Side-effects associated with ketamine use in depression: a systematic review

Ketamine*

Long-Term Regular Use of Low-Dose Aspirin and Neovascular Age-Related Macular Degeneration: National Sample Cohort 2010–2015

Ketamine was originally synthesised for use as a dissociative anaesthetic, and it remains widely used legitimately for this indication. However, there is increasing evidence of non-medical recreational use of ketamine, particularly in individuals who frequent the night-time economy. The population-level and sub-population (clubbers) prevalence of recreational use of ketamine is not known but is likely to be similar, or slightly lower than, that of other recreational drugs such as cocaine, MDMA, and amphetamine.The predominant features of acute toxicity associated with the recreational use of ketamine are neuro-behavioural abnormalities such as agitation, hallucinations, anxiety, and psychosis. Secondary to these, individuals put themselves at greater risk of physical harm/trauma. Cardiovascular features (hypertension and tachycardia) occur less frequently and the risk of death from recreational use is low and is predominately due to the physical harm/trauma.Long-term recreational use of ketamine can be associated with the development of psychological dependence and tolerance. There are reports of gastro-intestinal toxicity, particularly abdominal pain and abnormal liver function tests, and of neuropsychiatric disorders, typically a schizophrenia-like syndrome, in long-term users. Finally, there are increasing reports of urological disorders, particularly haemorrhagic cystitis, associated with long-term use. The management of these problems associated with the long-term use of ketamine is largely supportive and abstinence from ongoing exposure to ketamine.In this review we will collate the available information on the epidemiology of recreational use of ketamine and describe the patterns of acute and chronic toxicity associated with its recreational use and the management of this toxicity.

We conducted a population-based cohort study to determine the effect of long-term regular use of statins on the risk of colorectal cancer (CRC). Individuals who were dispensed statins regularly were identified from Manitoba's population-based prescription drug database and followed up until diagnosis of CRC, migration out of province, death, or December 2005. The incidence of CRC in this group was compared with that among individuals who were never dispensed statins. Stratified analysis was performed to determine the risk after 5 years of regular statin use. Multivariate Poisson regression models were used to adjust for potential confounding by age, sex, and history of diabetes, inflammatory bowel disease, coronary heart disease, lower gastrointestinal endoscopy, resective colorectal surgery, use of nonsteroidal anti-inflammatory drugs, hormone replacement therapy (among women), and median household income. The dose effect was evaluated in defined daily dose units. In total, 35,739 individuals were dispensed statins regularly. In all, 10,287 (49% males; 51% females) long-term (>or=5 years) regular statin users were followed up for up to 5 additional years. In multivariate analysis, the incidence rate ratio (IRR) of CRC among those dispensed statins regularly compared with those who were never dispensed statins (n=377,532) was 1.13 (95% confidence interval (CI): 1.02-1.25). The CRC risk among the long-term regular statin users was similar to that for individuals never dispensed statins (IRR, 0.89; 95% CI: 0.70-1.13). A statistically nonsignificant risk reduction was observed among high-dose long-term regular statin users. These findings suggest that long-term regular use of statins for the current clinical indications does not protect against CRC. The benefit of high-dose long-term statin use needs further evaluation.

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Opioids are associated with higher risk for ataxic breathing and sleep apnea. We conducted a systematic literature review and meta-analysis to assess the influence of long-term opioid use on the apnea-hypopnea and central apnea indices (AHI and CAI, respectively). A systematic review protocol (Cochrane Handbook guidelines) was developed for the search and analysis. We searched Embase, Medline, ACP Journal Club, and Cochrane Database up to November 2014 for three topics: (1) narcotics, (2) sleep apnea, and (3) apnea-hypopnea index. The outcome of interest was the variation in AHI and CAI in opioid users versus non-users. Two reviewers performed the data search and extraction, and disagreements were resolved by discussion. Results were combined by standardized mean difference using a random effect model, and heterogeneity was tested by χ(2) and presented as I(2) statistics. Seven studies met the inclusion criteria, for a total of 803 patients with obstructive sleep apnea (OSA). We compared 2 outcomes: AHI (320 opioid users and 483 non-users) and 790 patients with CAI (315 opioid users and 475 non-users). The absolute effect size for opioid use was a small increased in apnea measured by AHI = 0.25 (95% CI: 0.02-0.49) and a medium for CAI = 0.45 (95% CI: 0.27-0.63). Effect consistency across studies was calculated, showing moderate heterogeneity at I(2) = 59% and 29% for AHI and CAI, respectively. The meta-analysis results suggest that long-term opioid use in OSA patients has a medium effect on central sleep apnea.

Backgrounds Ketamine is a dissociative anesthetic that is currently considered for several new indications. Aim To deduce the safety of long-term ketamine treatment using the harm of heavy recreational (non-medical) ketamine use as a proxy for maximal possible harm of ketamine treatment. Methods Systematic literature review according to PRISMA guidelines to identify controlled studies on ketamine-related harm in heavy recreational ketamine users. Results were compared with serious adverse events (SAEs) in patients treated with ketamine according to three systematic reviews considering dosing regimen and cumulative dose. Results The systematic search yielded 25 studies. Heavy recreational ketamine use can escalate to ketamine dependency and was often dose-dependently associated with other SAEs, including cognitive and mental disorders, and gastrointestinal and urinary tract symptoms, which disappeared upon marked reduction of ketamine use. Heavy ketamine users have a much higher cumulative exposure to ketamine than ketamine treated patients (> 90 times), which may explain why SAEs in the clinical context are mostly mild and reversible and why ketamine dependence was not reported in these patients. Conclusion Treatment of patients with ketamine is not associated with ketamine dependency or SAEs. However, caution is needed since data on long-term clinical ketamine use with a long-term follow-up is lacking.

Ketamine is a new and promising treatment for depression but comes with challenges to implement because of its potential for abuse. We sought the views of patients to inform policy and practical decisions about the clinical use of ketamine before large-scale roll-out is considered. This qualitative study used three focus groups and three validation sessions from 14 patients with prior diagnoses of depression but no experience of ketamine treatment. Focus groups explored their views about clinical use of ketamine and the best way for ketamine to be administered and monitored. The qualitative data were analysed by three service-user researchers using thematic analysis. Five themes were generated: changing public perceptions, risks, monitoring, privacy and data protection, and practical aspects. Participants were conscious of the stigma attached to ketamine as a street drug and wanted better public education, and evidence on the safety of ketamine after long-term use. They felt that monitoring was required to provide evidence for ketamine's safe use and administration, but there were concerns about the misuse of this information. Practical aspects included discussions about treatment duration, administration and accessibility (for example who would receive it, under what criteria and how). Patients are enthusiastic about ketamine treatment but need more information before national roll-out. The wider societal impact of ketamine treatment also needs to be considered and patients need to be part of any future roll-out to ensure its success.

Ketamine*

Long-term regular use of ketamine has been reported to be associated with severe symptomatic urinary tract problems. Methoxetamine, an arylcyclohexylamine derivative of ketamine, is marketed as a "bladder safe" derivative of ketamine, and no cases of acute toxicity following analytically confirmed methoxetamine use have been reported to date. We report here a case series of three individuals with acute toxicity related to the analytically confirmed use of methoxetamine. Three patients aged between 28 and 42 years presented to the Emergency Department (ED) on unrelated occasions having used methoxetamine. Clinical features were suggestive of a "dissociative/catatonic" state similar to that seen with ketamine; in addition, they had clinical features of acute sympathomimetic toxicity with significant tachycardia and hypertension. All were managed with low-dose benzodiazepines and discharged home once their symptoms/signs had settled. TOXICOLOGICAL SCREENING: Serum collected at the time of presentation to the ED was analysed qualitatively and quantitatively by gas chromatography-mass spectrometry. Serum concentrations ranged from 0.09 to 0.2 mg/L; in addition, detectable levels of 6-APB/5-APB were found in one of the patients. These three analytically confirmed cases demonstrate that acute methoxetamine-related toxicity is associated with both "dissociative" and "sympathomimetic" clinical features. The information from these three cases is useful to clinical pharmacologists, not only in managing individuals with acute methoxetamine toxicity but also in advising the appropriate legislative authorities on the risk of acute harm related to methoxetamine use. Further work is needed to determine whether methoxetamine is more "bladder friendly" than ketamine, as has been suggested by those marketing methoxetamine.

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAID), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in previous epidemiologic studies. Acetaminophen, a commonly used pain reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects. Few studies have examined the association between long-term acetaminophen use and prostate cancer incidence. We examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated by using follow-up questionnaires in 1997 and every two years thereafter. Relative risks (RR) were estimated by using proportional hazards regression models. All models were adjusted for age, race, education, body mass index, diabetes, NSAID use, and history of prostate-specific antigen testing. During follow-up from 1992 through 2007, 8,092 incident prostate cancer cases were identified. Current regular use of acetaminophen (30 or more pills per month) for 5 or more years was associated with lower risk of overall prostate cancer (RR = 0.62, 95% CI: 0.44-0.87) and aggressive prostate cancer (RR = 0.49, 95% CI: 0.27-0.88). Current regular use of less than 5 years duration was not associated with prostate cancer risk. These results suggest that long-term regular acetaminophen use may be associated with lower prostate cancer risk. If the association between acetaminophen use and lower risk of prostate cancer is confirmed, it could provide clues about biological mechanisms that are important in prostate carcinogenesis.

What Is the Issue?
 
 Doctors use ketamine to induce loss of consciousness as general anesthesia during surgery. At low doses that do not produce dissociation, practitioners use ketamine to relieve acute or chronic pain.
 The previous CADTH report published in 2020 found that IV ketamine, compared to placebo, could only provide short-term pain relief in patients with chronic non-cancer pain, with increased risks of nausea, vomiting, and psychomimetic effects. The included guidelines did not provide definitive recommendations due to insufficient evidence.
 Decision-makers want to know if there is any new evidence to support the use of ketamine for treating of chronic non-cancer pain in adults.
 
 What Did We Do?
 
 To inform decisions about the use of ketamine for treating of chronic non-cancer pain, CADTH sought to update the previous report by identifying and summarizing literature comparing the clinical effectiveness and cost-effectiveness of ketamine with placebo or other pharmacological therapies for chronic non-cancer pain. We also attempted to identify evidence-based recommendations from most recent guidelines for the use of ketamine for chronic non-cancer pain.
 A research information specialist conducted a literature search of the peer-reviewed and grey literature with a search strategy focused on ketamine, chronic non-cancer pain, and adults. The search was limited to English-language documents published since 2020 up to November 06, 2023. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.
 
 What Did We Find?
 
 We found 3 SRs and 1 randomized controlled trial on the use of ketamine for the treatment of patients with neuropathic pain, complex regional pain syndrome, fibromyalgia, and other chronic pain conditions. Collective evidence from the included studies suggests that ketamine treatment was associated with short-term pain reduction in patients with chronic non-cancer pain. However, the long-term efficacy of ketamine in pain relief remains unclear.
 Adverse events (AEs) associated with ketamine treatment were with psychedelic effects, discomfort, dizziness, fatigue, headache, and nausea; all of those events appeared to be short-lasting.
 There were mixed results regarding the effect of ketamine on quality of life and functional improvement.
 We did not find any studies on the cost-effectiveness of ketamine or new evidence-based guidelines on the use of ketamine for treating chronic non-cancer pain.
 
 What Does It Mean?
 
 The findings in this review are consistent with the previous CADTH report published in 2020.
 Well-controlled studies with larger populations and longer follow-ups are needed to determine the optimal treatment protocol of ketamine for each specific type of chronic pain.
 Given that ketamine is a dissociative drug that could be associated with the development of a substance use disorder, decision-makers may wish to consider the use of ketamine for long-term treatment of chronic non-cancer pain. The long-term effects and dangers of ketamine remain to be determined.

Long-term use of anxiolytics has been a cause for concern because of the possibility of dependency and other adverse consequences. In a nationally representative probability survey of adults conducted in 1979, we found that long-term use (defined as regular daily use for a year or longer) was relatively rare, occurring among 15% of all anxiolytic users--a rate of 1.6% of all adults between the ages of 18 and 79 years in the general population. The data indicate that long-term regular users tend to be older persons with high levels of emotional distress and chronic somatic health problems. They are preponderantly women, and many are sufficiently distressed to seek out other sources of help (mental health professionals and other psychotherapeutic medications) as well. The sizable majority of long-term users is being monitored by their physicians at reasonably frequent intervals. The data give little support to current stereotypes of long-term users and suggest, instead, that such use is associated with bona fide health problems that are being treated within the broader context of the health system.

Background: Experimental evidence suggests that aspirin may inhibit breast tumor growth and reduce invasiveness of breast cancer cells. In large population-based studies (including our own), post-diagnostic aspirin use was associated with reduced breast cancer-specific and all-cause mortality. Here, we have extended our prior study with an additional 10 years of follow-up (3,785 more breast cancer cases) and investigation of the molecular underpinnings of the role of aspirin in breast cancer prognosis. Methods: Our study included 7,949 women diagnosed with stage I, II or III breast cancer from the Nurses’ Health Study (NHS) and NHSII. Cox proportional hazards regression was used to compute the multivariate hazard ratio (HR) for death, adjusting for tumor characteristics, treatment information and lifestyle factors. Post-diagnostic aspirin use was obtained at least 12 months after diagnosis and updated at every 2-year follow-up interval. We also evaluated the association between post-diagnostic aspirin use and survival according to tumor characteristics. Estrogen receptor (ER), insulin receptor (IR), PTEN, and Ki67 protein expression was evaluated by immunohistochemistry. PIK3CA mutation status was determined via polymerase chain reaction and pyrosequencing. In an exploratory analysis to identify functional enrichment of biologic pathways associated with long-term pre-diagnostic aspirin use (ever use of aspirin for ≥10 years with >2d/wk), we used a competitive gene-set testing procedure in a subgroup of cases with gene expression data (N=453). In this subset, we also computed the abundance of immune cell infiltration (B cell, CD4+ T cell, CD8+T cell, macrophage, neutrophil and dendritic cell) using Tumor IMmune Estimation Resource (TIMER). Results: During a median follow-up of 12 years after breast cancer diagnosis, we documented 2,502 deaths, including 1,373 from breast cancer. Compared with nonusers, women who regularly used aspirin after diagnosis had lower breast cancer-specific mortality: HR for 1, 2-5, 6-7 days of aspirin use per week were 0.65 (95% CI: 0.49, 0.86), 0.41 (95% CI: 0.29, 0.57) and 0.61 (95% CI: 0.47, 0.78) for, respectively (p-trend<0.0001). The association did not differ statistically by PTEN loss, PIK3CA mutation, or expression of IR (PI3K—AKT—mTOR), ER or Ki67 expression (proliferation pathways), or immune cell infiltration of the primary tumors (p-heterogeneity>0.05). Long-term regular aspirin use before diagnosis was associated with the downregulation of pathways related to inflammation (INF-α, INF-γ, and TNF-α), PI3K—AKT—mTOR signaling (mTOR and PI3K—AKT), and other proliferation (E2F and myc targets) in primary breast tumors and/or normal-adjacent tissues (FDR≤0.05). Long-term regular aspirin use prior to diagnosis was also associated with higher CD8+T cell (mean±SD=0.20±0.02 for non-users and 0.21±0.02 for users, p=0.01) and macrophage (mean±SD=0.05±0.03 for non-users and 0.06±0.02 for users, p=0.0002) relative abundance in primary tumors. Conclusion: Regular aspirin use after breast cancer diagnosis was associated with lower risk of breast cancer-specific and total mortality. The association between aspirin and mortality did not differ by molecular characteristics of primary tumors. Long-term aspirin use prior to breast cancer diagnosis was associated with downregulation of inflammatory and proliferation pathways and higher immune cell infiltration of CD8+ T cells and macrophages in breast tumors. Taken together, our large-scale population-based analysis with long-term of follow-up highlight the potential benefit of aspirin as a secondary prevention strategy across different tumor molecular characteristics. Citation Format: Cheng Peng, Michelle D. Holmes, Tengteng Wang, Alexandra Harris, Wendy Chen, Kristen Brantley, Yujing J Heng, Vanessa C. Bret-Mounet, Gabrielle M Baker, Bernard Rosner, Walter Willett, Rulla Tamimi, A. Heather Eliassen. Regular aspirin use, breast tumor characteristics and long-term breast cancer survival [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-01.

Ketamine, initially developed as a dissociative anaesthetic, has seen expanding therapeutic applications, in managing treatment-resistant depression and chronic pain. However, its psychoactive properties have also been associated with a significant rise in recreational use globally. Chronic, high-dose recreational ketamine use is associated with dependence potential and a spectrum of long-term complications affecting multiple organ systems. This narrative review details the major chronic urological, neurological, neuropsychiatric and hepatobiliary complications that clinicians may encounter in individuals with long-term ketamine use, along with an overview of the potential risk of dependence. This review highlights the importance of heightened awareness among clinicians of the issues related to long-term ketamine use, enabling early identification and prompt, appropriate investigation and management.