Six of 8 (75%) participants maintained 3 or more weeks of post-study abstinence, confirmed by urine samples and reports on the TLFB. While no significant improvements were observed in pre-to-post assessments of craving, there was an increased capacity to abstain from cannabis use over time, with an average baseline DCQ of 44.7 increasing to an average of 87.5 by end of study. No significant differences between abstinence or confidence in abstaining were found between those who received single or multiple infusions. 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. SL and/or IM ketamine was administered to patients, with doses titrated in office and then adjusted for home-use. Patients were started on SL ketamine in office to induce a trance state with respect to dosage so patients could replicate the effect at home if needed.

Associated Data

The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. 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. We included 16 studies in our review, totaling 440 chronic ketamine users with a mean ketamine use of 2–9.7 years and 2.4 grams per day, compared to 259 drug-free controls and 44 poly-drug controls. Five studies were based on the same sample (Liao et al., 2010, 2011, 2012, 2016, 2018). The included studies described structural gray matter and white matter differences, differences in brain functionality and differences in neurotransmitter receptor binding.

Brain Changes Associated With Long-Term Ketamine Abuse, A Systematic Review PMC

Therefore, the different functional connectivity patterns could in part be caused or influenced by the direct, short term effects of ketamine. In case-control studies, it is important to include possible confounders, notably antipsychotic drugs. The great majority of neurophysiological investigations included antipsychotic-treated subjects. Although medication-free first-episode psychosis patients demonstrate comparable neurophysiological abnormalities to chronic patients, these deficits are often considered to be less severe 33. The combined use of neurophysiological indicators and genetics has the potential to shed light on the genesis of psychosis and assist the development of novel medications, whilst research on high-risk individuals might expedite psychosis patients’ access to psychological and medical therapy. The commonly reported adverse drug reactions include psychotomimetic phenomena that are dose-related and self-limiting in time with no sequelae and symptomatology abatement at the time of treatment 6.

• Azhari et al46 examined the efficacy of ketamine-assisted MET and MBRP in the treatment of 8 cannabis-dependent individuals.
• Reductions in pre-post pain as measured by the Numeric Pain Rating Scale (NPRS) was reported for 6 patients, whereas 2 showed no change and 3 reported increased pain intensity.
• This section collects any data citations, data availability statements, or supplementary materials included in this article.
• Part of the structural and functional neuroanatomical differences could therefore be attributed to these concomitant conditions.
• However, these observations are still based on comparison between subjects rather than longitudinal data.

Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users. Using resting-state functional MRI (fMRI), Liao al. investigated the functional connectivity between the thalamus and specific cortical regions in 40 chronic ketamine users with a mean use of 2 grams/day for 3.4 years, compared to 88 drug-free controls (Liao et al., 2016). Lower functional connectivity was found between the thalamus and the motor-, posterior parietal- and prefrontal cortex. Functional connectivity between the posterior parietal cortex and right lateral dorsal nucleus was significantly correlated to individual ketamine craving scores (Liao et al., 2016).

Efficacy and Duration of KAP on Alleviating Distressing Symptoms

Converging lines of evidence point to a critical role of brain extracellular matrix (ECM) molecules in the pathophysiology of substance use disorders. An increasing number of preclinical studies highlight the ECM as a promising target for development of novel cessation pharmacotherapies. The brain ECM is dynamically regulated during learning and memory processes, thus the time course of ECM alterations in substance use disorders is a critical factor that may impact interpretation of the current studies and development of pharmacological therapies. This review highlights the evidence for the involvement of ECM molecules in reward learning, including drug reward and natural reward such as food, as well as evidence regarding the pathophysiological state of the brain’s ECM in substance use disorders and metabolic disorders. The results were subdivided into structural differences in gray and white matter, functional differences and effects on neurotransmission.

Ketamine Route of Administration, Dosage, and Frequency

Neuroimaging studies specifically examining how ketamine modulates glutamate and gamma-aminobutryic acid (GABA) have been reviewed.11 Despite the immediate glutamate surge during infusions, it is unclear if glutamate levels remain elevated post-infusion. One study finds increased glutamate levels in the ACC 35 minutes post infusion, and another found no change.12,13 Multiple studies attempted to find a correlation between antidepressant response and glutamate/GABA levels before, during, and after infusion.14–16 However, no such correlations were found. The timing of psychotherapy in relation to ketamine administration is shown in Table 2. In 5 studies, psychotherapy session(s) were provided separately, before and after the ketamine administration(s). Two studies provided psychotherapy concurrently with ketamine administration, and one provided psychotherapy concurrently and again after ketamine infusion. Two studies provided psychotherapy after ketamine administration(s) only, and 7 studies provided psychotherapy before, during, and after ketamine administration(s).

In contrast, they found higher functional connectivity in the left middle occipital gyrus. A study with 34 chronic ketamine users and 19 healthy controls found lower gray matter volume in the right insula, the left dorsolateral prefrontal cortex (DLPFC), the rOFC and the left inferior parietal cortex in ketamine users compared to controls (Hung et al., 2020a). Within the ketamine users group, adolescent onset users were compared to adult-onset users. Adolescent-onset users showed a significantly smaller left precuneus volume than the adult-onset group and the healthy control group. Thus, here we review current human neuroimaging literature as it pertains to ketamine’s mechanism of action in specific brain areas, with an emphasis on key regions that are implicated in the pathophysiology of MDD. However, because there is very little literature that specifically examines ketamine’s actions in patients with MDD, we are including research with healthy volunteers.

• Nonetheless, we have extracted this information from each study and present it in Table S1.
• The results showed significant decreases in anxiety and depression scores as measured by the Hamilton Anxiety Scale (HAM-A) and the Beck Depression Inventory (BDI).
• While no significant improvements were observed in pre-to-post assessments of craving, there was an increased capacity to abstain from cannabis use over time, with an average baseline DCQ of 44.7 increasing to an average of 87.5 by end of study.
• However, given the scarcity of research on the topic, these findings are worth mentioning.

In the present study, the long-term effects on memory caused by repeated ketamine exposure during late adolescence were examined. Rats were used as nonhuman models in order to investigate the cognitive risks resulting from chronic use of ketamine. The results indicated that low-ketamine dosed rats demonstrated significantly better spatial memory recall compared to high-ketamine dosed rats. In addition, high-ketamine dosed rats appeared to struggle more with working memory than the rats in the low-ketamine and control groups. Similarly, both drug groups showed significantly more working memory and reference memory errors than the control group. This indicates that higher doses of ketamine during late adolescence may cause working and spatial memory impairments later in life.

Materials and methods Medically healthy subjects with no personal or familial Axis I psychotic spectrum disorders were administered subanesthetic doses of ketamine by intravenous infusion in a series of clinical investigations from 1989 to 2005. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions).

Two researchers (MM and SD) independently screened the 255 titles and abstracts for relevance based on the inclusion and exclusion criteria. Abstracts were excluded if they did not include both ketamine and psychotherapy; did not contain original data; included preclinical animal models; did not have abstracts available in English; and did not specify a pain, substance abuse, or mental health condition. After review, a further 70 articles were deemed not relevant (Figure 1), leaving 17 articles for data extraction. Any discrepancies between reviewers were resolved by consultation with the senior author (KL). While most participants tolerated KAP well, some were unable to complete ketamine administration and dropped out of treatment.23,37,41,44,45 Therefore, drop out in relation to administration patterns should be addressed in further investigations with the aims of increasing tolerability and response rates.

Participants received a 90 minutes CBT session the day before a single 40-minutes IV ketamine (0.5mg/kg) infusion, followed by 10 hours of exposure sessions delivered over 2 weeks. A significant decrease in OCD symptoms as measured by the YBOCS was reported at 4 weeks post infusion among 8 of the 9 patients who completed the ketamine infusion. Patients who had the least pre-ketamine engagement of the pgACC with increasing memory load showed the greatest antidepressant improvement to ketamine at 4 hours post-infusion.

While the published literature on Ketamine Assisted Psychotherapy (KAP) and the use of the intervention has grown substantially in recent years, there has yet to be a systematic review of the available evidence. This review of current KAP research aims to identify standard practices in pain, mental health, and addiction conditions, levels and patterns of effectiveness in symptom reduction, and the duration of treatment effects. The more treatment failures a patient experiences, the less likely they are to respond to subsequent treatment trials—perpetuating the cycle of disability.

Furthermore, ketamine may decrease the ability to self-monitor, may increase brain changes associated with long-term ketamine abuse, a systematic review pmc emotional blunting, and may increase activity in reward processing. Further studies are needed, however, to elucidate ketamine’s mechanism of antidepressant action. A possible mechanism for the white matter changes identified in the reviewed recreational ketamine studies could be AMPA-receptor mediated excitotoxicity.

The most frequently reported side effects of short term ketamine (hours/days) are related to the nervous system, such as dissociation, sedation, headache, dizziness, blurred vision and memory impairment (Short et al., 2017). Small case series of ketamine administration in various doses for up to one year in patients with MDD or chronic pain suggest that some of these neural side effects may remain with prolonged ketamine use (Cvrcek, 2008; Szymkowicz et al., 2013). Rationale A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of subanesthetic doses of ketamine in experimental psychopharmacology studies. Objective To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset.