The story behind ketamine begins not with a planned discovery, but with a scientist's keen observation of a surprising side effect.
When Dr. Edward Domino and his colleagues administered a new experimental drug to a human volunteer in 1964, they witnessed something unprecedented. The patient became disconnected from his environment, entering a trance-like state before swiftly recovering. It was Domino's wife who aptly named this strange condition "dissociative anesthesia." The drug was ketamine, and its discovery would ripple through the fields of anesthesiology, psychiatry, and pain medicine for decades to come, all thanks to the relentless curiosity of one remarkable scientist 6 .
University of Michigan pharmacology professor whose work left an indelible mark on neuropsychopharmacology 3 .
Compound synthesized in 1962 by Calvin Stevens, one-tenth the potency of its parent drug PCP.
First ketamine preparation approved by the FDA for human use in 1970 6 .
Researchers at the Parke Davis Company had developed phencyclidine (PCP), an effective anesthetic that unfortunately caused intense, prolonged emergence delirium in patients, making it unsuitable for human use 6 .
The quest was on for a safer, shorter-acting analog. In 1962, chemist Calvin Stevens synthesized a compound known as CI-581.
On August 3, 1964, Domino and his colleague, anesthesiologist Dr. Guenter Corssen, administered this drug to a human for the first time 6 .
They found it produced rapid analgesia and altered consciousness with a limited duration and a better side-effect profile than PCP. In 1966, they published their findings on 130 patients.
This breakthrough cemented Domino's legacy and provided medicine with one of its most unique and versatile drugs.
Domino's scientific curiosity was not limited to ketamine. In a fascinating 2009 study, his team investigated how tobacco smoking, and specifically nicotine, affects brain function 1 .
The researchers tested whether tobacco smoking produces widespread increases in the brain's dominant alpha EEG frequencies, consistent with the stimulant effect of nicotine on the brainstem's reticular activating system 1 .
The team studied 22 male tobacco smokers who had not smoked for at least an hour before the experiment. In a controlled setting, the participants first "sham smoked" (inhaling room air) and then smoked one of their favorite brand cigarettes. Their brain waves were recorded via electroencephalography (EEG) during both sessions 1 .
The data revealed a clear and significant finding. While sham smoking caused only minor changes, smoking a real cigarette produced a significant, generalized increase in dominant alpha frequencies across most areas of the brain's cortex 1 . This demonstrated that nicotine's stimulant effect is not localized but creates a state of widespread bilateral cortical arousal. This work provided a detailed neurophysiological understanding of how a common habit alters our brain's electrical activity.
| Experimental Condition | Effect on Dominant Alpha Frequency | Statistical Significance |
|---|---|---|
| Sham Smoking (Session 1) | Minor increase | Statistically significant |
| Sham Smoking (Session 2) | Minor increase | Statistically significant |
| Tobacco Smoking (Session 1) | Widespread, generalized increase | Statistically significant |
| Tobacco Smoking (Session 2) | Widespread, generalized increase | Statistically significant |
Interactive chart showing EEG alpha frequency changes would appear here
Domino's work created a "Domino Effect" of scientific innovation. The path he started did not end in the operating room.
Decades after his initial discovery, researchers found that low doses of ketamine could produce rapid and profound antidepressant effects in patients with treatment-resistant depression 7 . This discovery revolutionized the field of psychiatry, which had been dominated by monoaminergic-targeted drugs (like SSRIs) for half a century 7 .
It introduced the glutamatergic system as a new target for antidepressant drugs, pulling the field out of a developmental stagnation and offering hope to millions. Ketamine's mechanism for treating depression is distinct from its anesthetic action, believed to involve promoting neural growth and connectivity 7 . This unexpected application of Domino's work underscores how a fundamental discovery in one area can unlock transformative advances in another.
Ketamine works in hours compared to weeks for traditional antidepressants.
| Clinical Setting | Primary Use of Ketamine | Key Advantage |
|---|---|---|
| Anesthesiology | Induction and maintenance of anesthesia | Maintains cardiovascular stability and breathing |
| Pain Medicine | Management of acute and chronic pain | Powerful analgesic, reduces opioid needs |
| Psychiatry | Treatment of refractory depression and PTSD | Rapid onset of antidepressant effects (hours vs. weeks) |
| Emergency Medicine | Sedation for painful procedures | Effective and safe in resource-limited settings |
Domino's research, and the work he inspired, relied on a suite of critical reagents and methods.
A non-invasive method used to record electrical activity from the scalp, allowing researchers like Domino to measure changes in brain state, such as the alpha frequency increases caused by nicotine 1 .
A crucial control procedure in smoking studies where participants mimic the act of smoking without inhaling any nicotine. This helps researchers separate the pharmacological effects of nicotine from the psychological and behavioral rituals of smoking 1 .
A camelid antibody fragment that acts as a conformational biosensor. In modern pharmacology, it is used to detect the active state of G-protein-coupled receptors (GPCRs) like the mu-opioid receptor, allowing scientists to precisely measure a drug's intrinsic efficacy in a cell-free system 2 .
A class of drugs that bind to a secondary (allosteric) site on a receptor to enhance the effect of the primary (orthosteric) ligand. For example, BMS 986187 is a PAM for the delta-opioid receptor, which can fine-tune the receptor's activity and is being explored for treating chronic pain and depression with potentially fewer side effects 4 .
| Reagent / Method | Function | Example from Research |
|---|---|---|
| Target-Controlled Infusion (TCI) | Delivers intravenous drugs to achieve and maintain a precise plasma concentration. | Used in ketamine studies to maintain stable blood levels during cognitive testing . |
| Benzylideneoxymorphone (BOM) | A bifunctional chemical scaffold that interacts with both mu and delta opioid receptors. | Studied to develop new analgesics with less tolerance and abuse liability than current opioids 5 . |
| Biased Agonists | Ligands that preferentially activate one downstream signaling pathway over others at a receptor. | A strategy to develop drugs that provide therapeutic benefit (pain relief) while minimizing side effects 4 . |
Edward F. Domino's career exemplifies how a scientist's curiosity and willingness to follow the evidence—wherever it may lead—can trigger a cascade of progress. From the initial, curious state of "dissociative anesthesia" to the modern understanding of brain arousal and the revolutionary treatment of depression, the Domino Effect continues to shape our understanding of the mind and how to heal it.