The present section highlights the primary findings and duration of effect when applicable according to the participants’ diagnosis or substance of abuse. Karim S Ladha reports they are co-PI of an observational study on medical cannabis funded by Shoppers Drug Mart. The authors would like to thank David Lightfoot, Information Specialist from St. Michael’s Hospital Health Sciences Library, for his assistance in designing and carrying out a systematic search and identifying articles for this review. As summarized in Figure 1, a detailed search strategy was used to identify relevant studies. The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors. This section collects any data citations, data availability statements, or supplementary materials included in this article.
Links to NCBI Databases
ReHo describes the summarized local functional connectivity between a voxel and its neighboring voxels. This is an index of network centrality, showing the importance of a voxel in a functional network. In 41 chronic ketamine users with a mean use of 2 grams/day for 3.4 years compared to 44 drug-free controls, lower ReHo in the right anterior cingulate cortex and higher ReHo in the left precentral frontal gyrus were found (Liao et al., 2012). The higher ReHo in the left precentral frontal gyrus was negatively correlated with estimated total lifetime ketamine consumption and ketamine craving (Liao et al., 2012). This may suggest that ReHo is initially increased more by ketamine use but that this increase eventually decreases with more prolonged and intensive use, which may alter functional organization in frontal networks. However, since subjects had to be abstinent from brain changes associated with long-term ketamine abuse, a systematic review pmc ketamine for only 48 hours, and since the direct effect of ketamine can last for more than 48 hours, the altered frontal network organization might also be a direct result of ketamine instead of a long-term side effect (Zarate et al., 2012).
Severe Encephalatrophy and Related Disorders From Long-Term Ketamine Abuse: A Case Report and Literature Review
- Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls.
- Dore et al23 collected data from 235 patients with a wide range of psychological and substance use related disorders (MDD, PTSD, ADHD, GAD, BPD, SUD, OCD) in three private psychiatric practices in Northern California.
- Moreover, a 6-month follow-up interview revealed that of the 27 individuals in the ketamine group, twelve (44%) remained abstinent compared to none in the midazolam group.
- Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse.
- Although the identified lower gray and white matter volumes or integrity could suggest direct neurotoxic effects of ketamine, the observed higher structural and functional connectivity and dopamine binding may suggest indirect compensatory effects.
Additional large-scale randomized control trials are warranted to understand better the mutually influential relationships between psychotherapy and ketamine in optimizing responsiveness and sustaining long-term benefits in patients with chronic pain. Such investigations will assist in developing standardized practices and maintenance programs. With the goal of studying whether higher doses of intramuscular ketamine in combination with psychotherapy resulted in heroin abstinence, Krupitsky et al43 randomly assigned 70 detoxified heroin-addicted inpatients into two groups where low-dose ketamine (0.2 mg/kg) was compared with a high-dose ketamine group (2.0 mg/kg).
Also, the ventral striatum (VS) showed lower connectivity with the right superior temporal sulcus (STS) and the left superior frontal gyrus (SFG) which was mediated by higher scores on the Barratt Impulsiveness Scale (BIS-11) (Hung et al., 2020b). Shiroma et al41 investigated the feasibility of integrating multiple (3) ketamine infusions with standardized prolonged exposure therapy for 12 veterans with chronic PTSD. Participants received a IV ketamine (0.5mg/kg) infusion 24-hours before weekly prolonged exposure therapy sessions over 3 weeks. Ten veterans completed treatment, and the 4-month follow-up demonstrated a significant decrease in the severity of PTSD symptoms as measured by PLC-5 and the Clinical Global Impression-Severity (CDI-S) scale following treatment.
Data Extraction
Both high and low-dose groups reported significantly reduced cravings for heroin as evaluated by the Visual Analog Scale of Cravings, with greater reductions experienced by the high-dose group immediately after the psychotherapy-ketamine sessions, and at the 1 and 3-month post psychotherapy-ketamine follow-up. The high-dose group reported reductions in cravings at the 24-month follow-up but not the low-dose group. Additional data collected on anxiety and depression, as measured by the Spielberger Anxiety Scale and the Zung Depression Scale, respectively, revealed that the high and low-dose groups both experienced reductions in anxiety and depression, but there were no significant between-group differences. Li et al. (2017) assessed resting-state functional connectivity of the subgenual anterior cingulate cortex (sgACC) in relation to depression scores of 36 chronic ketamine users with an average ketamine use of 4.9 years (dose not reported) compared to 20 drug-free controls. Overall, no difference in sgACC connectivity was found between groups, but in ketamine users higher depression scores correlated with lower sgACC connectivity to the right lateral and bilateral medial OFC. Further analysis revealed functional connectivity changes, with male and female ketamine users showing higher sgACC connectivity than controls to the bilateral superior temporal gyrus or dorsomedial prefrontal cortex (dmPFC), respectively (Li et al., 2017).
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One 1.5–2-hour psychotherapy session was then administered concurrently with a single low-dose (0.2mg/kg) or high-dose (2.0mg/kg) of IM ketamine. Soothing instrumental music was played during the ketamine-induced psychotherapy session, and the content of the session was based on the individual subjects’ case history. An additional 5 hours of psychotherapy was administered within several days following the ketamine-psychotherapy session, with aim to integrate insights from the ketamine experience into daily life.
- Finally, we found our complete dataset consisting of 16 studies (see Figure 1) for the inclusion flowchart.
- The authors would like to thank David Lightfoot, Information Specialist from St. Michael’s Hospital Health Sciences Library, for his assistance in designing and carrying out a systematic search and identifying articles for this review.
- Seventeen articles and abstracts involving 603 participants were identified and reviewed.
- We end by summarizing the results as they pertain to the neurobiology of depression and ketamine’s antidepressant effects.
- Though the duration of effect was not reported for Case 1, both women reported an increased capacity to make effective use of psychological insight facilitated by the KAP experience.
This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls.
They found that ketamine increased “background noise” in the brain, making sensory signals less defined or pronounced. This, they noted, may explain the distorted perception of reality among people with schizophrenia or psychosis. A drug known as ketamine induces a mental state similar to psychosis in healthy individuals by inhibiting NMDA receptors in the brain. It is possible, then, that ketamine is acting indirectly to produce its antidepressant effect. Ketamine may work through additional receptors, as it is known to have effects on several opioid receptors, adrenergic receptors, and several serotonin and norepinephrine transporters.17–19 It is also possible that acute dissociative side effects of ketamine may be mediating antidepressant response.
Many of the observed changes were correlated with the amount and duration of ketamine consumption, suggesting a possible dose dependent effect of prolonged ketamine on brain structure and function. Although the identified lower gray and white matter volumes or integrity could suggest direct neurotoxic effects of ketamine, the observed higher structural and functional connectivity and dopamine binding may suggest indirect compensatory effects. Together, these findings suggest that long-term intensive ketamine use may affect the structure and function of cortical gray and white matter, especially in frontoparietal regions. Using diffusion-weighted MRI scans, fractional anisotropy (FA) can be used for estimating white matter fiber density, myelination and axonal diameter. FA reductions were found in bilateral frontal and left temporoparietal white matter in 41 ketamine users with a mean use of 2 grams/day for 3.4 years, in comparison with 44 drug-free controls (Liao et al., 2010). FA in the left and right frontal white matter was negatively correlated with the total lifetime consumption of ketamine.
Ketamine is derived from phencyclidine and acts as a noncompetitive antagonist and allosteric modulator of N-methyl-D-aspartate receptors. Ketamine has been used to treat a variety of psychiatric disorders, with the most notable being treatment-resistant depression. With the rise of at-home ketamine treatment companies, the safety of unsupervised administration remains under evaluation. A study with ketamine and a ketamine-like medication, rapasitnel, showed that those who were given ketamine experienced more sleepiness and had decreased self-reported motivation and confidence in their driving abilities. Moreover, there seem to be significant differences in the acute versus persistent effects of ketamine, as well as the anesthetic versus subanesthetic doses, both in terms of effects and outcomes.
This systematic narrative review suggest that KAP may be effective in initiating rapid, significant benefits for a wide range of disorders. However, variability in study design, intervention structure, patient diagnoses, and outcome measurement, along with small sample sizes, limit firm conclusions. Nonetheless, some commonalities in the reviewed studies are identifiable and worthy of mention.
Dopamine D1 binding potential was studied using positron emission tomography (PET) imaging after intravenously injecting the selective D1 receptor radio ligand 11CNNC 112 in 14 ketamine users with a mean use of 0.75 gram/week for 4.1 years and 14 drug-free controls. D1 receptor availability was significantly upregulated in the dorsolateral prefrontal cortex of ketamine users compared to controls, which could result from increased receptor density or affinity. D1 binding potential correlated with the total amount of ketamine consumption (Narendran et al., 2005). Case 1 was diagnosed with MDD comorbid with an Eating Disorder Not Otherwise Specified (EDNOS), and received two concurrent ketamine and psychotherapy sessions resulting in normalized caloric intake and improvements in treatment engagement and adherence. Case 2 had a diagnosis of BPD-I with a current depressive episode and received a single concurrent ketamine and psychotherapy session that resulted in immediate (next day) improvements in depressive symptoms that were sustained at the 2-month follow-up.