This systematic review (2017) examined the reported side-effects of ketamine treatment for depression across 288 published reports and identified that headache, dizziness, dissociation, elevated blood pressure, and blurred vision were the most common in response to intravenous infusion. The most common acute psychiatric side-effect was anxiety, but there was no conclusive evidence about long-term side effects from the currently available studies.
Introduction
This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses.
Methods
We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria.
Results
After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depresssion. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users.
Discussion
We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.
Major depressive disorder is highly prevalent and existing monoaminergic antidepressants are effective in only about 50% of patients, with a protracted onset of action. In this context, ketamine has emerged as a promising rapidly acting antidepressant, but uncertainty remains about its safety profile. Short and colleagues note that most clinical trials to date have been small, short-term, frequently assessed a single dose only, and were not designed to detect rare, cumulative, or long-term harms. Evidence from other populations exposed to ketamine (for example, people with chronic pain or recreational users) has linked repeated use to urinary, hepatic, cognitive, and dependence-related harms, raising concern about the generalisability of short-term depression trial safety data. This paper therefore set out to systematically aggregate and evaluate reporting of side-effects associated with ketamine when used to treat depression. The primary objective was to identify and categorise adverse effects reported after single (acute) and repeated (cumulative and long-term) dosing in studies of adults with unipolar or bipolar depression, and to assess the extent and quality of side-effect surveillance in the published literature.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Sos, P., Klirova, M., Novák, T. et al. · Neuropsychiatric Disease And Treatment (2013)
Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J. et al. · Bipolar Disorders (2014)
Papers in Blossom that reference this study
Veraart, J. K. E., Smith-Apeldoorn, S. Y., van der Meij, A. et al. · Journal of Psychopharmacology (2025)
The review followed PRISMA guidelines. Eligible studies had to report original findings in adult humans with a validated diagnosis of unipolar or bipolar depression, include one or more doses of ketamine by any route, and report changes in depression as a primary outcome. Exclusions were animal studies, non-original or mechanistic reports, and studies in paediatric or adolescent populations. Two authors (JF and WS) conducted a two-step literature search (title/abstract screening followed by full-text review); disagreements were resolved by consensus and consultation with a senior author. The investigators intentionally included a broad range of study designs—including randomised trials, open-label studies, case series, and letters reporting case material—to increase the chance of detecting rare or delayed adverse effects. Data extracted from each article included study design and sample characteristics, ketamine administration details (route, dose, and number of doses), pre-treatment health screening, pre-existing morbidity, concomitant medications, and timing and method of side-effect assessment. Each article was quality-appraised with an appropriate checklist (appendix). For analysis, adverse effects were categorised into psychiatric, psychotomimetic/dissociative, cardiovascular, neurological (including cognitive), and other systems. The authors applied the Cochrane Adverse Effects Methods Group framework to examine selective outcome reporting, withdrawal/dropout, and the presence of control groups, and distinguished active surveillance (structured enquiry) from passive monitoring (spontaneous reports). Timeframes were defined as acute (immediately after a single dose), cumulative (after repeated doses), and long-term (at least 2 weeks after the last dose). A meta-analysis had been planned a priori, but after data extraction the investigators judged quantitative pooling inappropriate because studies were clinically heterogeneous (different routes, doses, comparators), used inconsistent reporting formats (often qualitative), and had variable risk of bias. Consequently, the review presents a qualitative synthesis of side-effect reporting across the included studies.
The review included 60 studies comprising 899 patients who received at least one dose of ketamine. Most study reports did not include a placebo or other control arm. Assessment of side-effects was concentrated on the acute period: 55 (92%) studies assessed acute side-effects, 24 (40%) assessed cumulative effects after repeated dosing, and 12 (20%) reported any long-term follow-up. Across studies that included a comparator, adverse events in all categories were reported more frequently in patients who received ketamine than in controls. Psychiatric side-effects were described in 23 (38%) studies and psychotomimetic or dissociative effects in 43 (72%) studies; some of these used structured scales. Timepoints for measurement varied between studies, but reported changes were generally transient. The most common acute psychiatric reactions were anxiety, agitation or irritability, euphoria or mood elevation, delusions or unusual thoughts, panic, and apathy. Withdrawal from trials for psychiatric reasons most commonly reflected worsening mood (12 participants), followed by anxiety (6 participants) and suicidal ideation (5 participants); less frequent causes included panic attacks and irritability. One isolated suicide attempt was reported in a single study. Dissociation was the predominant psychotomimetic phenomenon, followed by perceptual disturbances, derealisation, hallucinations, and depersonalisation. No long-term psychotomimetic effects were reported, but most assessments for these phenomena were limited to the short term (usually within 4 hours post-dose). Dissociation led to withdrawal in two participants. Intravenous administration was associated with a higher frequency of psychotomimetic or dissociative reports (72% of intravenous studies) compared with non-intravenous routes (36%). Cardiovascular changes were reported in 23 (38%) studies; the most common findings were increased blood pressure and heart rate. Other cardiovascular events included palpitations or arrhythmia, chest symptoms, orthostatic dizziness, and, less commonly, decreased blood pressure or heart rate. Five participants were withdrawn because of cardiovascular side-effects. Most cardiovascular effects occurred during or immediately after intravenous dosing and generally resolved within 90 minutes. Neurological side-effects most often consisted of headache and dizziness; less common reports included sedation, faintness, poor coordination, and tremor. Cognitive complaints—poor memory, poor concentration, confusion—were reported but typically only over the short term, and prospective cognitive assessment was lacking in most studies. Other adverse effects were described in 32 (53%) studies and encompassed gastrointestinal, ocular, respiratory, and urological symptoms; blurred vision and nausea were the most frequently reported. Urinary adverse effects were evaluated in only five studies. Liver function tests were specifically reported in seven studies, with two noting abnormalities after ketamine dosing. Only two studies explicitly enquired about dependence or abuse potential. Regarding assessment methods, structured side-effect scales (for example, SAFTEE, PRISE) were used in 15 (25%) studies. Most studies relied on passive monitoring and ad hoc reporting rather than active, systematic enquiry. When systematic reporting was present, it occurred in only a minority of studies: psychiatric or psychotomimetic effects were systematically reported in 25 (42%) studies, cardiovascular effects in 19 (32%), neurological or cognitive effects in 14 (23%), and other side-effects in 14 (23%). Randomised controlled trials tended to report similar rates of acute side-effects as other designs, but rarely assessed or reported longer-term risks such as cognition, urinary tract effects, or dependence.
Short and colleagues conclude that acute side-effects after ketamine treatment for depression are common but usually transient, and that the existing literature provides inadequate active surveillance of adverse effects. The main findings highlighted were: frequent acute reactions (psychiatric, psychotomimetic, cardiovascular, neurological, and other), predominant use of passive monitoring in studies, higher frequency of reported side-effects with intravenous administration, and insufficient data to draw conclusions about cumulative or long-term harms because most trials assessed only single doses with short follow-up. The authors place these results in the context of reports from other populations exposed to ketamine. Repeated or frequent ketamine use in recreational users and some clinical groups has been linked with ulcerative cystitis and other urological toxicity, liver injury, cognitive deficits (short-term and long-term memory impairments), and dependence-related behaviours. The review summarises case reports and series describing bladder dysfunction, renal complications in severe cases, and hepatotoxicity after prolonged or repeated infusions. Experimental human studies have demonstrated dose-dependent acute impairment of short-term memory after intravenous ketamine, whereas findings from clinical treatment populations are mixed but limited by short follow-up durations. Safety concerns in patients with medical comorbidity are also emphasised. Given common acute blood-pressure elevations after ketamine, the authors note that WHO contraindications for ketamine (moderate-to-severe hypertension, congestive cardiac failure, prior stroke) are pertinent and that clinicians should exercise caution, particularly with repeated dosing and rapid delivery routes. Dependency risk is discussed: preclinical and clinical evidence indicates rapid development of tolerance (tachyphylaxis) and in recreational settings craving and compulsive use are reported, although fewer than 15 well-documented human dependence cases have been described in the past two decades. Key limitations acknowledged by the investigators include heterogeneity in study designs and reporting, inconsistent and often qualitative side-effect descriptions, variable timepoints, and insufficient numerical detail to permit meta-analysis or robust incidence estimates. Because most included studies used passive or ad hoc reporting, the true frequency and longer-term trajectory of many adverse effects remain uncertain. The authors recommend that future ketamine trials for depression adopt active surveillance and standardised, structured scales to assess side-effects across acute, between-dose, and long-term periods, and implement pre-treatment screening for comorbid conditions and concomitant medications. They note ongoing work to develop a Ketamine Side Effect Tool and a Ketamine Safety Screening Tool, and highlight outstanding questions about differences between racemic ketamine and single isomers or metabolites with respect to adverse-effect profiles.
Ketamine has pharmacological properties that make it a potentially useful treatment for refractory depression, but the evidence base for its safety is incomplete. Acute side-effects after single-dose use are common yet generally transient. By contrast, higher doses and repeated administration have been associated—outside depression trials—with potentially serious and sometimes persistent toxicities, including urological and hepatic injury, cognitive impairment, and craving or dependence. These longer-term risks have not been adequately assessed in studies of ketamine for depression, most of which evaluated single-session treatments with only short-term follow-up. The safety of long-term, repeated ketamine dosing in depression therefore remains uncertain. The authors recommend further large-scale clinical trials that include multiple doses, long-term follow-up, careful monitoring, and systematic reporting of all potential side-effects before ketamine is adopted widely as a clinical antidepressant.
Major depression affects about 350 million people, making it the leading cause of disability worldwide.Anti depressant treatments targeting the monoamine system alleviate depressive symptoms in only 50% of patients,and rates become substantially lower in those whose depression has not responded adequately to two or more adequate antidepressant trials.Moreover, these treatments have a long onset of action, usually 3-4 weeks.Hence, there is an indisputable need for more efficacious and rapidly acting antidepressants, with ketamine being a key candidate. However, have investigations on ketamine in depression thus far addressed essential factors such as acute and longterm safety? A balanced assessment of an intervention requires investigation of both benefits and harms. Usually designed to evaluate treatment efficacy or effectiveness, randomised controlled trials are often completed in a short period of time, using a limited number of doses and a relatively small number of participants. These trials are known to be poor at identifying and reporting harms,which can lead to a misconception that a given intervention is safe when its safety is actually unknown. Since Berman and colleagues, in 2000,reported the results of their initial pilot placebocontrolled trial investigating ketamine for the treatment of depression, a plethora of articles, including original studies, narrative reviews, and metaanalyses, have been published, endorsing the efficacy of ketamine in depression. Only a few of the original studies, however, were randomised controlled trials or systematically assessed ketamine's efficacy and safety compared to placebo or a control drug in patients with depression.To date, findings from 20 randomised controlled trials have been reported, which all together include 430 participants who received ketamine. Most of these were proof of concept studies and examined the efficacy of a single dose only, and only a small number comprehensively assessed ketamine's safety, tolerability, and abuse potential. Very few examined the safety (or efficacy) of repeated treatments, relative to placebo or control treatment, although repeated treatments are increasingly being used in open label studies,case studies,and some clinical services. Importantly, safety concerns have been reported in other patient groups exposed to ketamine, such as individuals with chronic pain, and recreational users. Reviews, including from WHO,highlighted urinary tract symptoms as a welldocumented sideeffect of ketamine and listed liver toxicity, cognitive changes, and dependence as potential harms.In 2012, Morgan and Curran, 36 on behalf of the Independent Scientific Committee on Drugs, concluded that frequent, daily use of ketamine is associated with ulcerative cystitis and neurocognitive deficits in working and episodic memory; they also reported that many frequent users are concerned about addiction. Despite the 15 years that have passed since Berman and colleagues' report, there remains a large gap in knowledge regarding the longterm efficacy of ketamine in depression, potential longterm safety issues, and the absence of approved clinical guidelines for its use. With a growing interest in ketamine as a treatment for depression, as well as the increasing use of repeated dosing in both clinical and research settings,acute and longterm safety issues must be further explored and systematically assessed. In this systematic review, we aggregate and analyse reporting of data on the safety of ketamine in depression and comment on experience from human clinical trials to date.
We followed PRISMA reporting guidelines in this systematic review. Studies were eligible for inclusion if they reported findings with adult human populations who had a validated diagnosis of unipolar or bipolar depression and had received one or more doses of ketamine (any administration route, frequency of dose, and time course were accepted). Studies also had to describe changes in depression status as a primary outcome measure. Exclusion criteria included: animal trials; studies that were nonoriginal or mechanistic in nature; studies that described paediatric or adolescent population outcomes Two authors (JF, WS) did a twostep literature search; when a title or abstract seemed to describe a study eligible for inclusion, the full article was reviewed to assess its relevance based on the inclusion criteria. Any disputes in results were settled by consensus. Any discrepancies between the two authors were resolved by consultations with a senior author. Although randomised clinical trials provide the most reliable estimates of effect, rare serious adverse events or longterm adverse effects are unlikely to be detected. We therefore included many types of study designs.Letters or comments to editors were included if they reported on a case study or series. We collected information about study design, sample characteristics, ketamine administration details (route, dosage, number of doses), health screening before ketamine administration, preexisting medical morbidity, concomitant medications, and timing of sideeffects assessment. Using the same time definitions, we also collected information on which specific sideeffects were reported to have occurred (we considered a sideeffect as having occurred if the report listed its occurrence in at least one patient); and, where relevant, whether structured assessment tools or questionnaires were used to assess adverse effects or safety. Each article was qualityappraised with a relevant appraisal checklist or tool (appendix).
Initially, we took a broad approach to assessing potential sideeffects of ketamine for depression to detect a variety of adverse effects or events, whether known or previously unrecognised. We then categorised adverse effects into subgroups (psychiatric, psychotomimetic or dissociative, cardiovascular, neurological [including cognitive], and other sideeffects) to include the sideeffects that had been reported most frequently. In accordance with the Cochrane Adverse Effects Methods Group approach, 42 we addressed the following issues that affect data quality: (1) selective outcome reporting; (2) withdrawal or dropout; and (3) presence of a control group. For selective outcome reporting, we identified whether, and to what extent, sideeffects were assessed and reported, which approach was used for assessing sideeffects (active surveillance [ie, method described for actively enquiring about sideeffects] versus passive monitoring [no method for active enquiry described, thus reports considered to represent side effects spontaneously reported by patients]), whether structured scales or questionnaires for the assessment of sideeffects were used, whether sideeffects were reported systematically (ie, both presence and absence of side effects were reported) or ad hoc (ie, only reported if they occurred), and the timeframe in which sideeffects had been assessed and reported (ie, immediately after a single dose [acute], after repeated doses [cumulative], or at least 2 weeks after the last dose [long term]). To analyse
withdrawal or dropout, we gathered as much information as possible to avoid directly interpreting such data as surrogate markers for safety or tolerability because of potential bias. We assessed the presence of a control group in order to distinguish between adverse events (ie, those which appear after intervention onset) and adverse effects (ie, adverse events for which causality is likely). A metaanalysis was initially planned, but after data extraction it was deemed that quantitative analysis via metaanalytical methods was not appropriate for the sideeffects reported because the articles reviewed were clinically diverse, including a variety of different administrative routes and doses with different control comparators, differences in reporting methods (including nonspecific qualitative statements about sideeffects), and bias for some of the individual studies (including reporting bias). Thus, a qualitative review of data was undertaken.
We included 60 studies in our analysis (figure 1, table 1), which included 899 patients who had received at least one dose of ketamine (table). Most study reports did not include a placebo or control group (figure). Acute sideeffects were assessed in 55 (92%) studies, whereas cumulative sideeffects were analysed in 24 (40%) studies, and longterm sideeffects were assessed in 12 (20%) studies (figure). In studies that did include a placebo or comparator intervention, sideeffects across all categories were more commonly reported in patients who received ketamine. Acute psychiatric sideeffects from ketamine were described in 23 (38%) studies, whereas psychotomimetic or dissociative sideeffects were described in 43 (72%) studies, some of which used structured scales (figure). Overall, the timepoints used for measurements differed between studies; however, any changes in score were generally selflimiting. The most common acute psychiatric sideeffect was anxiety, followed by agitation or irritability, euphoria or mood elevation, delusions or unusual thoughts, panic, and apathy. Less common sideeffects were detachment, emotional blunting, psychosis, emotional lability, craving attention, and formalthought disorder. When symptoms were delayed, such as with anxiety, worsening depression or suicidality, or both, and hypomania, it was unclear if they were explicitly linked to the ketamine treatment. An isolated case of a suicide attempt was reported in one study.Across all the studies analysed, the most common psychiatric reason for withdrawal from a trial was worsening mood (12 participants), followed by anxiety (six participants) and suicidal ideation (five participants). Less common psychiatric reasons for withdrawal included panic attack (two participants) and irritability (one participant). An
absence of psychosis or mania as a potential sideeffect was reported in five (8%) studies. The most common psychotomimetic sideeffect reported was dissociation, followed by perceptual dis turbance, odd or abnormal sensation, derealisation, hallucinations, feeling strange, weird, bizarre, or unreal, and depersonalisation. No longterm psychotomimetic sideeffects were reported; however, most studies assessed for psychotomimetic sideeffects only over the short term (usually within 4 h postketamine dose). Dissociation was the only psychotomimetic cause cited for withdrawal from studies (two participants in total). The absence of psychotomimetic or dissociative effects was reported in five (8%) studies. In general, studies using the intravenous route of administration tended to report more psychotomimetic or dissociative sideeffects than those that used other routes of administration (eg, oral, subcutaneous, intra muscular). 36% of nonintravenous studies reported psychotomimetic sideeffects, compared with 72% of intravenous studies. Of the 60 studies included in this analysis, 23 (38%) reported acute changes in the cardiovascular status of patients. The most common cardiovascular changes were increased blood pressure and increased heart rate.Other reported cardiovascular sideeffects included palpitations or arrhythmia, chest pain, tightness, or pressure, dizziness on standing, decreased blood pressure, and decreased heart rate. Five patients were withdrawn because of cardiovascular sideeffects. Most cardiovascular effects were reported as occurring during or immediately after intravenous ketamine administration. In general, these effects resolved within 90 min of the administered dose. The most common neurological sideeffects cited were headache and dizzi ness. Less common neuro logical side effects included sedation or drowsiness, faintness or lightheadedness, poor coordination or un steadiness, and tremor or involuntary movements. Most studies reported only shortterm neurological effects. Cognitive sideeffects included poor memory or memory loss, poor concentration, confusion, and cognitive impairment or diminished mental capacity. Similarly, if cognitive sideeffects were described, these were reported over the short term only. Potential cognitive sideeffects were not assessed in most studies. Numerous other sideeffects were reported in 32 (53%) studies, with the greatest variety reported in patients receiving intravenous ketamine. These side effects mainly related to the gastrointestinal, ocular, respiratory, and urological systems. The most frequently reported other sideeffects were blurred vision and nausea. Less common side effects included insomnia or sleep disturbance, decreased energy, general malaise, or fatigue, restlessness, dry mouth, vomiting, and crying or tearfulness. Urinary sideeffects were assessed in only five studies. Liver function tests were specifically reported to have been completed in seven studies, with two study outcomes including abnormalities postketamine dose.Only two studies enquired about the development of ketamine dependence or abuse.Scales (eg, SAFTEE, PRISE) to systematically assess other sideeffects were used in 15 (25%) studies. Most study groups relied on passive monitoring of treatment emergent adverse events, and only a few groups followed
up on these other adverse events beyond the acute treatment period. Thus, the longterm trajectory and consequences of these reported other sideeffects are largely unknown. If sideeffects were assessed for, they were predominantly reported in an adhoc fashion. Psychiatric or psycho tomimetic sideeffects were systematically reported in only 25 (42%) studies; cardiovascular side effects were systematically reported in 19 (32%) studies; neurological or cognitive effects were systematically reported in 14 (23%) studies; and all other sideeffects were systematically reported in 14 (23%) studies. When considering the sideeffect reporting from randomised controlled trials only, the most common acute sideeffects were reported at similar rates as for other study designs. However, longterm sideeffect risks or other potential sideeffects, including cognition, urinary tract symptoms, or dependency risk, were rarely assessed or commented on in randomised controlled trials (figure).
We systematically reviewed 288 published reports of studies in which ketamine was administered to people who had depression. Our objective was to identify the main sideeffects related to this intervention and to discern whether differences were apparent between single (acute) versus repeated dosing (cumulative and longterm). Sideeffects were categorised to facilitate collation and analysis of results; notably, most people receiving ketamine had acute sideeffects. In summary, our main findings were: (1) acute sideeffects are common after a treatment of ketamine; (2) active assessment, surveillance, and reporting of sideeffects during trials of ketamine for patients with depression are inadequate; (3) most of the sideeffects reported were associated with ketamine given intravenously; (4) most of the assessed sideeffects were reported to occur immediately after singledose administration (acute); (5) the most common sideeffects to be reported were headache, dizziness, dissociation, elevated blood pressure, and blurred vision (figure); (6) most sideeffects were reported to have resolved shortly after dose administration; (7) psychiatric sideeffects were also apparent, the most common being anxiety; (8) many sideeffects were assessed through passive monitoring only; (9) if sideeffect assessment was completed, it was predominantly reported in adhoc form; and (10) from the analysis, we could only draw conclusions regarding single dosing and acute sideeffects because insufficient data were available regarding the sideeffects of repeated dosing and possible cumulative and long term risks. Passive monitoring of sideeffects relies on spontaneous reports and is very helpful to detect new, rare, and serious sideeffects.Active surveillance includes a preorganised process to discover more information on sideeffects, including additional detail, which usually cannot be achieved via passive monitoring methods.An important factor that has emerged from our literature analysis is the inadequacy of active and structured inquiry of known or potential sideeffects. Although the brief psychiatric rating scale, the clinicianadministered dissociative states
Studies that reported the occurrence of side-effects Review scale, and basic cardiovascular measures are used in many studies, methods for assessing other categories of sideeffects, including neurological, cognitive, gastro intestinal, and urological sideeffects, were not specifically reported. This is particularly important in view of our findings that neurological and other sideeffects, when considered categorically, were reported to occur just as often as or more often than cardiovascular or psychiatric sideeffects. Although ketamine is considered a safe drug for its principal approved application regarding anaesthesia (which usually involves a single oneoff dose),the prospect of ketamine use in depression will likely entail multiple and repeated doses during a long period of time. Repeated use of ketamine in other adult populations, including patients undergoing anaesthesia, patients with chronic pain, and recreational users, has been linked with urological toxicity, hepatotoxicity, cognitive deficits, and dependency risks. For example, in 2007, Shahani and colleaguesfirst described chronic users of ketamine who developed severe genitourinary symptoms. Since then, a large volume of additional reports associating ketamine with bladder toxicity have described cystitis and bladder dysfunction, an increase in urinary frequency, urgency, dysuria, urge incontinence, and occasionally painful haematuria.Secondary renal damage has also been described in severe cases,and Chen and colleagueshave published the first case of renal infarction after nasal insufflation of ketamine. Ketamine use has also been linked with urological toxicity in patients receiving treatment for chronic pain, with some patients developing genitourinary symptoms after only 9 days of treatment.More than 20% of people who use ketamine for recreational purposes are estimated to have urinary tract symptoms,although investigators from Spain and Hong Kong report a much higher prevalence (46% and 90%, respectively).The mechanism by which ketamine causes urological toxicity is not understood, but findings from invitro studies have shown a direct interaction between ketamine and the bladder urothelium,and in one study, ketamine exposure was associated with apoptosis of urothelial cells.The damage appears to be dose related, and although initially thought to improve or resolve entirely after cessation of ketamine use, this might not be the case.Ketamine has been reported to negatively affect the liver and biliary tract. Noppers and colleaguesshowed that liver injury might occur after prolonged or repeated infusion of ketamine, or both. Six patients were scheduled to receive two continuous, intravenous, 100 h ketamine infusions (infusion rate 10-20 mg/h) separated by 16 days. Three patients developed hepatotoxicity after the start of the second infusion. Other reports of liver toxicity in users of recreational ketamine exist,and Belland Sear 100 have expressed serious concerns. The mechanism by which ketamine causes liver injury is not understood but might be related to metabolic events causing increased lipid peroxidation and free radical formation.In a preclinical study, ketamine was found to increase flow resistance across the sphincter of Oddi, 101 but in a more recent study in human beings, ketamine use in a single dose of 20 mg did not affect sphincter of Oddi parameters.Other authors have proposed that the NmethylDaspartate receptor antagonistic effect of ketamine might cause smooth muscle relaxation and subsequent dilatation of the biliary tree and gallbladder dyskinesia via a central pathway.Compared with healthy controls without a history of drug abuse, people who use ketamine frequently can also have severe impairments in both shortterm and longterm memory.In a doubleblind randomised
crossover study, Hartvig and colleagues 105 found that shortterm memory could be acutely impaired dose dependently by intravenous administration of 0•1 mg/kg and 0•2 mg/kg, as assessed by a word recall test. Krystal and colleagues 106 and Malhotra and colleagues 107 have replicated these results. People who have become chronic recreational ketamine users have a regionally selective upregulation of D1 receptor availability in the dorsolateral prefrontal cortex, an effect also seen after chronic dopamine depletion in animals.These data suggest that repeated use of ketamine affects prefrontal dopaminergic transmission, a system involved in working memory and executive function. Data from studies of people with chronic pain and depression have been less conclusive. In a study by Koffler and colleagues, 109 cognitive effects of ketamine in patients treated for chronic pain were extensively assessed with several neuropsychological tests before infusion and at 6 weeks postinfusion; they concluded that ketamine had no residual cognitive effects at 6 weeks. Murrough and colleagues (2014and 2015) reported that low dose ketamine was associated with minimal acute neurocognitive effects in patients with treatmentresistant depression 40 min after ketamine infusion. They also reported that any changes in cognition appeared to be transient in nature, with no adverse neurocognitive effects 7 days after treatment. In both Koffler's and Murrough's studies, however, the followup periods were short, making it difficult to comment on longterm risks associated with repeated use. Another question raised from this literature review relates to the safety of using ketamine in patients with depression who might have other comorbid medical disorders. It is unclear in many studies whether comprehensive health screens were completed before ketamine initiation. For instance, given that acute blood pressure changes are commonly reported after a ketamine dose, particularly if given intravenously, should practitioners be more cautious in administering ketamine to patients with a history of cardiovascular disease? According to WHO, ketamine is contraindicated in patients with moderatetosevere hypertension, congestive cardiac failure, or a history of cerebrovascular accident. 110 Despite low doses of ketamine being used in depression studies, caution should be taken if repeatedly used. This concern is also reflected in the scientific literature about chronic pain, in which investigators conclude that ketamine use should be restricted because of sideeffects, 111 that rapid acting routes of administration of ketamine such as injection or intranasal route should be avoided, and doses should be kept as low as possible for other administration routes.Ketamine is a drug of recreational misuse. The incidence of dependency is unknown, but findings from both preclinical and clinical studies in the anaesthesia setting have shown that repeated doses of ketamine are associated with rapid development of tachyphylaxis, 36 and in the scientific literature describing recreational misuse, craving for ketamine, compulsive behaviour, and rapid development of tolerance are common in people who use ketamine frequently.This phenomenon has also been described in pigeons and monkeys, who repeatedly self administered freely available ketamine and at increasing amounts with time.Only a very few cases (fewer than 15) of human ketamine dependence have been described in the past 20 years, 116-121 including a recent report of tolerance leading to escalating use of ketamine in an individual with depression.Repeated ketamine administration in depression might be associated with the risk of dependency in susceptible individuals. Despite low ketamine doses being used in depression studies, urological toxicity, liver function abnormalities, negative cognitive effects, and risk of dependence might limit the safe use of ketamine as a longterm antidepressant treatment. These aspects require further careful examination before ketamine is adopted as a clinical treatment for depression. Systematic reviews of sideeffects can provide valuable information to describe adverse events (frequency, nature, seriousness), but they are hampered by a lack of standardised methods to report these events and the fact that sideeffects are not usually the primary outcome of included studies.An important limiting factor in our analysis was our inability to conduct a formal meta analysis because of the heterogeneity in the assessment and reporting of sideeffects between studies as well as many differences in study designs and methods and because of the difficulty of analysing the actual incidence of sideeffects versus the reporting of sideeffects. Most reports of the occurrence of a sideeffect were qualitative, using inconsistent terminology and varying timepoints, and sometimes the reports did not specify the number of patients who had the sideeffect, but stated in generic terms that the sideeffect was observed to have occurred. A major implication of our review findings is that data for sideeffects should be collected though active surveillance in future ketaminerelated depression studies and sideeffects potentially related to ketamine should be reported systematically (panel). Structured rating scales should be used to enquire about specific potential sideeffects that appear just after a treatment
dose, between doses, and during the long term. The frequency of reported sideeffects or adverse drug reactions is greater when patients are directly questioned than when unstructured methods are used.Similarly, screening before treatment begins would help identify those patients who might be at high risk of particular sideeffects. This screening could include the collection of information around comorbid physical health and concomitant medications. We are developing and validating the Ketamine Side Effect Tool and Ketamine Safety Screening Tool for these purposes. Most of the studies we identified used racemic ketamine. Large depression trials using the Sisomer of ketamine are now underway. The incidence and severity of acute and longterm sideeffects with Risomers and Sisomers of ketamine versus the racemic mixture, and metabolites of these primary compounds, are questions that remain to be answered.
Ketamine's pharmacological profile makes it an interesting and possibly useful drug for the treatment of refractory depression. Acute sideeffects associated with singledose use in depression are common, although generally transient and resolve spontaneously. High doses and repeated administration have been associated with potentially serious and possibly persistent toxic effects both in patients treated for chronic pain and in people who use recreational ketamine. These sideeffects include urological, hepatic, craving or dependence, and cognitive changes. To date, these sideeffects have not been adequately assessed in studies investigating ketamine use in depression. Almost all randomised controlled trials assessed the safety of single sessions of ketamine, but with only shortterm follow up. The safety of longterm, repeated ketamine dosing, as is increasingly used in clinical practice, is therefore uncertain. Data on the safety of this practice, including longterm outcomes, are essential before ketamine can be used for clinical treatment of depression. Further largescale clinical trials including patients with depression, which include multiple doses of ketamine, longterm follow up, careful monitoring, and reporting of all potential sideeffects are recommended. Contributors BS, JF, and WS completed the literature search. BS and JF collected data. BS, FJ, VG, and WS extracted data. BS, VG, and CKL interpreted the data. BS, VG, and CL wrote this paper. BS and JF compiled the tables. BS, VG, and CKL developed the Ketamine Side Effect Tool, and JF revised the references.
CKL declares fees for attending a Janssen Advisory Board Meeting. All other authors declare no competing interests.
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