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Ketamine use for addiction
Ketamine has been found to have effectiveness in prolonging abstinence in alcohol and heroin dependent individuals as well as decreasing cocaine cravings. This has been seen in preclinical and clinical studies. This may be a result of ketamine-induced neuroplasticity, disruption of maladaptive networks, improvement of depression, reducing drug-related memories, enhancement of psychological therapies, and even neurogenesis.
There are few effective therapies for addictions. Addiction is a chronic relapsing disorder associated with cravings, drug-seeking behavior, and unpleasant feelings during abstinence. Relapse rates can be 40-80% in the first year, with death being more common in relapse as the individual tends to use higher quantities at the time of relapse. As ~3% of the US population is dependent on an illicit substance, this represents a large impact on the economy in both productivity, medical treatment costs, interpersonal costs, accidents, and death.
Ketamine was synthesized in 1962 by the chemist Calvin L. Stevens for Parke Davis and initially was known as CI-581. It is an arylcyclohexylamine related to PCP (Phencyclidine) Because of its safety profile, it can be administered without oxygen or electricity to monitor its use and is recognized by the World Health Organization as an essential medicine as it is an excellent, safe choice for anesthesia. It produces a dissociative sedation and also provides analgesia. It does cause delirium, confusion, mystical experiences, ‘out of body’ experiences, ‘melting into the surroundings’, hallucinations, and dizziness when administered in varying doses to patients. In 1972, Collier studied low doses of ketamine as they produced floating, ‘disembodiment as if being a soul or mind’, disconnection from the surroundings, dying, or even traveling to other worlds.
Studies by Jansen and Sferios (2001) demonstrated that at low 25-50 mg I.M. doses people experience happiness and increased awareness and empathy while at medium does (75-125 mg I.M.) a person may experience out-of-body experiences. In the 1990’s, the ‘rave’ culture began using ketamine as part of a recreational construct.
Ketamine impacts the NMDA (N-methyl-D-aspartate) receptor as an antagonist, but it also blocks acetylcholine ion channels, increases dopaminergic transmission as well as noradrenergic transmission. There is also evidence that it also is a weak agonist at the delta and mu-opioid receptors. It does cross the blood-brain barrier as it is lipid soluble and acts within 5 minutes of administration, but its effects resolve entirely within one to three hours. It is effective in diminishing the production of hypersensitivity in neurons of the dorsal horn of the spinal cord (the ‘wind-up’ phenomenon) and so ketamine has been effective in the treatment of burns, neuropathic pain, post-herpetic neuralgia, migraines, and fibromyalgia. Ketamine is also effective in depression, with studies starting in 2000 (Berman et al) and 2006 (Zarate et al) demonstrating rapid resolution of depression with ketamine infusions.
Preclinical studies in rats (Sabino et al 2013) showed that ketamine can decrease the intake of alcohol in rats and that this effect was blocked by rapamycin, which blocks the effects of Ketamine. Ketamine has been shown to disrupt reconsolidation of environmental drug memories. (Zhai et al., 2008) It is known that addiction is characterized by an error of learning in which certain cue-triggered responses result from drug-related cues and these pathways are triggered when a person is using but can be disrupted by ketamine administration so the memories of using are not reconsolidated. Our ability to recall events is periodically reconsolidated over time as a trigger of the memory is presented. This reconsolidation happens during sleep or during an active learning event and this can be altered by the use of ketamine.
Studies in Ketamine use for addiction were initiated in Mexico by Salvador Roquet as a form of psychotherapy from 1964 to 1974 (Barney, 1977) . Continued studies were completed by Krupitsky and Grinenko (1997) in which ketamine reduced relapse in alcoholics. Also included in this process was Ketamine Psychedelic Therapy (KPT) which was used in the Soviet Union. KPT involved a procession in which the patient would learn about the ketamine psychedelic experience and that they would become aware of their addiction with it’s negative aspects as well as personal problems and self-identity. After this, the person would receive an injection of Ketamine and would be guided to see new meaning and purpose in life as well as being presented with the cue of the smell of alcohol at intense moments during the infusion to create negative emotional valence of the thoughts of alcohol. After the ketamine session, the person would use therapy sessions to integrate the insights of what they learned from the ketamine session.
In another study by Krupitskey (1997) 111 alcoholics and 100 patients (controls with usual therapy) were compared after the active group received 2.5 mg/kg IM Ketamine with corresponding preparation. 66% of the KPT group had abstinence at a year whereas only 24% of the controls remained sober.
In 2002, Krupitsky studied 70 heroin detoxed patients who were injected with varying amounts of ketamine in a double-blind manner. The higher dosed patients (2 mg/kg I.M. ) had a greater abstinence at 2 years (17% vs 2%) and it was felt the ketamine effect was dose-dependent. In 2007, Krupitsky found that using three KPT sessions for heroin addiction had better outcomes than one KPT session ( 50% versus 22%) Other addictions have been treated anecdotally with success by Kolp et al (2009, 2006) and these addiction even included food addictions.
Dkwar et al in 2015 used three ketamine infusions (one every 48 hours) and found that cue-induced craving and motivation to quit were higher in cocaine addiction when the individual had greater mystical experiences during the infusion. This generally occurred at the .71 mg/kg dosing. Dissociation did not impact the results as much as did the mystical experience of the infusion. This treatment decreased the frequency and amount of cocaine consumed after the infusion as well. In 2016 the same research group studied a single infusion of ketamine 0.71 mg/kg on cocaine use and this demonstrated a 67% decrease in cocaine choice. Cravings decreased significantly in treated groups and this is a marker of less relapse. Abstinence lasted over the two-week follow up.
Why does Ketamine work?
The brain is always learning about the environment and this occurs through neural plasticity and synaptogenesis, the formation of new connections within the brain. Reduced gutamatergic synaptic transmission and plasticity are thought to be associated with addiction. Ketamine allows synaptogenesis to occur by blocking NMDA receptors and stimulating protein synthesis that increases AMPA receptors to be inserted in the membranes of the neurons. Also addiction has been associated with a reduction in neurogenesis, which is the formation of new neurons in the hippocampus (the learning center) [ zhaoZhao et al 2008 and Ernst 2014] In fact, depression and other mental health disorders are associated with decreased neurogenesis. A marker of neurogenesis and neural plasticity is increased serum levels of BDNF (Brain derived neurotrophic factor), and it has been noticed that there are decreased levels of BDNF in addiction patients as well as depressed patients. BDNF levels correspond to improvement in depression scores in ketamine treated patients. (Haile et al 2014) and also slow wave sleep increases with BDNF levels (Duncan et al 2013) Slow wave sleep is associated with improved neuroplasticity. Ketamine’s ability to affect BDNF levels is also age -dependent. As one gets older, there is less BDNF produced with ketamine (Huang et al 2016 Keilhoff et al 2014)
Ketamine does modulate the glutamanergic corticolimbic circuits that serotonergic psychedelic agents also modify. The use of ketamine decreases the default mode network between the posterior cingulate gyrus and the medial prefrontal cortex (mPFC) (Carhart-Harris et al 2012) The thalamus, putamen, and high-level cortices are all affected and the functional networks involving salience, attention, and visual cortices are desegregated. During an infusion an individual loses sense of time and can effectively experience synesthesia (tasting colors or hearing colors as an example). Connections within resting-state conscious networks such as the mPFC and the DMN ( via posterior cingulate cortex) and also salience and visual networks are diminished in connectivity. One may think that when we aren’t actively doing something that our mind is resting, but in fact, it is actually daydreaming and thinking of future ‘what if’, ‘woulda’, ‘could’, ‘shoulda’ scenarios which are generally anxiety provoking. People are less depressed when they are in a flow state of activity and focused on a task as opposed to daydreaming activities or ruminating over the past, which cannot be changed. Flow state activities such as skiing, exercise, and physical activity tend to also temporarily disarm the DFM which is more active in depression. Ketamine disarms the DMN. ( Bonhomme et al 2016, Niesters et al 2012, Scheidegger et al 2012) Connectivity with the mPFC is increased in depression (Sheline et al., 2010) . The key to decreasing depression and addiction seems to be by decreasing the default mode network connectivity. This also goes hand-in-hand with the fact that unstructured time and boredom tend to be associated with more depression and addiction.
PET studies do show an increase in neuronal activity with Ketamine in the prefrontal cortex, anterior cingulate gyrus, and the insula.. (Vollenweider et al 1997) Normalization of the corticolimbic system connectivity may be what is needed for the treatment of depression and addiction. Depression and addiction frequently go together, so depression treatment is critical in addiction responses (Curran et al 2016, Markou et al., 1998). There have been many studies demonstrating the efficacy of ketamine in depression treatment. A systematic review by McGirr et al. , 2015 showed higher rates of response to ketamine up to 7 days later for depression. Ketamine has a 70% response rate within 24 hours and last a week versus a 47% response rate after months with traditional therapies (Lener et al 2017). Suicidal ideation after ketamine therapy is also reduced. (Ballard et al 2014, Diaz Granados et al., 2010, and Larkin and Beautrais 2011)
Depression may be a trigger of relapse. Antidepressants do not decrease relapse in alcoholism. (Mason et al 1996; Pettinati, 2004) Ketamine is a rapid antidepressant and given the role of depression in addiction, ketamine has robust evidence for addiction treatment (Kessler et al 2003; Grant et al., 2004, Quello et al., 2005) Ketamine also decreases alcohol relapse.
When it comes to drug memories and cues, anytime the memory of using is retriggered, the memory is transiently rendered unstable and labile before they are reconsolidated and remembered again. This is a target for ketamine to potentially alter the reconsolidation of drug cues and manipulate them in a way to decrease relapse. Reward memories can be paired with unpleasant experiences to disrupt a behavior. This can be done with ketamine. (Lee et al 2006; miller and Marshall 2005; Xue et al., 2012 Corlett et all 2013; Goulart et al 2010., Parwani et al 2005, Zhai et al., 2012) The key to addiction treatment with ketamine is to disrupt maladaptive appetitive memories (Fattore et al., 2017)
Life-changing, eye-opening, and spiritually meaningful psychedelic effects of an infusion have been linked to good outcomes. (Garcia-Romeu et al., 2014; Griffiths et al., 2008, 2006; Johnson et al., 2017) Ketamine allows an individual to undergo a cathartic experience and enhanced self-awareness to enable personal growth. After a ketamine experience, many people expressed spirituality, emotional attitudes, self-concept, and positive changes in life-values and purposes. ( Krupitsky et al., 2002; Krupitsky and Grinenko , 1997) In fact the mystical experiences of ketamine infusions were more valuable in motivating cocaine addicts to quit than were the dissociative effects (Dakwar et al 2014). This may allow an addict to accept a sober lifestyle. Disruption of the DMN may be a key in reducing ruminative thoughts and maladaptive repetitive thoughts in addiction and depression. Models have demonstrated that ketamine can be an antidepressant without the psychomimetic effects ( Zanos et al. 2016) but the psychomimetic effects may be an important role in the treatment of addiction.
Ketamine therapy may enhance psychological therapy by providing an enhanced mental state after the infusion and providing synaptogenesis and neurogenesis to allow new learning in the following days after an infusion. (Grof 1985, Hansen et al., 1988,; Kolp et al., 2014), Giese 2012) The new neurogenesis may allow the learning of relapse-reducing strategies of Cognitive behavioral therapy by removing cognitive rigidity.
For alcohol use disorder, Ketamine treatment increased one-year abstinence from 24% to 67% *Krupitskey and Grineko 1997) and reduced cocaine use by 67% in another study (Dakwar et al., 2016). Thus, ketamine treatment is much more successful that traditional therapies. Daily therapy is not needed for efficacy and doses can be isolated and given for a limited time frame yet still be effective. In fact, intranasal therapy has been shown to be effective as well for depression. (Lapidus et al 2014).
Depression and addiction affect similar neural circuitry that involves the default mode network, neurogenesis (nerve growth formation), and synaptogenesis (synapse formation between nerve cells involved in learning). It is known that addiction and depression result in reduced brain volume sizes in key learning parts of the brain such as the hippocampus and over wiring in the anxiety producing areas of the brain (the amygdala) These changes can be seen on MRI scans. In effect depression and addiction can be seen as problems with learning as effectively the brain has decreased potential of creating new pathways in the face of ritualistic cues and triggers. This leads to ruminative thoughts and dysfunctional behaviors with responses to cues and triggers that are repetitive and maladaptive. Over time there are fewer adaptive responses that are made by individuals that are depressed or addicted to substances and new stressors tend to be met with increased drug use or ritualistic responses. There is less learning done by the addicted or depressed mind. This correlates with less neuroplasticity and nerve growth (neurogenesis) that are all a result of less Brain derived neurotrophic factor that is involved in healthy brain growth.
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