Ketamine
Dissociative anesthetic used medically and recreationally. Known for inducing the 'K-hole' at higher doses. FDA-approved for treatment-resistant depression.
Important information
This information is for educational purposes only. Always research thoroughly, test your substances, understand legal implications, and consult healthcare professionals. Never use substances alone or in unsafe environments.
Dosage information
Ketamine · Insufflated · non-clinical reference ranges
Tier labels reproduce reported amount and intensity terminology; they do not indicate safety or a recommendation.
| Tier | Amount | Note |
|---|---|---|
| Threshold | 10 milligrams | |
| Light | 15 to 30 milligrams | |
| Common | 30 to 75 milligrams | |
| Strong | 75 to 150 milligrams | |
| K-hole | Reported lower bound: 150 milligrams; no upper bound is established. |
Dosage ranges are reference values from published literature, not recommendations. Potency varies by source, body weight, and individual sensitivity — harm-reduction practice starts well below the ranges listed.
Limitations: Figures are transcribed from a reference compilation, not measured in a controlled study; the potency of any given material is unknown until tested.
Evidence: Review or reference work
Before any number: set, setting, purity, dose · LD50 · microdosing
On this page: known interactions · harm reduction
Duration
1-2 hours | Onset: 5-15 minutes (insufflated)
Insufflated: 1-2 hours. Most common recreational route.
IM: Medical/clinical setting. Rapid onset, reliable absorption.
Known interactions
Dangerous Ketamine + Fentanyl
Despite some medical co-administration, unsupervised combination of ketamine and opioids creates severe respiratory depression risk.
Risks: Respiratory depression · Loss of consciousness · Inability to detect overdose symptoms · Death
Mechanism: Ketamine's dissociative sedation masks opioid overdose signs. Combined respiratory depression can be fatal.
What reduces the risk
- Never combine without medical supervision
- Have naloxone available
- Never use alone
Sources: TripSit Interaction Chart · PsychonautWiki: Ketamine Interactions
Dangerous Ketamine + Heroin (Diacetylmorphine)
Combining dissociatives with opioids is extremely dangerous. Ketamine masks overdose signs while both suppress breathing.
Risks: Fatal respiratory depression · Unable to recognize overdose · Aspiration · Death
Mechanism: Ketamine-induced dissociation prevents awareness of opioid overdose. Additive respiratory depression.
What reduces the risk
- NEVER combine
- Have naloxone available
- Never use alone
Sources: TripSit Interaction Chart · PsychonautWiki: Ketamine Interactions
Unsafe Ketamine + Alcohol (Ethanol)
Both are CNS depressants. Combining significantly increases risk of vomiting, aspiration, and loss of consciousness.
Risks: Aspiration (vomiting while unconscious) · Respiratory depression · Severe disorientation · Loss of consciousness · Memory blackout
Mechanism: Alcohol's GABA-mediated CNS depression adds to ketamine's NMDA antagonism. Both impair motor function and consciousness.
What reduces the risk
- Avoid combining ketamine with alcohol
- If both are used, reduce doses significantly
- Never lie on your back — recovery position
- Have a sitter present
Sources: TripSit Interaction Chart · PsychonautWiki: Ketamine Interactions · DanceSafe: Ketamine Safety
Caution Ketamine + Psilocybin
Both produce altered states through different mechanisms. The combination can be intensely disorienting but is not typically physiologically dangerous.
Risks: Extreme disorientation · Loss of motor control · Nausea · Overwhelming psychological effects
Mechanism: Psilocybin's 5-HT2A agonism + ketamine's NMDA antagonism = dual dissociative-psychedelic state.
What reduces the risk
- Only for very experienced users
- Reduce doses of both significantly
- Sitter essential
- Safe physical environment mandatory
Sources: TripSit Interaction Chart · PsychonautWiki: Ketamine Combinations
Absence of a listed interaction never implies safety. Check any combination in the app's 23×23 interaction matrix.
Harm reduction
- Sitting/lying position essential
- Safe environment
- Sitter recommended
- Avoid alcohol and opioids
- Don't redose quickly
- Limit frequency of use
- Stay hydrated
Risks & side effects
- Bladder damage with chronic use
- Addiction potential
- Impaired motor function
- Confusion
- Nausea
- Respiratory depression at high doses
Effects
- Dissociation
- Analgesia
- Dream-like state
- Out-of-body experiences
- Reduced sensory perception
- Philosophical insights
Legal status
Schedule III (USA). Prescription medication. Illegal for recreational use.
Pharmacology
NMDA receptor antagonist. Also affects opioid and dopamine systems.
Therapeutic research
- FDA-approved: Esketamine (Spravato) nasal spray for treatment-resistant depression (2019)
- Rapid-acting antidepressant: Effects within hours vs. weeks for traditional antidepressants (Berman et al., 2000; Zarate et al., 2006)
- Ketamine-assisted psychotherapy (KAP) offered at hundreds of clinics in the US
- Research for PTSD, suicidal ideation, OCD, and chronic pain
- WHO Essential Medicine for anesthesia — one of the safest general anesthetics known
- Studies on ketamine's neuroplasticity-promoting effects via BDNF and mTOR pathways
Clinical studies 27
Dose-related effects of ketamine for antidepressant-resistant symptoms of PTSD in veterans
Landmark multi-center RCT (Abdallah et al., 2022) showing dose-related ketamine effects for treatment-resistant PTSD symptoms in veterans and active duty military. Published in Neuropsychopharmacology.
Personalized Use of Ketamine for Treatment-Resistant Depression
Nature Translational Psychiatry study on personalized ketamine dosing strategies for treatment-resistant depression.
Ketamine-assisted psychotherapy for trauma-exposed patients
Clinical chart review study examining ketamine-assisted psychotherapy outcomes in trauma-exposed patients.
The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence
Liriano, Hatten & Schwartz 2023 review in Therapeutic Advances in Psychopharmacology synthesizing clinical evidence for ketamine in PTSD, including effects on symptom severity and the limits of current trial data.
The Role of Ketamine in Managing Depression and PTSD
Journal of Affective Disorders review of ketamine's role in depression and PTSD management.
Clinical Efficacy of Ketamine for Treatment-resistant Depression
Bratsos, Saleh 2019 Cureus. Systematic review examining ketamine efficacy in treatment-resistant major depressive disorder.
Adjunctive Intranasal Esketamine in Treatment-Resistant Depression
Daly et al. 2018 JAMA Psychiatry. Phase 2 RCT demonstrating intranasal esketamine efficacy for treatment-resistant depression, leading to FDA approval.
Qin et al. 2023 Eur J Neuroscience. Ketamine increases 'background noise' in thalamo-cortical system, potentially explaining psychosis-like symptoms.
Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability
Bonaventura et al. 2021 study showing S-ketamine (not R-ketamine) is responsible for abuse potential. Key for understanding esketamine vs racemic ketamine. Published in Molecular Psychiatry.
Chang, Hashimoto et al. 2019 Pharmacol Biochem Behav. Preclinical comparison showing R-ketamine had greater antidepressant effect with fewer side effects than S-ketamine via intranasal route. Informs enantiomer selection.
Ketamine for suicidal ideation: A systematic review and meta-analysis
Witt et al. 2020 meta-analysis of 15 trials (572 participants) showing single ketamine infusion reduces suicidal thoughts for up to 72 hours. Published in ANZ J Psychiatry.
Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression
Grunebaum et al. 2018 American Journal of Psychiatry. Midazolam-controlled RCT showing ketamine rapidly reduced suicidal ideation within 24 hours in major depression. Key evidence for ketamine's anti-suicidal effects.
Singh et al. 2016 Biological Psychiatry RCT establishing esketamine efficacy for treatment-resistant depression. Led to FDA approval of Spravato nasal spray.
Mechanisms of ketamine action as an antidepressant
Zanos & Gould 2018 Molecular Psychiatry comprehensive review of ketamine's antidepressant mechanisms including NMDA antagonism, AMPA potentiation, and neuroplasticity.
A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression
Zarate et al. 2006 landmark NIH study that launched ketamine depression research. First RCT showing single IV ketamine infusion produced rapid antidepressant effects within hours. Published in Arch Gen Psychiatry.
Ketamine Mechanism of Action: Separating the Wheat from the Chaff
Gould, Zanos, Zarate 2016 Neuropsychopharmacology. Comprehensive review dissecting ketamine's antidepressant mechanisms—NMDA antagonism, AMPA enhancement, mTOR signaling, and metabolite roles. Key mechanistic overview.
Rapid effectiveness of intravenous ketamine for ultraresistant depression in a clinical setting
Thomas et al. 2018 J Psychopharmacology. Real-world clinical evidence of IV ketamine effectiveness in ultraresistant depression. Identified anhedonia and bipolarity as clinical predictors.
Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder
Bloch et al. 2012 Biological Psychiatry. First study of ketamine for treatment-refractory OCD showing rapid but transient anti-obsessional effects.
Wilkinson, Zarate et al. 2018 Am J Psychiatry. Meta-analysis showing single IV ketamine rapidly reduces suicidal ideation within hours, with effects lasting up to one week.
The rapid anti-suicidal ideation effect of ketamine: A systematic review
Hochschild, Grunebaum, Mann 2021 Preventive Medicine. Systematic review synthesizing evidence for ketamine's rapid anti-suicidal effects, examining onset, duration, and clinical implications.
A meta-analysis of the effects of ketamine on suicidal ideation in depression patients
Shen, Gao, Lv et al. 2024 Translational Psychiatry. Comprehensive meta-analysis examining ketamine's anti-suicidal effects across multiple trials in depressed patients.
Ketamine–NMDA receptor binding structure
Rogers 2021 Nature Reviews Neuroscience. Structural analysis of ketamine's binding to NMDA receptors revealed through cryo-EM imaging.
Glutamate and Glycine Binding to the NMDA Receptor
Yu & Bhatt 2018 Structure. Structural study of glutamate and glycine co-agonist binding to NMDA receptor, foundational for understanding ketamine's mechanism.
Price et al. 2023 JAMA Network Open. One-year follow-up of RCT showing sustained benefits of IV ketamine combined with digital cognitive training for TRD.
Andrade 2022 J Clinical Psychiatry. Analysis of RCTs comparing ketamine to ECT for severe depression, providing clinical guidance.
KheirAbadi & Golkar 2023 Iranian J Psychiatry and Behavioral Sciences. RCT comparing high vs low dose oral ketamine for TRD control and relapse prevention.
Ouyang & Li 2025 Medicine. Meta-analysis of RCTs evaluating esketamine nasal spray efficacy for treatment-resistant depression.
Sources 2
- Rapid-acting antidepressant ketamine: A review. Pharmacology Biochemistry and Behavior, 164, pp. 32-44 (2018) doi:10.1016/j.pbb.2017.08.005
- Erowid Ketamine Vault
History & culture
Ketamine was first synthesized by Calvin Stevens at Parke-Davis in 1962 as a safer alternative to phencyclidine (PCP). It was first used on humans in 1964 and approved by the FDA in 1970. It saw extensive use as a battlefield anesthetic during the Vietnam War due to its wide safety margin. Recreational use emerged in the 1970s–80s, particularly in club and rave scenes. John Lilly's sensory deprivation tank experiments with ketamine in the 1970s explored its dissociative and visionary properties. The discovery of ketamine's rapid antidepressant effects by Berman et al. in 2000 launched a revolution in psychiatry.
Natural origins
Ketamine is entirely synthetic — no natural source exists. It belongs to the arylcyclohexylamine chemical class, related to PCP. Its structure features a cyclohexanone ring bonded to a chlorophenyl group. Ketamine exists as two enantiomers: S-ketamine (esketamine, more potent, FDA-approved as Spravato) and R-ketamine (arketamine, under investigation, may have fewer side effects). The drug's mechanism is unique among anesthetics — it blocks NMDA glutamate receptors rather than enhancing GABA.
Molecular family: Arylcyclohexylamines
Arylcyclohexylamines are dissociatives featuring an aryl group (like phenyl) attached to a cyclohexylamine core. This scaffold includes ketamine and related compounds. Unlike psychedelics, these substances work primarily on NMDA receptors and produce dissociation and anesthesia. The structural modification from simple aryl substitution produces dramatic shifts in consciousness. Key characteristics: - Aryl group (benzene or substituted benzene) connected to cyclohexylamine - NMDA receptor antagonists - Produce dissociation rather than visual/perceptual effects - Include both medical anesthetics and research compounds - Shorter duration than tryptamine psychedelics Dissociatives represent a distinct pharmacological category. While psychedelics primarily enhance perception and connectivity, dissociatives disconnect consciousness from body awareness—a fundamentally different altered state produced by targeting different receptors.
Structurally related to None identified
