Psychedelic Effects of Ketamine in Healthy Volunteers: Relationship to Steady-state Plasma Concentrations

Earlier clinical work established ketamine as an anesthetic that produces a characteristic dissociative state and so-called "emergence reactions"—a set of subjective effects variably described as psychotomimetic, hallucinogenic, or psychedelic, including marked alterations in mood, perception, thinking and sense of self. Despite the potential for anaesthetic drugs to profoundly alter conscious experience, relatively little quantitative research has examined the psychological side effects of anaesthetics such as ketamine. The purpose of this study was to quantify the psychedelic effects of subanesthetic ketamine in psychiatrically healthy volunteers and to relate those effects to steady-state venous plasma concentrations. The authors hypothesised that psychedelic effects would be directly related to steady-state ketamine concentrations and sought to characterise the concentration–effect relationship across a clinically relevant range of plasma levels.

Participants were psychiatrically healthy volunteers who gave informed consent and completed a structured clinical interview for DSM-IV to exclude axis I disorders, including substance abuse. Cardiovascular and respiratory status were monitored during infusions by pulse oximetry and intermittent noninvasive blood pressure measurement. The extracted text indicates a single-blinded, crossover design in which racemic ketamine and saline placebo were administered in separate sessions using a computer-assisted continuous infusion algorithm that aimed to establish a series of steady-state plasma concentrations. Plasma concentrations were measured after 28 min at each infusion step. Subjective effects were measured using visual analogue scales (VAS) for specific items (examples in the extraction include MEANING, SUSPICIOUS, HIGH, DROWSY, ANXIOUS) and the Hallucinogen Rating Scale (HRS), a questionnaire developed to assess psychedelic drug effects; HRS items are scored 0–4 and grouped into six clinically derived clusters. The HRS was completed approximately 1 hour after discontinuation of the infusion, with participants asked to recall their experience from the immediate session. The HRS results for ketamine were compared with previously collected data from a dose–response study of intravenous N,N-dimethyltryptamine (DMT). Statistical analyses reported in the extracted text included linear regression to examine the relation between steady-state ketamine plasma concentration and VAS effects, and repeated-measures analysis of variance to compare ketamine versus saline on VAS and HRS measures. Performance error of the infusion algorithm was summarised as percentage performance error (%PE = (measured − predicted)/predicted × 100) and absolute %PE. The infusion targeted a sequence of steady-state concentrations that, from the Results, correspond to approximately 50, 100, 150 and 200 ng/ml.

The extracted text indicates the study included ten male volunteers (this is implied by later text referencing "ten volunteers"), mean age 22.3 years (range 21–25). No heart rate, blood pressure, or oxygen saturation disturbances required treatment. Lateral gaze nystagmus was observed in all participants at the 200 ng/ml target concentration. Measured mean ketamine plasma concentrations tracked the target concentrations with a highly linear relation (correlation coefficient r = 0.997, P = 0.0027). However, the regression slope exceeded unity (slope = 1.28), so mean concentrations were close to the 50 and 100 ng/ml targets but about 15–20% higher than the 150 and 200 ng/ml targets. Reported mean performance errors (%PE) were −7.3%, −1.1%, 12.6% and 19.2% for the 50, 100, 150 and 200 ng/ml targets, respectively; mean absolute performance errors were reported to be less than 30%. Ketamine produced dose-related psychedelic effects. The relation between steady-state plasma concentration and VAS scores was highly linear across items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P values from < 0.024 to < 0.0005). Repeated-measures analysis showed significant differences between ketamine and saline for most VAS items; SUSPICIOUS did not reach significance at the stated threshold (P = 0.05). On the HRS, ketamine produced higher cluster scores than saline for all clusters except VOLITION (the difference for VOLITION was not significant). The authors report that HRS scores for ketamine were similar to those previously observed with psychedelic doses of intravenous DMT in earlier work. Subjective reports indicated that all but one participant spontaneously reported intoxication and perceptual distortion during ketamine; one of these participants also reported such symptoms during placebo. Three participants experienced moderate dysphoria during ketamine (none during placebo); one participant developed a mildly paranoid state, and another experienced tearfulness and sad mood with rumination about recent stress. Participant comments included descriptions such as "floating in space," feelings of annihilation of the physical self, and one account describing an incomprehensible or mystical-type experience. A retrospective comparison with an earlier diazepam study in eight overlapping participants suggested that diazepam produced much smaller effects on comparable VAS items than ketamine: ketamine VAS scores for HIGH and BODY reached approximately 83% and 45% of the maximum possible scores, whereas diazepam produced mean scores around 12% of the maximum for comparable items. A paragraph in the extracted text refers to positron emission tomography (PET) scanning performed to quantify ketamine binding in the brain; it states that dose-related psychedelic effects were accompanied by evidence of increased regional binding of S‑ketamine. The extraction does not provide detailed methods or results for the PET measurements, and it is not clear from the provided text whether PET was performed in all participants as part of the same protocol or in a subset.

The authors interpret the findings as demonstrating a clear, highly linear relation between steady-state venous ketamine concentrations and psychedelic effects across the 50–200 ng/ml range. They note that the infusion algorithm produced concentrations reasonably close to targets but that individual pharmacokinetic variability can produce deviations; the observed overshoot at the higher targets is attributed to likely discrepancies between the pharmacokinetic parameters used by the infusion system and the actual kinetics of individual participants. Mean performance errors were reported to be under 30%, which the authors consider acceptable for a computer-assisted infusion system. The concentration–effect relation was described as continuous and graded, with the largest subjective effects on VAS items indicative of psychedelic experience (HIGH, REALITY, TIME, SURROUNDINGS, THOUGHT, SOUND) and smaller effects on items more suggestive of psychotomimetic features (ANXIETY, SUSPICIOUS, MEANING). Small but statistically significant effects of saline on BODY and TIME were attributed to immobility and confinement during the laboratory sessions. The authors argue that the graded linearity implies that even small doses of ketamine can produce measurable mind‑altering effects. Strengths noted include the ability to achieve a series of steady-state concentrations within a single experimental session. A principal limitation discussed is the fixed ascending step design; participants might anticipate increasing effects at each step and bias responses. The authors considered an alternative randomised dosing design but judged it impractical given ketamine's half‑life and the resulting time and fatigue issues. They acknowledge they cannot exclude some expectation bias but contend that the differing magnitudes across VAS scales suggest responses reflected genuine pharmacologic effects. The HRS profile for ketamine was similar to previously reported DMT data, but the authors caution that this comparison is retrospective and not within the same participants. They place their results in the context of earlier work with phencyclidine and other psychedelics, and they report a limited retrospective comparison with diazepam suggesting ketamine's effects are distinct from a prototypical sedative‑hypnotic. Clinically, the authors note these findings have relevance because the plasma concentration range studied overlaps with concentrations used for analgesia or sedation (approximately 100–200 ng/ml) and is lower than concentrations reported on awakening from general anaesthesia (reported elsewhere as 600–1100 ng/ml). They suggest awareness of ketamine's psychedelic effects may aid clinicians in managing patients receiving subanesthetic ketamine, particularly in communication and expectations. The authors conclude that this is the first study to quantify psychedelic effects of ketamine in psychiatrically healthy volunteers across a range of subanesthetic, steady‑state plasma concentrations and that the effects are dose related and clinically relevant.