This crossover study of healthy volunteers (n=10) given computer-assisted continuous infusions, subanaesthetic ketamine (50–200 ng/ml steady-state plasma concentrations) produced dose-related psychedelic effects. Subjective ratings (VAS and the Hallucinogen Rating Scale) correlated highly linearly with venous ketamine concentrations (R ≈ 0.93–0.99 for VAS; overall plasma-target correlation R = 0.997) and yielded HRS scores comparable to those seen with DMT.
Background
Ketamine has been associated with a unique spectrum of subjective "psychedelic" effects in patients emerging from anesthesia. This study quantified these effects of ketamine and related them to steady-state plasma concentrations.
Methods
Ketamine or saline was administered in a single-blinded crossover protocol to 10 psychiatrically healthy volunteers using computer-assisted continuous infusion. A stepwise series of target plasma concentrations, 0, 50, 100, 150, and 200 ng/ml were maintained for 30 min each. After 20 min at each step, the volunteers completed a visual analog (VAS) rating of 13 symptom scales. Peripheral venous plasma ketamine concentrations were determined after 28 min at each step. One hour after discontinuation of the infusion, a psychological inventory, the hallucinogen rating scale, was completed.
Results
The relation of mean ketamine plasma concentrations to the target concentrations was highly linear, with a correlation coefficient of R = 0.997 (P = 0.0027). Ketamine produced dose-related psychedelic effects. The relation between steady-state ketamine plasma concentration and VAS scores was highly linear for all VAS items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P < 0.024 to P < 0.0005). Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like drug.
Conclusions
Subanesthetic doses of ketamine produce psychedelic effects in healthy volunteers. The relation between steady-state venous plasma ketamine concentrations and effects is highly linear between 50 and 200 ng/ml.
Papers cited by this study that are also in Blossom
Strassman, R. J. · Journal of Nervous and Mental Disease (1984)
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Dahan, J. D. C., Dadiomov, D., Bostoen, T. et al. · npj Mental Health Research (2024)
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.
Volunteers gave institutionally approved informed consent and received a structured clinical interview for DSM-1V, performed by a board-certified psychiatrist, demonstrating absence of all axis I disorders (psychiatrically healthy), including substance abuse. During drug infusions, participants were monitored continuously by pulse oximetry, and noninvasive blood pressure was determined intermittently. Racemic ketamine or saline was administered in a single-blinded, crossover protocol, using a computer-assisted continuous infusion with + I had the idea that events, objects, or other people had particular meaning that was specific for me (MEANING). * I had suspicious ideas or the belief that others were against me (SUSPICIOUS). « I felt high (HIGH). « I felt drowsy (DROWSY).
Approximately 1 h after discontinuation of the ketamine or saline infusion, the participants completed a psychological inventory, the hallucinogen rating scale (HRS), designed by one of the authors (RJ.S.) to assess the effects of psychedelic drugs.'' The HRS is based on interviews with experienced users of psychedelic drugs, especially N,N-dimethyltryptamine (also called DMT), an illicit drug with effects similar to LSD-25, mescaline, and psilocybin.'" Participants were asked to respond to the questions by recalling their experiences in the immediately preceding session. Questions were scored 0 to 4: 0, "not at all"; 1, "slightly''; 2, "moderately"; 3, "quite a bit"'; and 4, "extremely." The HRS items were grouped into six clinically derived cluste The results of the HRS for ketamine were compared with a previous dose-response study of intravenous N,N-dimethyltryptamine performed by one of the authors
The relations between ketamine plasma concentration and VAS effects were analyzed by linear regression Differences between saline control and ketamine VAS effects were analyzed by repeated-measures analysis of The slope of the regression line (1.28) was greater than unity, resulting in plasma concentrations that were close to the 50 and 100 ng/ml target, but 15-20% higher than predicted at the 150 and 200 ng/ml targets. expressed as the percentage performance error: %PE = (measuredpredicted)/predicted X 100. The absolute value of the percentage performance error was also determined.">"*
All the volunteers were men, with a mean age of 22.3 yr (range, 21-25 yr). There were no perturbations of heart rate, blood pressure, or oxygen saturation that required treatment during the study. All participants had lateral gaze nystagmus at the 200 ng/ml target concentration. The relation between mean ketamine plasma concentrations and target concentrations was highly linear, with a correlation coefficient of 0.997 (P = 0.0027; fi 1). Mean ketamine concentrations were nearly identic. to 50 and 100 ng/ml targets but about 15 -20% higher than the 150 and 200 ng/ml targets, resulting in a linear regression slope greater than unity of 1.28. The mean performance error was -7.3%, -1.1%, 12.6%, and 19.2% for the 50, 100, 150, and 200 ng/ml target concentrations, respectively. The mean absolute perfor-Anesthesiology, V 88, No 1, Jan 1998 peated-measures analysis of variance; P = 0.05) for all items except SUSPICIOUS (table). Ffigure 3 shows the HRS cluster scores for ketamine and saline. The difference between ketamine and was significant (by repeated-measures analysis of v ance; P < 0.05) for all clusters except VOLITION. The core for VOLITION was elevated for ketamine and s: The difference between ketamine and saline was statistically significant (analysis of variance; P < 0.05) for all clusters except VOLITION. Anesthesiology, V 88, No 1, Jan 1998 elt so different. Wasn't able to describe the way I was feeling"; "floating in space''; "'almost complete annihilation of physical self, shrunken"; "dizzy, shaky, lightheaded." One subj summary: '"The experience seems to be a mystical expe rience, an incomprehensible comprehension of the universe. There seemed to be no past, present or future, no time, just existence. Life and death at the same time."" All but one participant spontaneously reported feelings of intoxication and perceptual distortion during the ketamine infusion; one of these persons also reported these symptoms during the placebo infusion. Three participants became moderately dysphoric during the ketamine infusion, but none of them experienced dysphoria during the placebo infusion. One participant developed a mildly paranoid state characterized by multiple questions about the procedure and an intense affect. Another volunteer, who had experienced emotional stress in the recent past, experienced tearfulness, a sad mood, and moderately intense ruminations about recent stressful events.
Plasma ketamine concentrations were reasonably to target concentrations. The infusion algorithm is based on average ketamine pharmacokinetic parame-ters from a study of a relatively small number of persons. Any randomly selected participant is likely to deviate from the average. Therefore the targets will not be achieved precisely in each participant. A mean variation of the measured concentrations of 20-30% from the target concentrations is expected with a computer-assisted continuous infusion system."""* The mean performance error and the mean absolute performance error in this study were less than 30%. The relation between the target concentration and the measured concentration was highly linear, but the slope was greater than unity, resulting in a trend for plasma ket mine concentrations in the last two steps, 150 and 200 ng/kg, to exceed the target. The cause for this overshooting of the target concentrations is unknown; presumably there was a discrepancy between the pharma cokinetic parameters used in the computer-assisted continuous infusion system and the actual pharmacokinetic behavior of the participants. There was a highly linear relation between ketamine steady-state concentration and effect for all of the VAS items. The intensity of effects varied considerably for different items. The intensity was greatest for HIGH, REALITY, TIME, SURROUNDINGS, THOUGHT, and SOUND, items that might be regarded as indicating p: chedelic effects. The intensity was lowest for ANXIETY, SUSPICIOUS, and MEANING, items that might be re. garded as indicating psychotomimetic effects. Furthermore, the difference between ketamine and saline for SUSPICIOUS was not significant (by analysis of variance; P = 0.05); the difference for all other items wa Significant. There was a significant linear relation between saline target concentration and effect for BODY and TIME, although the magnitude of the effect was much smaller than with ketamine. Probably these small but significant effects of saline on BODY and TIME were due to immobility and confinement in the laboratory for several hours. The linearity of the concentration versus effect relation suggests that the mind-altering effects of ketamine are continuous and graded, and that even very small doses of ketamine produce these effects to some degree. Anesthesiologists tend to associate the psychedelic effects of ketamine with emergence from anesthesia, after use of ketamine as an induction agent, which is often referred to a s "'emergence reactions." The published descriptions of this syndrome do not give any sense of a dose versus effect relation. However, the: data clearly demonstrate a relation between ketamine Anesthesiology, V 88, No 1, Jan 1998 plasma concentration and psychedelic effects. Awareness of these effects may help clinicians using subanesthetic doses of ketamine improve their management of patients, particularly with regard to effective commu cation with patients. The cumulative dose -respon: has strengths and weaknesses. The major strength lie: in the ability to attain a series of steady-steady plasma concentrations during a single experimental session The major weakness is that participants might anticipate an increase in drug effects at each step up and bias their responses accordingly. An alternative design that avoids the bias problem is dose randomization. Because ketamine has a relatively long halflife, stepping plasma concentrations up and down randomly requires substantially more time than a series of steps up, with attendant problems of participant fatigue and possibly development of tolerance. We cannot preclude the pPossibility that some responses were inflated by the expectation that effects would increase. However, there were large differences in the maximum responses between the VAS scales (table 1), suggesting that participants were responding to "real" pharmacologic effects rather than simply marking the VAS based on an expectation of increasing effects. The effect of ketamine on HRS subscales was similar to results reported previously for psychedelic doses (0.2 and 0.4 mg/kg) of intravenous N,N-dimethyltryptamine, a potent, LSD-25-like psychedelic drug.' The implications of this similarity are uncertain, because the comparison is retrospective and not in the same participants. However, these HRS data suggest that ketamine has substantial psychedelic effects, a conclusion that is reinforced by the comments written by volunteers on the HRS (see Results). No contemporary studies have directly compared the effects of ketamine and LSD-25 or N,N-dimethyltryptamine, probably because of the regulatory and ethical barriers to performing research with these Food and Drug Administration Schedule 1 agents. Davies and Beech'® studied the effects of the ketamine analog, phencyclidine, in volunteers and compared phencyclidine effects with those reported for LSD-25 and mescaline. They concluded that the effects were similar and noted a greater tendency for LSD-25 and mescaline to produce "hallucinations." Cohen et al.'® compared phencyclidine with LSD-25 and amobarbital and found that phencyclidine impaired interpretation of proverbs and performance on a standard serial sevens task (that is, participants ¢ design of this study very count backwards from 100 by sevens) but LSD-25 did not. There was a peculiarity of the HRS results that requires comment. The VOLITION score for saline was elevated and similar to the score for ketamine. Probably this was due to the enforced immobility of the participants in the laboratory, which they may have interpreted as impaired volition on HRS volition items such as "Able to move around if asked to do so" and "In control." A comparison of the mind-altering effects of ketamine with a sedative-hypnotic drug would also be of intere: Although we did not compare ketamine directly with a sedative-hypnotic drug, eight of the ten volunteers in this study participated in a previous cumulative doseresponse study of diazepam.'" A total diazepam dose of 200 mg/kg given intravenously resulted in a mean peak plasma concentration of approximately 600 ng/ml. Participants completed a VAS that was similar but not identical to the VAS used in the present study of ketamine. Three scales on the diazepam VAS, "high," "distorted sense of time,"" and "'feelings of floating," were comparable to ketamine VAS scales, HIGH, TIME, and BODY. We reanalyzed the data from the diazepam study for the eight persons who participated in the diazepam and the ketamine studies to compare the effects of ketamine with diazepam. The maximum effect of diazepam on "distorted sense of time"' was not significantly different from saline control (P = 0.12), whereas the effect of ketamine on TIME was highly significant. The effects of diazepam on "high" and *'feelings of floating"" were significantly different from control (diazepam vs. control: "high," 14.2 + 10.2 vs. 24 + 3.8; P = 0.014; "feelings of floating," 14.1 + 13.8 vs. 1.9 + 3.8; P 0.040). However, the magnitude of the diazepam effects was small: the mean VAS scores for "high" and "'feelings of floating™" were only about 12% of the maximum po: ble VAS score, whereas the mean VAS scores for ketamine were 83% and 45% of the maximum possible scores for HIGH and BODY, respectively. This limited, retrospective comparison suggests that the effects of ketamine are distinct from those of diazepam. This is the first study to quantify the psychedelic effects of ketamine in psychiatrically healthy volunteers over a range of subanesthetic, steady-state plasma concentrations. However, previous studies of subanesthetic doses of ketamine also found evidence of psychedelic
nning was then performed for 45-55 min to quantify ketamine binding in the brain. After positron emission tomography scanning, participants answered a psychological questionnaire. Plasma ketamine concentrations were measured during positron emission tomography scanning but not afterward. Dose-related psychedelic effects were accompanied by evidence of increased regional binding of Sketamine in the brain. There is also anecdotal evidence of psychedelic effects of ketamine. Phencyclidine and ketamine have been used as drugs of abuse, and users have clearly described the effects as psychedelic in nature.* Extensive descriptions of the psychedelic effects of ketamine in recreational users have been published.** The results of this randomized, blinded, placebo-controlled study of psychiatrically healthy volunteers demonstrate a linear relation between psychedelic effects of ketamine and steady-state plasma concentrations between 50 and 200 ng/ml, a range of plasma concentra tions that is clinically relevant for patients receiving ketamine for analgesia or sedation, or awakening from general anesthesia with ketamine. Plasma concentrations of ketamine on awakening from general anesthesia have been reported in the range of 600-1100 ng/ml.** Analgesic concentrations are approximately 100-200 ng/ml.** This should be considered when weighing the advantages and disadvantages of ketamine as an anesthetic, analgesic, or sedative drug.
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