initial studies observed that low doses of ketamine produced rapid, albeit short-lived, improvements in mood and symptoms of depression. These findings were particularly notable because the effects occurred much faster than those of traditional antidepressants, which often take weeks to show benefits.

Despite these promising early observations, research into ketamine’s psychiatric applications was limited. Several factors contributed to this, including the stigma associated with its recreational use, known as “Special K” on the street, and the broader focus of psychiatric research on developing new classes of antidepressants that targeted serotonin and other monoamine systems.

Throughout the late 20th century, ketamine remained primarily known for its anesthetic and analgesic properties. Its use as a recreational drug also grew, leading to negative perceptions and stricter regulations. This recreational misuse overshadowed legitimate research into its therapeutic potential, and for a time, ketamine’s exploration as a treatment for psychiatric conditions was largely sidelined.

Interest in ketamine’s psychiatric potential experienced a resurgence in the late 1990s and early 2000s. Researchers revisited earlier findings and conducted new studies, exploring its rapid antidepressant effects in more rigorous clinical trials. In 2000, a groundbreaking study published in Biological Psychiatry demonstrated that a single low-dose intravenous (IV) infusion of ketamine produced rapid and significant reductions in depression symptoms in patients with treatment-resistant depression.

These findings spurred a wave of new research, leading to a deeper understanding of ketamine’s unique mechanism of action, particularly its effects on the glutamate system and neuroplasticity. The positive outcomes from these studies, combined with increasing awareness of the limitations of traditional antidepressants, led to growing interest and acceptance of ketamine as a viable treatment option.

By the 2010s, ketamine had gained considerable attention within the medical community for its rapid and effective treatment of severe, treatment-resistant depression. This led to the development of ketamine clinics and the use of off-label ketamine infusions for depression, anxiety, PTSD, and chronic pain conditions. Medically, ketamine is currently used off-label via several routes, including intravenous (IV) infusions, intramuscular (IM) injections, and sublingual (under the tongue) formulations.

A significant milestone occurred in 2019 when the U.S. Food and Drug Administration (FDA) approved esketamine (Spravato), a derivative of ketamine, as a nasal spray for the treatment of treatment-resistant depression. This approval marked the first major advancement in the treatment of depression in decades and helped legitimize ketamine’s use in mainstream psychiatry.

Since then, ketamine and esketamine have become increasingly integrated into treatment protocols for various psychiatric conditions, offering hope and relief to patients who have not responded to traditional therapies. Ongoing research continues to explore the full range of ketamine’s therapeutic potential, including its long-term effects and applications for other mental health disorders.