Ketamine belongs to a class of drugs called dissociative anesthetics, and its closest chemical relative is PCP (phencyclidine). But ketamine also shares meaningful similarities with several other substances, from common cough suppressants to nitrous oxide to newer psychiatric medications. Understanding these connections helps clarify what ketamine actually does in the brain and body.
PCP: Ketamine’s Closest Chemical Relative
Ketamine and PCP are chemical congeners, meaning they share a core molecular structure and were developed from the same line of research. Both are classified as dissociative anesthetics, capable of producing pain relief, altered perception, and a trance-like state of unconsciousness. At the receptor level, both work by blocking NMDA receptors, which are key gatekeepers for excitatory signaling in the brain. This shared mechanism is what produces the characteristic “dissociated” feeling, where your mind seems separated from your body and surroundings.
The critical difference is duration and intensity. PCP is far more potent, lasts much longer, and carries a much higher risk of psychosis, agitation, and dangerous behavior. Ketamine was actually developed in the 1960s as a safer, shorter-acting alternative to PCP for surgical anesthesia, and it received FDA approval in 1970. While PCP was abandoned medically decades ago, ketamine remains a widely used anesthetic and has gained a second life as a treatment for depression.
DXM: The Over-the-Counter Cousin
Dextromethorphan (DXM), the active ingredient in many cough syrups, works through a surprisingly similar set of receptors. Like ketamine, DXM is a noncompetitive, low-affinity NMDA receptor antagonist. It also activates sigma-1 receptors and affects serotonin and norepinephrine transporters, giving it a more complex pharmacological profile than ketamine alone.
At normal cough-suppressing doses, DXM produces no noticeable mental effects. At much higher doses, however, it can cause dissociation, perceptual disturbances, and an altered state that users describe as similar to ketamine. One clinical study found that 55% of participants receiving DXM experienced perceptual disturbances, compared to 30% in the control group. Researchers have investigated DXM for ketamine-like antidepressant effects, and a combination of DXM with another compound (marketed as Auvelity) is now FDA-approved for major depression, representing the first oral NMDA-targeting antidepressant.
Nitrous Oxide: A Lighter, Faster Version
Nitrous oxide, the “laughing gas” used in dentist offices, targets NMDA receptors like ketamine does, though through a different mechanism. Ketamine physically lodges inside the open NMDA receptor channel and blocks it. Nitrous oxide antagonizes the same receptors but is not an open channel blocker, and the exact way it interferes with NMDA signaling is still being worked out.
Both substances enhance excitatory transmission in brain regions tied to mood, including the hippocampus and prefrontal cortex, and both are being studied as rapid-acting antidepressants. The practical differences are significant, though. Nitrous oxide has an extremely rapid onset and offset because of its low blood solubility. Most patients recover within minutes after inhalation stops and can drive themselves home. Ketamine has a half-life of several hours and produces active metabolites that may continue exerting effects well after the initial dose. Esketamine (the prescription nasal spray version) requires a minimum two-hour monitored recovery period.
How Ketamine Differs From Classic Psychedelics
People sometimes group ketamine with psilocybin, LSD, and other psychedelics, but the comparison is mostly superficial. Classic psychedelics work primarily through serotonin receptors (specifically 5-HT2A), producing vivid visual imagery, emotional intensity, and a sense of expanded meaning. Ketamine’s dissociative effects come from NMDA receptor blockade, which tends to produce detachment, floating sensations, and distorted spatial awareness rather than the rich visual and emotional landscape of serotonergic psychedelics.
At high doses, ketamine can produce what recreational users call a “k-hole,” a state where mental activity becomes completely disconnected from external stimuli. This can progress into out-of-body experiences, seeing a bright light, altered sense of time, feelings of peacefulness, and the sensation of entering an unearthly environment. A study using natural language processing to compare written accounts of 165 different substances with narratives of near-death experiences found that ketamine reports had the highest similarity to near-death experience descriptions of any substance tested.
How Ketamine Compares to Other Anesthetics
In operating rooms and emergency departments, ketamine fills a distinct niche among anesthetics. The two most common alternatives for putting patients under are propofol and etomidate, and each has a different risk profile. Propofol tends to lower blood pressure, especially in patients who are already unstable. Etomidate is gentler on blood pressure but can trigger temporary adrenal insufficiency, which is particularly dangerous in patients with sepsis.
Ketamine typically causes a transient increase in blood pressure and heart rate, which historically made it the go-to choice for patients in shock or with unstable blood pressure. However, this reputation is somewhat misleading. In patients who are severely ill, ketamine can paradoxically cause sustained low blood pressure. One study found that up to 24% of high-risk patients experienced hypotension after ketamine. Unlike propofol and etomidate, which are purely sedatives, ketamine also provides significant pain relief, making it useful when both sedation and analgesia are needed simultaneously.
Esketamine: Ketamine’s Mirror Image
Esketamine is not a different drug from ketamine so much as a refined version of it. Regular ketamine is a 50/50 mix of two mirror-image molecules (called enantiomers). Esketamine is just the S-enantiomer, isolated on its own. It is roughly twice as potent as the racemic mixture. In clinical trials, 0.25 mg/kg of esketamine produced comparable effects to 0.5 mg/kg of standard ketamine. Patients receiving esketamine also showed lower impairment in concentration and memory compared to the full mixture.
Marketed as Spravato, esketamine is an FDA-approved nasal spray classified as a Schedule III controlled substance. It is approved for two specific uses: treatment-resistant depression in adults (with or without an oral antidepressant) and depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior (in combination with an oral antidepressant). It is not approved as an anesthetic. An observational study comparing intravenous racemic ketamine to intranasal esketamine found no clear difference in antidepressant effectiveness, though racemic ketamine appeared to act slightly faster.
Why the Antidepressant Mechanism Matters
Every major antidepressant from the late 1950s onward worked by increasing levels of serotonin, norepinephrine, or dopamine in the brain. These drugs typically take four to six weeks to produce noticeable improvement. Ketamine broke that pattern entirely. By blocking NMDA receptors, ketamine triggers a cascade that ultimately increases production of a growth factor called BDNF, which promotes new connections between neurons. This mechanism can produce measurable antidepressant effects within hours rather than weeks.
This makes ketamine most meaningfully similar to a small but growing group of drugs that target glutamate signaling rather than the traditional serotonin-norepinephrine-dopamine system. DXM-based antidepressants and nitrous oxide both fall into this category. After nearly seven decades of antidepressants that all worked through essentially the same mechanism, this glutamate-based approach represents the first genuinely new pathway for treating depression.