Common (>10% during/shortly after dose, all dose forms): Dissociation (intentional therapeutic effect during dose; problematic when uncontrolled). Transient hypertension and tachycardia (BP rise typically 10-20 mmHg systolic, HR rise 10-20 bpm; resolves within 1-2 hr). Nausea, sometimes vomiting (~10-30% depending on route — IM/IN > IV). Dizziness, sedation, mild confusion, blurred vision, headache.

Common — chronic regular use: Cognitive blunting in heavy daily users — working memory and episodic memory measurable decline (Morgan & Curran 2012 reviewed multiple cohorts). Reversibility is partial on cessation. Tolerance develops quickly — users escalate dose within weeks if using regularly. Psychological dependence — real and underestimated; users self-report compulsive patterns despite the early literature framing ketamine as "non-addictive."

Less common (1-10%): Anxiety/panic during dose (more common in users with low dissociative tolerance or trauma history triggering re-experiencing). Dysphoria. Emergence reactions (vivid dreams, distress on emerging from anesthesia — managed with benzodiazepine adjunct in clinical settings). Hypersalivation. Laryngospasm (rare, mostly pediatric anesthesia). Mild liver enzyme elevation with chronic high-dose use.

Rare-serious (<1% but worth knowing):

• Ketamine-induced cystitis / ketamine bladder. Most consequential chronic-use risk. Manifests as urinary frequency, urgency, dysuria, hematuria, suprapubic pain — progressing to ulcerative interstitial cystitis with bladder wall thickening, reduced bladder capacity, and (in severe cases) renal hydronephrosis requiring cystectomy. First reported in heavy recreational users 2007 (Shahani et al., Urology). Mechanism: ketamine and metabolites excreted in urine cause direct urothelial toxicity. Risk is dose-dependent and cumulative — most reports are in users taking >1 g/day for months; clinical-protocol patients (single 0.5 mg/kg infusions weekly to monthly) appear at very low risk. But: lower-frequency ketamine bladder cases have been reported in regular Spravato and at-home lozenge users. Symptoms can be irreversible if not caught early. For at-home lozenge users: any new urinary frequency, urgency, or hematuria mandates immediate cessation and urology consult.
• Hepatotoxicity — bile duct dilatation and elevated liver enzymes with chronic high-dose use; usually reverses on cessation.
• Neuropsychiatric — persistent dissociation / depersonalization-derealization disorder (DPDR) in a small subset. Risk factors: pre-existing dissociative tendencies, trauma history, very high doses, frequent recreational use.
• Cardiovascular — myocardial ischemia in patients with significant CAD due to BP/HR rise during dose. Pre-existing severe hypertension or unstable cardiac disease are relative contraindications.
• Suicidal ideation paradoxical worsening — extremely rare in clinical trials, but noted in Spravato post-marketing surveillance.
• Aspiration during anesthetic doses — mostly relevant to anesthetic-tier dosing in unmonitored settings.
• Anaphylactoid reactions — extremely rare.
• Respiratory depression — generally absent at sub-anesthetic doses; possible at high IV doses, particularly with concomitant opioids.

Specific watch periods:

• First 6 infusions of TRD induction: monitor BP/HR per dose, watch for dissociation tolerance, monitor for symptom shift including paradoxical anxiety.
• Ongoing monthly during maintenance: urinary symptoms questionnaire, liver panel every 3-6 months.
• Chronic at-home lozenge use: urinary symptoms screening every visit, LFTs every 3 months.
• Recreational/illicit use: all of the above, plus contamination risk.

Theoretical concern for healthy young brain (relevant-to-archetype): Chronic ketamine exposure in animal models produces persistent functional changes in PFC pyramidal cell dendritic morphology and PV interneuron function. The therapeutic single-dose model produces transient synaptogenesis (good); the chronic-heavy-exposure model produces what looks more like persistent dysregulation (bad). Where the line falls in humans is uncharacterized. Heavy chronic recreational users show measurable cognitive deficits that partially reverse on cessation. The honest verdict: sparing single doses in clinical TRD protocols appear safe over years of use; chronic heavy daily exposure clearly causes cognitive harm; the middle ground (e.g., weekly at-home lozenge for years) is uncharacterized in long-term studies. For a 20-year-old healthy brain, this uncharacterized middle ground is an additional reason to keep ketamine on WATCH-LIST rather than deploy.

Brain-development concern at age 20: Ketamine acutely silences PV interneurons and produces glutamate burst — important physiological signaling that's still maturing in PFC through mid-20s. Animal data on adolescent ketamine exposure shows persistent PFC changes (some interpret as schizophrenia-relevant, though human translation is debated). For occasional clinical use in a TRD context this concern is theoretical; for chronic recreational/biohacker use in a healthy 20-year-old it adds weight to the "skip" recommendation.

Abuse liability: Schedule III. Real abuse potential despite earlier "non-addictive" framing. UK reclassified ketamine to Class B in 2014 following rising recreational misuse and bladder-syndrome epidemic. Hong Kong has had a particularly severe ketamine-related public health response. Self-injection patterns escalate rapidly. Compulsive use is documented. Treat ketamine the same way you would treat any other Schedule III psychoactive.