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The “psychedelic effects” of ketamine – in the sense of creating more or less meaningful altered states of consciousness – have already been identified in the previous century. In 1998, Bowdle and colleagues investigated subanesthetic doses of ketamine in healthy volunteers and established that these effects are dose-dependent and linearly related to the steady-state venous plasma ketamine concentrations. The effectiveness of ketamine for the treatment of depression was something that Krystal and colleagues (2019) did not anticipate when they first studied it over 20 years ago (Krystal et al., 1999 and Berman et al., 2000). Since then, the introduction of ketamine has led to a rejection of the ‘monoamine hypothesis of depression’ – instead of a lack of monoamines (a neurotransmitter), other mechanisms could also contribute to the development of depression. The paradigm shift that has been found by studying ketamine’s effect on the brain lies in the understanding that cortico-limbic mechanisms play a role in depression. As discussed in the following sections, the glutamatergic and GABAergic signaling pathways play an important role in depression development.

To understand the function of ketamine on a molecular level, researchers often investigate its target neuronal receptors. Eldufani and colleagues (2018) reviewed the pharmacology of ketamine, which is an inhibitor of, among others, NMDA receptors, which activate signaling pathways leading to dissociative anesthesia. Another review by Jelen, Young, and Stone (2021) dives deeper into the biochemical and physiological effects (pharmacodynamics) of ketamine. The study investigated the different mechanisms and showed that arketamine, though less thoroughly studied, can potentially offer more effectiveness with fewer acute side effects. The AMPA receptor activation has a role in the antidepressant effects of ketamine, but the specific pathways need to be further investigated. Downstream from these effects, ketamine also influences BDNF-TrkB, mTORC1, and ERK signaling. Ketamine and its metabolites also interact with serotonin receptors, inhibit dopamine uptake, and interact with the gut-brain axis.

The number of studies investigating ketamine as a possible novel treatment of depression has been steadily growing over the past ten years. Even more rapidly, since in 2017, Sanacora and colleagues published a comprehensive guide to the safe and effective use of ketamine in the treatment of mood disorders. In 2018, Ionescu and colleagues published a comprehensive review of 47 neuroimaging studies investigating the effects of ketamine in the brain and discussed several emerging patterns which might be responsible for these effects. The researchers identified the reduction in the blood flow in the subgenual anterior cingulate cortex and the orbitofrontal cortex as a possible mechanism behind the dissociation effect. Although not consistently reported by all the reviewed studies, this particular action of ketamine leading to dissociation might play an important role in the antidepressant effect. Inhibition of the Default Mode Network (DMN) and self-monitoring behaviors may significantly contribute to mood improvements and increased emotional control. Other studies proposed further candidate mechanisms. Zanos and Gould (2018) discussed GABAergic synaptic inhibition, BNDF signaling, and NMDA receptor inhibition-independent mechanisms. In another publication by Zanos, Gould, and colleagues (2018), a convergent mechanism of ketamine antidepressant action in the brain was proposed. Nugent et al. (2019) investigated the gamma wave oscillations in antidepressant response to ketamine, while Siegel and colleagues (2021) focused on connectivity in the limbic system and the frontal lobe.

Suicidal ideation (SI) is a phenomenon characterized by thinking about, considering, or actively planning suicide. For those suffering from mental health disorders, an above-average percentage also suffers from SI. Currently, there are no effective treatments available, but ketamine is showing promise to rapidly lower scores of SI measures. A randomized controlled trial (RCT) with 80 participants who suffered from depression showed that a single treatment with ketamine (versus midazolam, an active placebo) led to significant reductions in suicidal ideation. Grunebaum and colleagues (2018) found that within 24h, 55% of subjects (versus 30% in the placebo group) had a 50% or greater reduction in SI scores. Part of this effect was mediated by the general mood improvement. With continued treatment, the reduction in SI was maintained for the whole six weeks of the study course. A meta-analysis on 167 patients suffering from a mental health disorder and suicidal ideation by Wilkinson and colleagues (2018) found that ketamine led to moderate- to large improvements of SI. This meta-analysis assessed the immediate relief that ketamine provides and posited that the effect on SI is partly independent of changes in mental health scores. A recent study by Can and colleagues (2021) provided further evidence of the positive effects of ketamine on SI. The study with 32 participants suffering from chronic SI was done with an open-label design – every subject received ketamine. The group used six repeated oral dosages over six weeks. The data showed that even four weeks after the study, 50% of the participants reported significant improvement, showing that with repeated dosages, the positive effects may continue for several weeks and offering a possible treatment for acute SI cases.

Electroconvulsive therapy (ECT) uses small electric currents to induce seizures in the brain. Via several mechanisms, this treatment can lead to positive outcomes for those suffering from depression, mania, and schizophrenia. Although the treatment is effective, it can lead to transient memory loss and other adverse effects. Currently, ECT is a standard practice in treating severe depression. Basso and colleagues (2020) compared repeated dosages of ketamine to ECT in 50 patients. They found that both led to similar improvements in depression scores. Ketamine also led to improvements in brain functions, whereas ECT led to small decreases. A broader outlook was explored in a recent review by Veraart and colleagues (2021). The researchers reviewed studies that combined ECT and ketamine treatments and did not find conclusive evidence for ketamine being more effective. Although the antidepressant effects are quicker, they are also more transient. When combining both treatments in the same patients, for a population that did not benefit from ECT alone, positive effects were found and sustained for seven days. A study by Zang and colleagues (2020) found that the combination also led to decreased connectivity in the default mode network (DMN). Overall, it is not clear yet if ketamine could entirely replace ECT in MDD treatment.

As already mentioned in the introduction, ketamine can be administered in two different enantiomers or a (race)mix of both. A systematic review and meta-analysis of over 1800 administrations investigated the effect differences between esketamine and the racemic mixture in depression. Bahji and colleagues (2020) found that the racemic ketamine led to greater overall response and lower dropout rates in the 24 trials they studied. Further studies are necessary to establish the exact differences in effects induced by arketamine, esketamine, and the racemic mixture. Update: A recent analysis of adverse events after esketamine administration for treatment-resistant depression by Gastaldon and colleagues (2020) found that suicidal ideation, but not suicide attempts, were higher when compared to those treated with antidepressants.

Patients suffering from chronic post-traumatic stress disorder (PTSD) have shown significant improvements after treatment with ketamine. A double-blind study with the active placebo control midazolam by Feder and colleagues (2021) found that two weeks after six infusions of ketamine, 67% of the group (versus 20% in the control group) positively responded to the treatment. The mean CAPS-5 score (a measure of PTSD symptoms) was 12 points lower than in the control group. The effects were maintained on average for one month, after which half of the responders (from the initial 67% of participants) were back at a high score on the PTSD scale. This study shows that extended treatment duration may promise to lengthen the treatment effects of ketamine on mental health disorders. An earlier review of the literature by Liriano and colleagues (2019) showed effects only lasting up to two weeks and only one earlier double-blind study was reported on. The review also concluded that there were no safety issues and that up to 49mg/70kg, no adverse events were reported.

Another important aspect of ketamine efficacy is its effect in the treatment of patients suffering from substance use disorders (SUDs). Ketamine treatment, after detoxification, has been shown to prolong abstinence from alcohol and heroin. Already an early study by Kruptsky and Grinenko (1997) showed that one-year post-treatment 66% of the ketamine treated group, versus 24% of the conventionally treated group, were abstinent from alcohol. The study with over 200 participants did, however, lack randomization and blinding. Participation in the ketamine group was based on motivation, and participants knew who received ketamine or not. Ezquerra-Romano and colleagues (2018) reviewed the recent literature and found that ketamine reduced cravings for cocaine in recreational users. The neuroplasticity effects and possibly blocking the reconsolidation of drug-related memories are the possible mechanisms playing an important role in this observation.

Ketamine and classical psychedelics (LSD, psilocybin) share the acute effect, which rapidly produces therapeutic outcomes (usually within 24h). Both types of substances lead to acute alterations in the brain network activity and, as discussed above, more subtle long-term changes. Although differences are present, some overlapping mechanisms are set in motion. Savalia and colleagues (2020) established a framework that proposes that both ketamine and classical psychedelics induce excitability effects on the dendrites (information receivers) of brain cells. This model overlaps with the findings of Jelen et al. (2021), from the second section. The neuronal calcium influx and accumulation leads to the upregulation of neurotrophins crucial in synapse formation, such as BDNF, mTOR, and TrkB. Ketamine and psychedelics both share this effect leading to an increase in neural plasticity. The glutamatergic system plays a role in the effects of both types of substances, according to Kadriu and colleagues (2020). A glutamate surge, specifically in the layer V pyramidal neurons with serotonin receptors, has been found in studies with classical psychedelics. Still, many of the overlaps and different actions of both types of substances remain to be explored. Interestingly, ketamine experiences may resemble psychedelic experiences because of the perceptual changes and the ‘afterglow’ effect. Sumner et al. (2021) suggested that, although the questionnaires used to measure the psychedelic experience might be inadequate for the psychedelic effects of ketamine, these effects are likely to contribute to the long-term antidepressant action of ketamine.

Alterations in dendritic spine morphology and spine density are possible markers of chronic stress and depression. The study of Sumner and colleagues (2020) investigated the effects of ketamine on neuroplasticity through the assessment of changes in predictive coding in patients suffering from treatment-resistant depression, based on the assumption that insensitivity to prediction error is one of the characteristics of depression. The results of this double-blind, active placebo-controlled study suggested that ketamine may have a positive effect on short-term plasticity through the restoration of sensitivity deficits of prediction error. This effect could improve the sensory context sensitivity, which is reduced by rumination and fatigue in depressed patients. Although there were several limitations to the study, such as the lack of a healthy control group and the fact that some patients were being treated with antidepressants during the course of the study, the data points out the potential of ketamine in improving short-term plasticity and sensitivity to prediction errors.

Lastly, ketamine has also been studied in the context of palliative care. Since classic psychedelics have previously shown positive effects on anxiety and depressive symptoms in cancer patients (Griffiths & Johnson, 2016), it seems worthwhile to investigate the effects shared with ketamine in terminal patients. Goldman and colleagues (2019) reviewed the literature and found that ketamine improved depression scores in a palliative care population. Another study on ketamine found mixed results on the analgesic (pain-relieving) effect on the palliative care population. The recent investigation by Falk and colleagues (2020) found that esketamine lowered anxiety but not depression and pain scores. Nevertheless, the effects of ketamine administration in end-of-life stages may induce relief of psychological distress and increase life quality in terminal patients.