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Ketamine is a purely synthetic, man made compound, that was originally used to treat pain inflicted on the battlefield and to help out people to sleep for a surgical procedure. It was noticed that some mental health struggles improved in those who'd undergone ketamine treatments.  The IV medication is currently being used off-label, (Not FDA approved for mental health conditions), to help treat conditions like, treatment resistant depression, post traumatic stress disorder, acute suicidal ideation, and more.  As part of a comprehensive mental health treatment plan, ketamine is showing promise.  Satori Healing will offer IV/IM ketamine treatments, with referral, in a safe, supportive, personalized environment.  For those who want to get more deeply into the weeds, below I've summarized a recent review article.

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Brief History of Ketamine

Ketamine chemically is an arylcycloexylmine. It was first synthetized in the 60s as a derivative of phencyclidine (McCarthy et al., 1965); approved as an anesthetic drug in the 70s, ketamine was soon widely abused as an illegal drug (Liao et al., 2017). Later, ketamine’s use was extended to analgesia for acute, chronic pain and cancer pain, and for the treatment of addiction (Jonkman et al., 2017Jones et al., 2018). The typical dissociative effect of ketamine, observed in patients and street users, encouraged scientists to explore its complex mechanism of action and its interaction with the central nervous system (Tyler et al., 2017). Ketamine is water-soluble anesthetic approved for specific pediatric procedures and for adult patients at risk for hypotension (Dahmani et al., 2011Marland et al., 2013); this indication is likely justified by the fact that ketamine increases the blood pressure, heart rate and cardiac output. Ketamine rapidly produces a hypnotic state, profound analgesia and anesthesia, without reducing the drive to breath. Ketamine is a bronchodilator and is particular indicated for patients at risk for bronchospasm (Golding et al., 2016). 

Looking at the View


The use of ketamine is associated with several side effects, among them are observed hallucinations, intense dreams, delusions and emergence delirium that can respond to benzodiazepine treatment, (Molero et al., 2018). Overall, ketamine is considered a satisfactory anesthetic; therefore the repurposing of ketamine as a fast-acting antidepressant has been a true breakthrough (remarkably, significant antidepressants effects are observed within 24 h).  Interestingly, as early as 1999, ketamine was shown to possess effects overlapping those of imipramine in the animal model of depression (Chaturvedi et al., 1999); these antidepressant-like effects in rodents were widely reproduced later.  The first report demonstrating the rapid antidepressant effect of ketamine dates back in 2000 (Berman et al., 2000); in particular, these authors reported a significant improvement in depressive symptoms within 72 h after infusion of ketamine, but not placebo, in drug-free patients who had not taken any medication for at least 2 weeks. Later, the safety and the efficacy of repeated ketamine i.v. infusion (0.5 mg/kg, 40 min), were demonstrated by several studies in treatment resistant depression patients (e.g., aan het Rot et al., 2009Murrough et al., 2013). Similar results were obtained in a randomized controlled trial by administering intranasal ketamine (50 mg), (Lapidus et al., 2014). Given this unique property of ketamine, its approval has provided an alternative or a complementary treatment to classic antidepressant drugs in the therapy of depression. In fact, classic antidepressants, mostly monoamine reuptake inhibitors, are characterized by a delay of several weeks to months before clinical improvement is observed; in addition, a substantial proportion of major depression disorder (MDD) patients do not respond to reuptake inhibitors (Ferrari and Villa, 2017). Patients who do not respond to two or more antidepressant treatments are classified as treatment resistant depression (TRD), and are considered the patients of choice for ketamine’s therapy (Mrazek et al., 2014).



Can Ketamine reduce the risk of suicide?

Although ketamine’s mechanism of action has not been fully clarified, there is no doubt that ketamine is effective in reducing suicidal ideation and attempts. Several studies demonstrated that either 0.5 mg/kg of ketamine infused over 40 min versus placebo (Zarate et al., 2012aBurger et al., 2016Hu et al., 2016) or versus midazolam (Price et al., 2014Murrough et al., 2015Fan et al., 2017Grunebaum et al., 20182017), definitively reduced suicidal ideation and depressive symptoms. A recent report showed that also intranasal esketamine (84 mg twice a week for 4 weeks), in addition to comprehensive standard of care treatment, may result in a significant reduction of depressive symptoms and suicidal ideation (Canuso et al., 2018). 

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Schematic representation of some potential mechanisms involved in the antidepressant actions of ketamine. (1): Ketamine reduces NMDA receptor mediated stimulation of GABA interneurons reducing the inhibitory action on presynaptic glutamatergic neuron; (2) the reduced inhibition produces a rapid glutamate burst acting on AMPA receptors located on pyramidal neurons; (3) Such activation leads to the opening of voltage-dependent calcium channels (VDCC) that stimulate BDNF; (4) BDNF induce the translation and synthesis of key synaptic proteins in synaptogenesis and maturation of dendritic spines, including GluA1 and PSD95), via the TrkB/Flk-1 - mTORC1-signaling pathway; (5) ketamine acting as NMDA inhibited the eukaryotic elongation factor2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and increased BDNF translation and protein synthesis; (6) ketamine metabolite can stimulate AMPA receptors independently of NMDA receptor blockade by ketamine; (7) kainate receptor can contribute to Na+ and Ca++ entry, neuronal depolarization and postsynaptic responses.



The use of ketamine as an add-on drug can help to erase memories of traumas and thus eliminate or attenuate nightmares, reduce the insomnia associated with the occurrence of nightmares (Wang X. et al., 2019), and assist recovery from depression. It has in fact been observed that ketamine infusion can increase total sleep time and reduce waking during the first and second night post infusion (Duncan and Zarate, 2013); ketamine can also reduce nocturnal sleeplessness in depressed patients with suicidal tendencies (Vande Voort et al., 2017). Interestingly, it has also been observed that baseline insomnia can be a predictor of the efficacy of ketamine when it is repeatedly administered intravenously for the treatment of unipolar and bipolar depression (Liu et al., 2020). Additionally, repeated ketamine infusions, in a comorbid population with PTSD and TRD, have proven to be an effective treatment (Albott et al., 2018). Overall, although repeated administration of ketamine is very promising for the treatment of PTSD, additional studies are needed to evaluate whether ketamine might enhance the efficacy of psychotherapy in individuals with chronic PTSD (Feder et al., 2020).

Navigating in Woods


From a pharmacological point of view, the rapid antidepressant effect and the sustained antidepressant effect of ketamine are both intriguing and puzzling; the former because unlike other antidepressant drugs, it manifests within a matter of hours of infusion; the latter because it continues to be observed well beyond the point when the concentration of ketamine in the plasma is pharmacologically irrelevant. A sustained antidepressant effect has important clinical relevance and has made it possible to schedule repeated treatment at relatively long intervals (48–72 h), which in addition to avoiding any accumulation of the substance, is associated with the appearance of adverse effects only for a short period of time (about 1–2 h) after administration.

This section was based on: REVIEW article

Front. Neurosci., 30 April 2021 |

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