The abuse liability of ketamine: A scoping review of preclinical and clinical studies

Le, Tuyen; Cordero, Isabel Pazos; Jawad, Muhammad Youshay; Swainson, Jennifer; Vincenzo, Joshua D. Di; Jaberi, Saja; Phan, Lee; Lui, Leanna M.W.; Ho, Roger; Rosenblat, Joshua D.; McIntyre, Roger S.

doi:10.1016/j.jpsychires.2022.04.035

Cited by 33 publications

(25 citation statements)

References 118 publications

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“…Many addicts are female individuals of childbearing age, which may put unborn babies at risk (Ni et al, 2018). Although ketamine is a promising treatment for psychiatric disorders, its toxicity limits its widespread use and raises concerns about the adverse consequences of its abuse (Le et al, 2022). Lots of studies in aquatic species have found that ketamine exposure during pregnancy can lead to phenotypic abnormalities, but the underlying mechanism has not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in humans (Ellingson, Haram, Sagen, & Solheim, 1977) and animal (Musk, Netto, Maker, & Trengove, 2012) have demonstrated that ketamine can easily pass through the placenta and its concentration in fetal plasma was comparable to that in maternal plasma. In our study, ketamine was administered at 5 mg/kg during the gestation days of heart formation (E7.5–E14.5) (Le et al, 2022; Schoepfer, Strong, Saland, Wright, & Kabbaj, 2019; Trujillo & Heller, 2020), which is equivalent to the first trimester of human embryonic development (3–10 weeks) (Krishnan et al, 2014; Sulik, Johnston, & Webb, 1981). Our study indicates that prenatal ketamine exposure causes a significant cardiac enlargement in neonates, which is consistent with previous research (Félix et al, 2014; Guo et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Effects of ketamine‐induced H3K9 hypoacetylation during pregnancy on cardiogenesis of mouse offspring

Quan

Zou

et al. 2023

Birth Defects Research

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Background: Prenatal exposure to adverse factors can cause congenital heart defects. Ketamine, a widely used anesthetic drug, produces several adverse reactions such as tachycardia, hypertension, and laryngospasm, especially in pediatric patients. This study aimed to detect the effects of ketamine exposure during pregnancy on the cardiogenesis of mouse offspring and the potential mechanisms.Methods: In this study, ketamine at an addictive dose (5 mg/kg) was administered to mice during early gestation to explore the epigenetic mechanism of its causing cardiac dysplasia. The cardiac morphology of the mouse offspring was observed through hematoxylin-eosin staining and transmission electron microscopy. The heart function of one-month-old neonates was detected by echocardiography. The expression of cardiomyogenesis-related genes was detected by western blot and RT-qPCR. The acetylation level of histone H3K9 at the Mlc2 promoter and its deacetylase level and activity were detected by CHIP-qPCR, RT-qPCR, and ELISA, respectively. Results: Our data revealed that ketamine exposure during pregnancy could cause cardiac enlargement, myocardial sarcomere disorganization, and decreased cardiac contractile function in mouse offspring. Moreover, ketamine reduced the expression of Myh6, Myh7, Mlc2, Mef2c, and cTnI. The histone H3K9 acetylation level at the Mlc2 promoter was down-regulated by increasing the histone deacetylase activity and HDAC3 level upon ketamine administration.Conclusions: Our work indicates that H3K9 acetylation is a vital player in cardiac dysplasia in offspring caused by prenatal ketamine exposure and HDAC3 is a key regulatory factor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of ketamine‐induced H3K9 hypoacetylation during pregnancy on cardiogenesis of mouse offspring

Quan

Zou

et al. 2023

Birth Defects Research

View full text Add to dashboard Cite

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“…These are summarized in Table 2. First, though the drugs covered in this review may be effective in the reduction of suicidal ideation and behaviour, they are also associated with significant risks, such as misuse or abuse (ketamine, buprenorphine, psilocybin, MDMA) [93,115,116,138], a narrow therapeutic index and a risk of toxicity in overdose (acetaminophen) [186] or other undesirable systemic adverse effects (NSAIDs, infliximab) [187,188]. A careful evaluation of the risk-benefit ratio should precede the initiation of any of these therapies, even if they are found effective, and practitioners prescribing these drugs should take appropriate precautions to ensure that these drugs are not diverted for misuse or prescribed in patients with significant contraindications to their use.…”

Section: Discussionmentioning

confidence: 99%

“…Given the known risks of misuse associated with ketamine [138], the polyamine molecule agmatine has also been investigated as a safer alternative. Agmatine appears to act at least partially through blockade of the NMDA receptor [139], and a post-mortem study has documented reduced agmatine levels in the cerebral cortex of completed suicides, independent of the presence of depression [140].…”

Section: E3 Glutamate Receptor Antagonistsmentioning

confidence: 99%

Pharmacotherapy for the Secondary Prevention of Suicide: Leads from the Social Pain Hypothesis

Rajkumar¹

2022

Preprint

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Suicidal behaviour is a public health problem whose magnitude is both substantial and increasing. Since many individuals seek medical treatment following a suicide attempt, strategies aimed at reducing further attempts in this population are a valid and feasible secondary prevention approach. An evaluation of the available evidence suggests that existing treatment approaches have limited efficacy in this setting, highlighting the need for innovative approaches to suicide prevention. Existing research on the neurobiology of social pain has highlighted the importance of this phenomenon as a risk factor for suicide, and has also yielded several attractive targets for pharmacological preventive strategies. In this paper, the available evidence related to these targets is synthesized and critically evaluated. The way in which social pain is related to the “anti-suicidal” properties of recently approved treatments, such as ketamine and psilocybin, is also examined. Such strategies may be effective for the short-term reduction of suicidal ideation and behaviour in individuals who have made a suicide attempt suicide prevention, particularly in cases where social pain is identified as a contributory factor. These pharmacological approaches may be effective regardless of the presence or absence of a specific psychiatric diagnosis.

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“…Ketamine has a longer history of use in pain medicine, and meta-analyses from the anesthesia literature have not reported any cases of dependence or addiction to IV ketamine when used for pain management ( 26 , 27 ). Similarly, two recent reviews on abuse potential for ketamine ( 4 , 28 ) noted that aside from select case studies, clinical ketamine studies to date have not indicated concern for misuse, dependence, diversion, addiction in patients with TRD, and interestingly, there is emerging evidence that ketamine may be a potential treatment option for addictions ( 29 ). Very few studies, however, have included measures related to addiction or abuse in measuring side effect profile.…”

Section: Introductionmentioning

confidence: 99%

A survey of drug liking and cravings in patients using sublingual or intranasal ketamine for treatment resistant depression: A preliminary evaluation of real world addictive potential

et al. 2022

Self Cite

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Ketamine has gained rapid popularity as a treatment option for treatment resistant depression (TRD). Though seen only in limited contexts, ketamine is a potential drug of abuse, addiction and diversion. Clinical ketamine studies to date have not systematically evaluated factors relevant to addiction risk in patients with TRD, but in treating patients with ketamine, risks of potential harms related to addiction must be considered. As clinical access to intravenous ketamine programs is limited in much of Canada, these considerations become even more important for clinicians who elect to offer patients less supervised, non-parenteral forms of ketamine treatment. This study explores factors relevant to addiction risk in a real-world sample of 33 patients with TRD currently or previously treated with sublingual (SL) or intranasal (IN) ketamine in the community. First, patients were surveyed using a Drug Liking and Craving Questionnaire (DLCQ) to assess their level of drug liking and craving for ketamine, and to screen for symptoms of a ketamine use disorder. Second, the pharmacy records of these patients were reviewed for red flags for addiction such as dose escalation or early refills. Third, surveys were administered to the treating psychiatrists of patients who had discontinued ketamine to determine if abuse concerns contributed to reason for discontinuation. Though limited to a small sample, results indicate that ketamine is not a universally liked or craved substance in patients with TRD. Prescribers of non-parenteral ketamine should monitor patients and prescribe cautiously. Factors related to addiction (as in the DLCQ) should be explored for clinicians to consider individual risk/benefit for judicious use of ketamine in patients with TRD.

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The abuse liability of ketamine: A scoping review of preclinical and clinical studies

Cited by 33 publications

References 118 publications

Effects of ketamine‐induced H3K9 hypoacetylation during pregnancy on cardiogenesis of mouse offspring

Effects of ketamine‐induced H3K9 hypoacetylation during pregnancy on cardiogenesis of mouse offspring

Pharmacotherapy for the Secondary Prevention of Suicide: Leads from the Social Pain Hypothesis

A survey of drug liking and cravings in patients using sublingual or intranasal ketamine for treatment resistant depression: A preliminary evaluation of real world addictive potential

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