This case report describes a 25-year-old woman who developed ketamine addiction after a single sub-anaesthetic intranasal dose given for acute suicidality. She later escalated to daily illicit ketamine use, with cocaine and 3-MMC misuse, leading to financial and housing problems and a suicide attempt when access was stopped.
This case report presents the case of a 25-year-old woman who developed ketamine addiction following a single sub-anaesthetic dose of intranasal ketamine in a pilot study investigating intranasal racemic ketamine for acute suicidality. She had a history of depression, obsessive–compulsive disorder, autism spectrum disorder and anorexia nervosa, and she had sporadically used alcohol and cannabis. Following the intervention, she reported a transient reduction in suicidal ideation but later sought illicit ketamine to recreate its calming effects on intrusive thoughts. Subsequently she also started abusing cocaine and 3-methylmethcathinone (3-MMC). Within weeks she had escalated to daily use, which led to financial distress, housing instability and a suicide attempt when access was cut off. Although she initially ceased use, she later relapsed into ketamine and cocaine addiction. This case highlights the addictive risk of ketamine, even in controlled settings. Given ketamine’s rising use in psychiatric treatment, careful screening, monitoring and awareness of addiction potential are essential. Future research should evaluate patient-specific risk factors and dosing strategies to minimise abuse liability.
Roelandt and colleagues introduce ketamine as a rapidly acting treatment that can reduce depressive symptoms and suicidal ideation, but they note that its addiction liability is a recognised concern, especially because intranasal and intravenous formulations are quickly absorbed and may be misused. They also point out that earlier controlled studies had not systematically assessed abuse liability in a way that would reliably detect craving, drug liking, or later dependence, so the true risk in clinical settings may be underestimated. The paper aims to report a case of ketamine addiction that developed after a single sub-anaesthetic intranasal dose given in the KETA pilot study for acute suicidality. The authors present the case to highlight potential patient-specific risk factors, to inform the design of the subsequent randomised controlled trial, and to argue for closer monitoring of abuse potential in future ketamine studies and clinical use.
Papers cited by this study that are also in Blossom
Wilkinson, S. T., Ballard, E. D., Bloch, M. H. et al. · American Journal of Psychiatry (2017)
Breeksema, J. J., Kuin, B. W., Kamphuis, J. et al. · Journal of Psychopharmacology (2022)
Andrade, C. · Journal of Clinical Psychiatry (2015)
This is a case report drawn from the KETA pilot study, which preceded a larger double-blind randomised controlled trial comparing 75 mg intranasal racemic ketamine with 4 mg intranasal midazolam as an active placebo for acute suicidality. In the pilot phase, a heterogeneous group of patients with acute increases in suicidality received a single open-label dose of 75 mg intranasal racemic ketamine. The pilot study was designed mainly to assess feasibility and acceptability for the later trial. Participants were recruited from different divisions of the Psychiatry Department of the University Medical Centre Groningen and from Lentis Mental Health Care in Groningen. Written informed consent was obtained, and the study was approved by the Institutional Review Board Groningen. Because of the acute suicidal state of potential participants, they were given at least 1 hour to decide whether to take part. In the pilot study, vital signs, adverse effects, mood and suicidality were monitored after dosing. Depression was measured with the Montgomery-Åsberg Depression Rating Scale (MADRS), and suicidal ideation was assessed with the Beck Scale for Suicidal Ideation (BSSI). These measures were collected at baseline and then at 60 min, 180 min, and 1, 3 and 7 days after ketamine administration. The case report also describes protocol changes made after this event. The authors state that, for the later randomised trial, they reconsidered exclusion criteria, extended follow-up from 7 days to 4 weeks, and added more systematic enquiry about craving or abuse at each follow-up point. They also state that a clinically experienced team member was present during the first hour after treatment to help detect distress or drug liking.
The patient was a 25-year-old woman with recurrent depression, obsessive-compulsive disorder, autism spectrum disorder and anorexia nervosa. She had no documented addiction history and only sporadic alcohol and cannabis use. She was admitted for acute suicidality after worsening distress related to changes in her care, and she enrolled in the KETA pilot study after giving consent. Her baseline MADRS and BSSI scores were 37 and 35, respectively. After the single intranasal ketamine dose, her symptoms improved quickly but only temporarily. At 1 hour, MADRS and BSSI had fallen to 31 and 29; at 1 day they were 32 and 25; and by 1 week they had risen again to 36 and 31. The authors interpret this as a rapid but transient reduction in depression and suicidal ideation. The patient reported that the ketamine produced a calming effect on intrusive thoughts and that this subjective experience motivated later recreational use. Around 4 weeks after the study dose, clinicians learned that she had obtained illicit ketamine and was using it intranasally in daily amounts of up to approximately 1 g. The type and purity of the illicit ketamine were unknown. She described craving the calming and perceptual effects, including altered body perception and time perception. She also began using cocaine and 3-methylmethcathinone (3-MMC), sometimes to counter ketamine and then using ketamine again to counter stimulants, creating a cycle of polysubstance use. Her ketamine use led to financial problems, housing instability and pressure from her sheltered living facility to stop. When she could no longer obtain ketamine, she attempted suicide, although she did not report physical withdrawal symptoms. She initially stopped after the threat of eviction and the impact on treatment, but later relapsed into ketamine and cocaine addiction. The report does not describe any formal addiction treatment being accepted by the patient.
The authors argue that this case shows ketamine can carry meaningful abuse risk even when it is given once in a controlled clinical setting and even in a patient without a prior substance use disorder. They suggest that the patient’s acute relief from intrusive thoughts, alongside the subjective psychoactive effects of ketamine, may have reinforced drug-seeking behaviour. They also emphasise that the case is particularly relevant because ketamine is increasingly used, or being considered, for severe psychiatric symptoms including suicidality. They place the case in the context of earlier work suggesting both therapeutic promise and addiction liability. The authors note that previous reports and reviews have offered mixed signals: one earlier case report described abuse after intended clinical use, whereas a scoping review found no misuse or dependence in controlled studies of treatment-resistant depression. However, they argue that those studies often did not use validated tools to assess abuse liability, which may have led to under-recognition of problems. The discussion also highlights broader harms associated with ketamine abuse, including potential urological, hepatic and neurological damage. The authors note that intranasal ketamine may have a particular abuse risk because of its rapid absorption, and they cite recreational use patterns and self-medication reports as reasons to consider contextual risk when prescribing. As limitations and uncertainties, the authors acknowledge that this is a single case and cannot establish how common this outcome is. They also note that the patient had complex psychiatric comorbidity, possible borderline personality traits, and acute social stressors, so the case may not generalise to all patients. They further state that there was no time for extensive diagnostic assessment during the acute suicidal crisis, which limited pre-treatment risk evaluation. In terms of implications, the authors report that this case led them to amend the subsequent trial protocol. They expanded follow-up from 7 days to 4 weeks, added routine questions about craving and abuse at all follow-up visits, and planned to alert treating psychiatrists to possible warning signs. They conclude that future ketamine studies and clinical practice should systematically monitor abuse liability, consider the patient group and treatment regimen, and use prolonged follow-up to detect emerging addiction.
Mrs. S. was, at time of treatment, a 25-year-old woman with a history of recurrent depressive episodes, obsessive-compulsive disorder, autism spectrum disorder and anorexia nervosa, with no history of addiction disorders. The substance abuse anamnesis revealed that her past substance use was limited to sporadic use of alcohol and cannabis, the adult use of these being legal and tolerated in law, respectively, in the Netherlands. This use pattern did not qualify as a substance use disorder. One day before enrolment in the KETA pilot, by means of a crisis intervention for her acute suicidality, she was admitted to the acute in-patient psychiatry ward of the UMCG. In the past the patient had exhibited recurrent suicidality, reflected by more than ten previous suicide attempts. Various therapeutic interventions were tried to attenuate her depressive symptoms and manage suicidality, namely pharmacotherapeutic interventions: venlafaxine, clomipramine, fluvoxamine, benzodiazepines and individual cognitive-behavioural therapy. Because therapeutic interventions had no lasting effect on her psychiatric multimorbidity and suicidality, she was living in a sheltered psychiatric housing facility. Besides this, acute exacerbations in suicidality or suicide attempts, often auto-intoxications, frequently necessitated admission to a secured psychiatric ward. Before her admission to the acute in-patient ward in November 2021, due to an acute increase in suicidal ideation. she had been treated at the acute out-patient clinic of the UMCG since March 2021. The exacerbation that led to her admission was triggered by the announcement from her psychiatrist at the UMCG that further care was going to be provided by a different mental healthcare institution, which caused significant emotional distress. Later that day the police found her wandering near railway tracks, and brought her to the hospital for psychiatric assessment. The evaluation showed acute suicidality in a patient with no social support, escalating hopelessness and frustration with her psychiatric care. Her symptoms and history raised the suspicion of a borderline personality disorder. At the time, however, this diagnosis had not been confirmed or documented. She voluntarily agreed to be admitted to our psychiatric hospital. The following daybecause she was still suffering from acute suicidalityafter receiving written informed consent she was screened for, and enrolled, in the KETA pilot study. The aim of the study was to treat suicidality specifically, taking into account that these patients may or may not have other, concurrent, psychiatric conditions. Although trying to stay as close to clinical reality as possible, we were very mindful of risk. Therefore, we critically evaluated and discussed the potential hazards for each individual patient before deciding whether that patient could participate. In the case of this subject, we consulted the physician who had treated her since March 2021. No past substance abuse was reported by this physician. Nevertheless, due to the setting and focus of the study on acute suicidality, there was no time available for extensive diagnostic trajectories. We acknowledge that ketamine is not an approved indication for suicidality, and this study explicitly explores its potential for this new patient group, which was also the reason for performing a pilot study before starting with a larger RCT. When the patient enrolled in the KETA study, her MADRS and BSSI scores at baseline were 37 and 35, respectively; 1 h postintervention these had reduced to 31 and 29, and to 32 and 25, respectively at 1 day following the intervention. After 1 week, at the end of follow-up, these had increased back to 36 and 31, respectively. These scores indicated a rapid but transient reduction in both depression symptoms and suicidal ideation. Post-intervention, the patient attributed the transient reduction in suicidal ideation to two factors: a positive experience from the direct psychoactive effects of ketamine and an abrupt diminution of her persistent intrusive and obsessive thoughts, which she described as 'the intrusive thoughts being pushed to the side of her head'. Around 2 h after receiving the intranasal spray, the intrusive thoughts returned. During the subsequent follow-up period of 1 week, the patient returned to her sheltered housing facility. Over the following weeks, the patient wanted to start consuming ketamine recreationally. For the first time she came into contact with a drug dealer, who provided her with ketamine. This became apparent to her psychiatric clinicians after approximately 4 weeks. She intranasally used illicitly obtained ketamine in powdered form, in daily doses reaching up to approximately 1 g. Given its illicit source, the specific type (S-ketamine, R-ketamine or racemic mixture) and purity were unknown. She reported no adverse urinary, cognitive or other effects. She described ketamine craving in the form of longing for the calming effect on her intrusive thoughts, which she had first experienced during study participation. Furthermore, she liked the visual effects and sensations caused by ketamine, such as having the feeling that her arms and legs were several metres long. Because of its subjective effect on time perception, she generally used ketamine throughout the day to make time pass faster. If she had to go outside, she started to take stimulants such as cocaine or 3-methylmethcathinone (3-MMC) to reduce the effects of ketamine. She obtained this drug via the dealer, who presented her with a list of the different drugs that were available. When she returned home, she felt a need to counter the effect of the stimulants in turn with ketamine, resulting in a loop of stimulant and ketamine use. She required increasing doses to achieve these effects. Eventually her drug abuse caused financial problems. Subsequently this resulted in an inability to acquire more ketamine, and her sheltered housing facility pressured her to quit using ketamine because she would probably be evicted if she continued abusing it. A subsequent suicide attempt resulted from this increasing stress and her inability to obtain more ketamine, even though she did not experience physical withdrawal symptoms. Although the patient had no prior history of addiction, and only sporadically used alcohol and cannabis, referral and treatment of her addiction were strongly advised after the discovery of her illicit abuse. The patient chose not to follow this advice. The threat of eviction from her home caused her to stop abusing ketamine and other drugs. When asked what had caused this sudden ability to stop, she mentioned that 'her autism helps her to really go for it when she has made a decision'. She also mentioned that the interference of ketamine abuse with her current treatment, the threat of losing her place at the sheltered living facility and financial problems were the main motivators to stop, because she realised that ketamine abuse was causing more harm than good. Unfortunately, the patient later relapsed into ketamine and cocaine addiction.
Ketamine has been shown to have a rapid and positive effect on depressive symptoms and suicidality.Moreover, it has been suggested that ketamine's effect on suicidality may be independent of an improvement in depressive symptoms.Given its ability to rapidly reduce depressive symptoms and its potential effectiveness for alleviating suicidal symptoms, ketamine may present a novel treatment for acute suicidality. To test the hypothesis that ketamine could have an antisuicidal effect, irrespective of the underlying diagnosis, we designed the KETA study and performed the KETA pilot beforehand. The protocol for the KETA study has been published elsewhere.Abuse liability of ketamine Despite these potential advantages, ketamine treatment carries a well-known risk for addiction. Both intranasal and intravenous treatments have a rapid absorption rate, which increases abuse liability.This potential abuse liability is further complicated by ketamine often being available through illicit means outside of medical control. Furthermore, preclinical evidence shows that dose escalation is needed to retain the same effect with repeated use, with S-ketamine having a higher addiction liability compared with R-ketamine.A 2015 case report by Bonnet, for the first time, shed light on ketamine abuse following intended clinical use. That article presents the case of a 50-year-old nurse with depression who, in an attempt to alleviate her symptoms, began intramuscularly injecting herself with ketamine that she had taken from hospital supplies. It needs to be taken into account that in this case the ketamine was not prescribed by a doctor, and thus was not properly monitored. Notwithstanding, this work provided a first signal of the abuse potential of ketamine when administered for the treatment of a mood disorder. Despite this addiction liability, a recent scoping review found that single or repeated ketamine administrations in controlled settings did not cause misuse, dependence or gateway activity in patients with treatment-resistant depression. It should, however, be noted that most studies did not systematically evaluate abuse liability via validated scales or questionnaires, which probably led to underreporting of these adverse events.Given the fact that ketamine addiction can have severe detrimental effects on the brain, reporting of abuse development in clinical settings is very important.Besides neurotoxic effects, ketamine can also devastatingly impact urological health, with prevalence rates of lower urinary tract symptoms in 44-77% of ketamine abusers and 8-30% for upper urinary tract disease.Although one may not directly draw conclusions from the abuse liability of recreational ketamine for clinical therapy, literature on this topic may provide insights. Recreational ketamine imposes a significant burden on society. In 2008/2009 the prevalence of ketamine abuse in the UK was 1.7%, with a lifetime prevalence of 4%,and ketamine abuse was around 1% in American college students.Furthermore, recreative ketamine use doubled in the UK between 2016 and 2025. We are aware that treating complex, multimorbid subjects may pose additional risk. Although not all of this has reached the medical literature, cases such as that of Matthew Perry painfully illustrate that risk.However, given the fact that ketamine may represent a promising treatment even for severely mentally ill multimorbid patients, it is surmisable that, in real-world clinical settings, these patients may receive ketamine treatment. Further exploration into patient-specific characteristics and dosing strategies is necessary to further optimise treatment and hopefully reduce the likelihood of addiction occurring as a result of ketamine treatment for a mental disorder.Several sources postulate that intranasal ketamine is absorbed by the olfactory nerve,which may in turn lead to its addictive potential. Furthermore, recent work has shed light on self-medication with ketamine; that study based its conclusions on the Global Drug Survey (GDS).The authors used a model that predicted level of use among several demographic groups. They inferred that yearly ketamine use could be as high as 33.3 g for males and 29.46 g for females. These doses far exceed clinically used dosing regimens and may lead to serious health consequences. This leads to the question of whether clinicians prescribing ketamine should take into account such contextual information when evaluating the risk of abuse. This in turn presents the dilemma of whether to prescribe ketamine to subjects who have used it in the past and who might benefit from it, but who may also be at increased risk of developing ketamine abuse.
This adverse outcome of ketamine treatment for acute suicidality led us to the decision to implement a number of amendments to the protocol of the subsequent RCT. The case was discussed in a departmental research meeting, and subsequently with the IRB and Data Safety Monitoring Board overseeing the KETA study. The main goal was to find ways to warrant the safety of future study participants and patients undergoing ketamine treatment. The following considerations were addressed. Inclusion and exclusion criteria: in the protocol for this pilot study, patients with a history of ketamine or phencyclidine addiction were excluded from participation. We subsequently debated whether we should also exclude patients with any other form of substance abuse or addiction in the past or present. However, the patient presented here had no prior history of any substance abuse and would therefore not have been excluded. Furthermore, patients with substance (e.g. alcohol) abuse may also suffer from suicidal ideation and could possibly benefit from ketamine treatment.Excluding this group would have limited the study's ability to investigate the general effectiveness of ketamine on suicidality. However, treatment may also harm subjects if they develop substance abuse as a result of it. Current contraindications for intranasal ketamine treatment for depression are a past history of cerebral haemorrhage, aneurysmatic vascular disease or malformations and hypersensitivity for ketamine. Although the Spravato monograph mentions substance abuse and addiction as risk factors for ketamine abuse, it is not considered a contraindication for treatment. However, it may be that future studies will find otherwise, which again highlights the importance of systematic monitoring of abuse post-treatment. Follow-up period: we increased the follow up period from 7 days to 4 weeks, in order to be better able to observe emerging ketamine addictions following treatment. A second amendment is that researchers enquire about signs of ketamine craving or abuse at all follow-up periods, and request that patients report craving or abuse to their treating psychiatrists. A member of the study team with clinical experience is always present during the first hour post-intervention to help subjects with any distress they experience. This could also facilitate the identification of drug-liking In summary, future studies on ketamine should evaluate abuse liability in light of the study medication and treatment regimen, patient group and inclusion and exclusion criteria. Monitoring during study treatment and prolonged follow-up of at least 1 month are important in identifying signs of drug craving, liking or abuse, either via direct enquiry or instruments such as the Ketamine Side Effect Tool (KSET).In addition, researchers should inform treating psychiatrists about the risks and signs of abuse or addiction and encourage them to actively inquire about these signs. Ketamine holds promise as a powerful, rapid-acting and effective treatment for depression,and possibly for other psychiatric disorders, but it is not without risks, as evidenced by the case presented here. Although the risks associated with subanaesthetic dosages (<0.5 mg intravenously or oral/intranasal equivalent dose) appear to be moderate, those associated with ketamine abuse may cause substantial harm to the urinary tract, liver and brain.What is more, this case suggests that patients may still be at risk for abuse even without a prior history of substance abuse. Monitoring of possible abuse or addiction in all patients receiving ketamine treatment is essential to improve safety, and to provide the necessary help for patients who do experience craving and/or tendencies towards addiction development. supporting the findings of this study are available on reasonable request from the corresponding author, J.F.M.S.
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