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).
We only considered quantitative and qualitative data from study visits when individuals were pre-treated with 0mg mGlur PAM (thus, “placebo” here refers to the period of saline does alcohol affect gallbladder infusion, which always preceded the period of ketamine infusion). It needs to be considered however, that there may be a U-shaped dose-effect relation between ketamine and cognitive changes. In rats, different 5–7-days dosing regimens of ketamine yielded opposite effects on cognitive tasks in which the rats had to detect novel objects, or novel placement of objects. Whereas, low ketamine enhanced novelty detection compared to controls, higher doses impaired novelty detection (Schumacher et al., 2016). It must be noted that the reported changes were dependent on the dosage and duration of ketamine use which were substantially higher than for clinical use, so our findings cannot be translated to clinical ketamine use.
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).
- 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.
- From available KAP publications, it is apparent that combined treatments can, in specific circumstances, initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms, while encouraging rapport and treatment engagement, and promoting abstinence in patients addicted to other substances.
- The second psychotherapist-guided ketamine session that was offered to non-responders and those experiencing difficulties was administered at week 4, and was also followed up by a same day MET session.
Dopamine D1 Receptors
Afterwards, IM ketamine was administered in-office with the clinician providing a safe and warm environment and guided psychotherapy during KAP sessions. A minimum of 2 therapists were present during the in-office KAP session(s) and subsequent monitoring, with each session lasting up to 3 hours. On average, KAP sessions were held in-office roughly 2 weeks apart, where psychotherapy was offered concurrently with IM ketamine. Patients were sometimes prescribed SL ketamine for home use and were encouraged to replicate the setting and procedure as demonstrated by the clinician.
Ketamine in Non-Depressed Subjects: Non-Task Based Resting State Scans
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.
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.
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 and Neuroimaging in Depression
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 brain changes associated with long-term ketamine abuse, a systematic review pmc 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.
Axial diffusivity is thought to be a measure of axonal density and radial diffusivity is thought to be related to the degree of myelination (Liao et al., 2010). In 16 ketamine users averaging 2.4 grams/day for 7.3 years, a lower level of axial diffusivity was found compared to 16 polydrug controls, especially in the frontal part of the right hemisphere (Edward Roberts et al., 2014). Axial diffusivity was significantly lower in eight white matter clusters in the right hemisphere in the ketamine group compared to the control group, the three largest being located in the frontal cortex (Edward Roberts et al., 2014). Also, probabilistic tractography was performed to investigate cortico-subcortical white matter connectivity profiles, which revealed that white matter connectivity between the caudate nucleus and the lateral prefrontal cortex was positively correlated with severity of long-term dissociative symptoms (Edward Roberts et al., 2014). While driving under the influence of drugs, drivers are more likely to be involved in and cause more accidents than drivers who do not drive under the influence.
- We only considered quantitative and qualitative data from study visits when individuals were pre-treated with 0mg mGlur PAM (thus, “placebo” here refers to the period of saline does alcohol affect gallbladder infusion, which always preceded the period of ketamine infusion).
- Participants self-reported cannabis use by the Timeline Follow-Back (TLFB) and were evaluated for their confidence in abstaining from further cannabis use by completion of Drug-Taking Confidence Questionnaire (DCQ) throughout the study.
- Afterwards, IM ketamine was administered in-office with the clinician providing a safe and warm environment and guided psychotherapy during KAP sessions.
- Conclusion Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation.
- A number of recent works (see 26–28) have posited a Bayesian framework for understanding the relationship between top-down predictive coding and bottom-up inference in perceptual processing.
Ketamine Route of Administration, Dosage, and Frequency
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.
We infer that the severity of the brain atrophy may not be related to abnormal renal and liver function. Additionally, the patient did not have a long history of using some drugs except dexamethasone more than 3 months. However, dexamethasone was used after the patient was found to have severe brain atrophy. Ketamine appears to have rapid and potent antidepressant effects in clinical studies, and the Federal Drug Agency approved the use of ketamine enantiomer esketamine-nasal spray for treatment-resistant depression pharmacotherapy in 2019. This study aimed to assess the usage of ketamine for major depressive disorder with psychotic features as an add-on treatment to the standard of care. Here we present four inpatients suffering from treatment-resistant depression with psychotic features, including one with severe suicidal crisis, all treated with 0.5 mg/kg intravenous infusion of ketamine.
Structural Differences: Gray Matter
It has been reported that levels of methylguanidine and guanidinosuccinate increase in uraemic patients, which is related to symptoms of convulsions and brain atrophy (56, 57). The patient’s renal function tests showed that creatinine and blood urea nitrogen were not significantly elevated with regular haemodialysis treatment, and brain atrophy was observed before renal failure. What’s more, with a negative liver-related auto-antibody test on the last admission, we inferred that the autoimmune hepatitis was treated properly. However, the patient also presented with abnormal liver function during the last admission, which may have been a result of ketamine or chronic cholecystitis and cholangitis. As we are unsure when the abnormal live function and brain atrophy began, the brain atrophy may have been liver mediated. However, as the liver symptoms lasted a short time and were treated quickly, it is unlikely that such severe brain atrophy was caused by abnormal liver function.
The search concept combination can be displayed as ketamine AND (chronic OR long term OR abuse OR dependence OR known long term use effects OR induced adverse effects). Craniocerebral computed tomography scan indicates wide and deep cerebral sulcus, flattened cerebral palsy, expanded ventricles, thickened cerebellum and reduced brain volume (A,B). (C) The patient was placed on a ventilator but soon died of persistent epilepsy and multiple organ failure.
Ketamine in Non-Depressed: Task-Based Scans
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.