Ketamine and Addiction
Dr. Ross is assistant professor of psychiatry and director of the Division of Alcoholism and Drug Abuse at Bellevue Hospital, and associate director for education at New York University School of Medicine in New York City.
Disclosures: Dr. Ross reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Stephen Ross, MD, 104 E 40th St, Suite 802, New York, NY, 10016; Tel: 212-562-4097; Fax: 212-562-2041; E-mail:stephen.ross@nyumc.org.
Abstract
Ketamine is a schedule III drug with a well-established safety profile that has been used extensively as an anesthetic for close to 4 decades. It has long been described as a drug of abuse and has become known as one of the “club drugs,” used by adolescents and young adults in rave and circuit party settings. Ketamine is a congener of phencyclidine and acts as a noncompetitive N-methyl-d-aspartate (NMDA) antagonist. Through a complicated and not completely understood process, NMDA antagonism increases dopamine levels in reward-related areas such as the ventral tegmental area and the nucleus accumbens. In addition to its addictive liability, there is also evidence to suggest that ketamine might have anti-addictive properties when used as an adjunct to psychotherapy that takes advantage of its ability to produce spiritually oriented altered states of consciousness. This technique has been applied to patients with alcohol and opiate use disorders. Ketamine’s potential anti-addictive properties can be understood by looking at biologic and psycho-spiritual models.
Introduction
Ketamine is a commonly used, safe, effective and well-known anesthetic agent that has been available as a schedule III agent for close to 4 decades. It has been known as a drug of abuse since its discovery and introduction as a medicine and has most recently become associated as a “club drug” used primarily by adolescents, young adults, and gay men at “raves” and “circuit parties.”1 It is primarily thought of as a drug of abuse; however, it is also starting to find its way into the pharmacopoeia of agents used to treat addictive disorders by taking advantage of its ability to be used as an adjunct to psychotherapy, where its ability to produce psychedelic and spiritual states of consciousness has been successfully applied to induce sobriety in addicted individuals, mostly in Russia.2 It is worth trying to understand this contradictory phenomenon. This can be addressed by looking at biologic and psycho-spiritual etiologic models. This article includes a brief historic review of research and use of ketamine for a variety of medical and psychiatric conditions, addictive liability of ketamine including biologic mechanisms, and potential anti-addictive properties of ketamine with an exploration of biologic and psycho-spiritual mechanisms of action.
History of Research and Current Use Practices of Ketamine
Ketamine was synthesized by the American chemist Calvin Stevens in 1962 at the University of Michigan for use as a novel anesthetic agent after phencyclidine (PCP) was discovered to be too psychotigenic when used as an anesthetic.1 In 1965, Domino coined the term “dissociative anesthetic”3 to describe its properties of disconnecting mind from body unlike conventional anesthetics that completely suppressed consciousness. It was patented in 1966 by Parke-Davis and in 1970 the Food and Drug Administration approved its use for anesthesia in children, adults, and the elderly. Since then, it has been used extensively for this purpose as a result of the properties of rapid onset, rapid patient recovery, and its ability to suppress conscious experience without altering respiratory and circulatory functioning. It has a well-established biologic safety profile based on >7,000 published reports. There is some evidence it may prevent neurotoxicity from strokes, head trauma, and seizures, likely a result of its antagonist properties at the N-methyl-d-aspartate (NMDA) receptor.2In addition, there is no evidence of long-term neurotoxicity or prolonged adverse psychological effects when used in controlled environments.4-7
In the 1970s and 1980s, ketamine was used and studied as an adjunct to psychotherapy in patients with depressive, anxiety, and psychosomatic spectrum disorders with anecdotal reports suggesting an effect on reducing symptom distress.8-10 Current research with ketamine has strongly suggested a role in treating refractory pain syndromes such as complex regional pain syndrome,11-13 and breakthrough pain in chronic pain syndromes such as that related to advanced cancer.14 Krystal15 has successfully used ketamine as a research tool for over a decade in normal volunteers and schizophrenics to explore the NMDA antagonist hypothesis of schizophrenia. As a serendipitous finding in Krystal’s research, subjects reported acute reductions in depressive symptomatology after ketamine administration.16 This laid the foundation for subsequent work by several investigators where ketamine was found to be the first known agent to effect acute antidepressant properties in patients with major depressive disorder (MDD) in randomized, placebo-controlled trials.17-19 Further research into this effect is actively being pursued at several centers in the country.
Addictive Liability
Illicit use and abuse of ketamine started soon after its introduction in 1970. Soldiers returning from Vietnam who received ketamine as an anesthetic reported vivid hallucinogenic experiences. It became linked with “intellectual hedonism” in the 1970s and 1980s, particularly in the United States, and the first reports of abuse by healthcare workers began to appear.20 Over the past decade, an increase in non-medical use of ketamine in Australia, Great Britain, Sweden, and the US (particularly in New York City) has been reported, with diversion from veterinary supplies a major source of obtaining the drug.1,21 There are two main groups of users, namely those who use in a solitary fashion seeking transcendental, psychedelic experiences and seeking spiritual growth, and those who use ketamine as a ‘“club drug” as part of the rave and circuit party scene. It is difficult to establish the true prevalence of ketamine use disorders as the users remain a mostly hidden group. One study21 in Britain reported that close to 30% of club-goers surveyed reported a lifetime use of ketamine. Another survey22 of mostly gay, Caucasian men who attended a “circuit party” in the New York City area in 1998 found that 86% of the 173 subjects reported drug or alcohol use at the party with ketamine being the second most common drug used (53%) after methylenedioxymethamphetamine (“ecstasy”; 71%). Several converging pieces of data point to ketamine having real addictive liability. These include positron emission tomography studies demonstrating that ketamine leads to increases in dopamine in the ventral tegmental area (VTA) in humans correlating with elevated mood23; ketamine induces increases in dopamine in the nucleus accumbens in humans24; ketamine induces self-administration in animal models25,26; repeated ketamine administration causes behavioral tolerance in animals27,28 and humans21; and heavy, habitual use of ketamine has been described in humans, including in anesthesiologists.29,30
Understanding ketamine’s addictive properties involves considering its mechanism of action. Ketamine is an arylcyclohexylamine and is part of the class of dissociative anesthetics, which also includes PCP (“angel dust”) and dextromethorphan. Its main receptor action is antagonism at the NMDA glutamate receptor complex at the same site as PCP, located inside the calcium channel leading to blockade of calcium influx through the channel.31 This action underlies its analgesic, dissociative, psychotigenic, psycho-spiritual, and neuroprotective properties. Ketamine mainly acts at the pre-frontal cortex (PFC) and limbic system, with the highest density of NMDA receptors being in the PFC and hippocampus.32Alcohol, as one of its several mechanisms of action, also antagonizes the NMDA receptor, and ketamine produces alcohol-like subjective effects in humans.33 In addition, ketamine has opioidergic effects (mu and sigma opiate agonism)16 contributing to its analgesic properties and stimulant-like properties by enhancing monoaminergic transmission (dopamine, norepinephrine, serotonin) through inhibition of re-uptake pumps.34 The above effects have led some to describe ketamine’s subjective state as “alcohol-like intoxication, cocaine-like stimulation, opiate-like calming, and cannabis-like imagery.”35
Next, it is first important to look at the biologic underpinning of the addicted state. Two effects that likely contribute significantly to the addicted state are changes in midbrain dopamine as well as PFC dopamine and glutamate function. Damage to the dopamine system leads to decreased dopamine receptor density and release in the nucleus accumbens and PFC, diminishing the ability of dopamine to signal novel salient events, leading to under-excitability to biologically relevant stimuli.36,37 As addiction progresses, the neurocircuity of the reward pathway becomes corrupted, re-organized, and dysregulated whereby the behavioral system changes from a dopamine-oriented one in the nucleus accumbens (involved in the acute high and the initiation of learning and conditioned responses) to a glutamate-based system in the PFC (especially the anterior cingulate and orbitofrontal cortex) marked by altered glutamatergic transmission in projections from the PFC to the nucleus accumbens.38 Specifically, the system becomes hyperexcitable to drug-conditioned cues and under-excitable to biologically oriented ones. As part of these dopaminergic and glutamatergic changes, pharmacotherapy development of anti-addictive agents is currently focusing on agents that can strengthen the saliency of natural reinforcers, such as enhancing dopamine function, and agents that can alter the dysfunctional response to conditioned cues (either drug related or biologically relevant) by altering glutamatergic transmission.
Along the lines of hyperglutamatergic states being associated with addiction, it is key to consider that subanesthetic doses of NMDA antagonists (ie, ketamine) may actually enhance glutamatergic transmission by disinhibiting glutamate release, shunting glutamate to the other glutamatergic receptors other than NMDA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], kainite, and the metabotropic G protein coupled glutamate receptor) and causing a hyperglutamatergic state.15 One may ask how this is possible and what is its significance. There is some evidence to suggest that NMDA receptor blockers may antagonize γ-aminobutyric acid (GABA) neurons with a greater potency than their inhibition at the NMDA receptor. The NMDA antagonism may therefore diminish activation of GABA inhibitory neurons, with a diminution of cortical extracellular GABA levels,39 which in turn would decrease GABA’s normal inhibition of glutamate neurons, causing a net disinhibition of glutamate neurons and an increase in glutamatergic transmission in non-NMDA glutamate receptors.40 In turn, cortical glutamatergic activation stimulates monoaminergic terminals within the cortex, limbic system, midbrain, and brainstem.15As part of this, extracellular dopamine levels are increased in reward-related areas (ie, VTA and nucleus accumbens) thereby likely explaining ketamine’s addictive liability. Given this, one can ask how we can understand a possible explanation—biologic or otherwise—for ketamine’s putative anti-addictive properties.
Anti-Addictive Properties
Brief History of the Use of Hallucinogens to Treat Addictive Disorders
Ketamine is not the first psychedelic agent to be tested to treat addictive disorders. In the 1950s and 1960s, serotonergic hallucinogens (predominantly d-lysergic acid diethylamide [LSD]; “acid”) were applied to patients with addictive disorders, mostly alcohol dependence and to a lesser degree opiate dependence. The most prominent researcher who studied this application was Humphrey Osmond, MD. He, in conjunction with Abram Hoffer, MD,41 treated >1,000 alcoholics using high-dose LSD. Their initial mechanistic hypothesis was based on aversive counterconditioning where they likened the intense LSD experience to the frightening altered state seen in the delirium tremens, which, in their experience, often served as a transformative, near-death (“bottoming out”) state that led to a sober conversion. However, soon after treating alcoholic patients with LSD in highly controlled environments paying careful attention to set and setting, they changed to a more positivist paradigm where they described that such agents had the capacity to produce a transcendental feeling of unity with the world, personal insights, self-understanding, increased sense of responsibility to self and others, and spiritual enlightenment.41 They reported high success rates including improved rates of abstinence, but the research was methodologically flawed with no randomization, no placebo controls, lack of blind raters, the use of unsophisticated severity measures, inadequate diagnostic specificity, inclusion of co-occurring psychiatric and substance use disorders (SUDs) other than alcohol, inadequate informed consent, and inadequate follow up.
Other studies looking at LSDs effect in alcoholism varied widely from astonishingly positive results to worsening of the alcoholism, depending on the design of the study and the set and setting. Unfortunately, almost all studies were methodologically flawed, leaving others unable to determine what if any effect might have existed.42However, this has laid the groundwork for current studies using these and similar agents (ie, ketamine) to determine if there is a true treatment efficacy signal. The correct methodology would have to include randomization, placebo control, use of specific diagnoses using validated measures (ie, Structured Clinical Interview for theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition), inclusion of severity measures, standardized psychotherapy dose, objective “blind” raters, and having adequate follow up.43
Current Use of Ketamine to Treat Addictive Disorders
The first psychiatrist to rigorously study the potential of ketamine to treat addictive disorders was Evgeny Krupitsky, MD, PhD. In 1985, he developed a technique using ketamine—ketamine psychedelic psychotherapy (KPT)—to treat patients with alcohol use disorders.2 Similar to Osmond, he first conceptualized an aversive counter-conditioning model utilizing preparation and suggestion in combination with the altered state of consciousness induced by ketamine to induce and amplify a negative psychological state paired with the continued negative consequences of alcoholism. It is worth considering a model of a pharmacologically initiated, precipitated or enhanced “hitting of rock bottom.” In the addiction field, we often hear the adage of needing to hit “rock bottom” before the initiation of sobriety. This event may be similar to near-death experiences, which have been described as triggering transformative and positive life changes,44and may serve to initiate a rapid change to a sober state. In Alcoholics Anonymous (AA), it is taught that this is what is needed before the individual can really get sober. Although this may be true for some, “rock bottom” for other addicts may be death. Rather than disengaging from the patient and waiting for this to happen, one may wonder if it could be possible to chemically induce or enhance this phenomenon, thereby speeding up the process to recovery initiation.
From an adverse psychiatric perspective, ketamine can induce frank psychotic states (with both positive and negative symptoms), dissociation, and cognitive impairment (including impaired attention, memory, and performance).21 However, this does not capture the phenomenology of the profound psychological, mystical, and spiritually oriented altered state of consciousness induced by ketamine. It is useful to define what is meant by “spirituality,” a broad construct that encompasses both faith and meaning.45,46 Faith can be defined as the belief in and relationship with a transcendent higher power, which does not have to be identified as “God” and does not have to occur through participation in traditional organized religion, while meaning can include feeling that one has a unique purpose in life and can achieve a sense of fulfillment and “even transcendence through connectedness with something greater than one’s self.”47 The spiritual types of experiences induced by ketamine, separate from its dissociative properties (ie, out of body experiences) and perhaps overlapping with and traditionally understood as psychotic phenomenon, can include feelings of ego dissolution and loss of identity; experience of psychological death and re-birth; emotionally intense visions and dream-like states; enhanced insight/self-reflection and meaning in life; and feelings of unity with humanity, nature, the universe and God.2 These effects led Krupitsky to change his model from an aversive one to an existential, spiritual model within a positivist framework with the goal of inducing peak/transcendental states to effect conversion to a sober state in addicted patients. He extended his research to include patients with opiate addiction, and from 1985 until 2002 treated >1,000 patients with addictive disorders using KPT.2 KPT includes three stages, namely, preparation, administration, and integration. The preparatory phase includes 5–10 hours of suggestive psychotherapy where the patient is told the ketamine experience may induce important insights related to personal problems, value systems, and the meaning of their lives and that these insights may lead to changes associated with sobriety. During administration, the patients receive 2–2.5 mg/kg intramuscular (IM) of ketamine with onset of action in 10 minutes and the duration of the experience lasting approximately 1 hour. Patients are told they will enter an altered state and to surrender to the experience. They lie supine with eyeshades and headphones, hearing pre-selected music. In the integration phase, a combination of individual and group psychotherapy is administered over time to help subjects interpret and integrate the ketamine experience with the goal of leveraging the experience to effect behavioral changes associated with abstinence. The therapist assists in the integration of the spiritual transformation.2
In a controlled trial48 of patients with alcohol dependence, a one-time dose of ketamine as part of KPT (added to standard psychosocial care for patients with alcohol dependence in Krupitsky’s treatment center) added considerable benefit to the standard treatment. Total abstinence from alcohol for >1 year was reported in approximately 66% (73 out of 111) of alcoholic subjects in the KPT group compared to 24% (24 out of 100) in the conventional treatment control group (P<.01). In addition, based on psychological measures administered in the study, the group receiving KPT had positive changes in their emotions and perception of themselves and others, positive changes in life values and purposes, important insights into the meaning of life, and increased spiritual development compared to the placebo group. Krupitsky further tested the use of KPT in patients with heroin dependence in a double-blind placebo-controlled, randomized trial49 where 70 detoxified heroin-dependent subjects were randomly assigned to two groups—one with a one-time hallucinogenic dose of ketamine (2 mg/kg IM), versus one group with a control, non-hallucinogenic dose (0.2 mg/kg IM). All patients received the same standardized dose of psychotherapy during the preparatory and integration phases. The experimental group had significantly higher rates of abstinence at multiple prospective points in time out until 2 years follow-up, compared to the active placebo group (Table 1).49 As with the above alcohol studies, compared to the control group, the experimental group also displayed improvements in other dimensions of psychological well being including decreased levels of anxiety/depression, enhanced understanding of the meaning and purpose of life, and increased spiritual development. In this study,49 there were no significant adverse physiologic or psychological events and no subjects became addicted to ketamine.
In these studies, it is unclear as to the exact nature of the pharmacologic or psychosocial component of substance abuse treatment before receiving KPT and especially following the administration stage. For example, in the above study with heroin dependent subjects,49 the integration phase appears to only consist of 5 hours of psychotherapy “carried out within several days after the KPT session” to help “integrate the insights from the ketamine session into everyday life.”49 It is not clear as to exactly what this entails and how such a brief “existentially oriented psychotherapy” intervention could promote long-term abstinence up to 2 years follow up. The follow-up treatment is not described in any detail and it is unknown if these patients received standard evidence-based addiction pharmacologic treatments, such as naltrexone (opiate agonist or partial agonist treatment is banned in Russia), or psychosocial ones, such as motivational interviewing, relapse prevention, contingency management, community reinforcement, or coercion. Furthermore, this was described as a double-blind study. However, there is no description of the integrity of the blinding procedures in terms of any reporting of the percentage of accurate identification, by either subjects or experimenters, of whether the experimental or placebo dose of ketamine was administered. A complete hallucinogenic or psychedelic ketamine experience would seem easily discernible from one that is sub-hallucinogenic given the pronounced phenomenology of the experience. Without data on the blinding integrity, it is unknown how much of the treatment effect could be influenced by either subject or experimenter expectancy biases.
Potential Biologic Anti-addictive Mechanisms of Ketamine
In a study52 of abstinent subjects with alcohol dependence, memantine diminished alcohol cue-induced craving in a dose-dependent manner. Finally, in a study53 of heroin dependent subjects, memantine was associated with modest reductions in the subjective but not reinforcing effects of heroin administration. It should be noted that memantine does not cause the pronounced altered states of consciousness seen with ketamine and so its anti-addictive properties can likely only be explained by its biologic mechanism. Other examples of anti-glutamatergic agents that have anti-addictive potential in humans include acamprosate (weak direct NMDA antagonism and direct interaction with the metabotropic glutamate receptor type 5, thereby indirectly acting as an inhibitory modulator at the NMDA receptor) for alcoholism,54 ibogaine (NMDA antagonism as one of its many receptor actions, although its exact anti-addictive mechanism remains unknown as 18-methoxycoronaridine, a congener of ibogaine, has anti-addictive properties without appreciably antagonizing the NMDA receptor) for opiate withdrawal,55lamotrigine (a glutamate release inhibitor) for alcoholism,56 and topiramate (AMPA/kainite receptor inhibitor) for alcoholism.57
Ketamine and Addiction
Dr. Ross is assistant professor of psychiatry and director of the Division of Alcoholism and Drug Abuse at Bellevue Hospital, and associate director for education at New York University School of Medicine in New York City.
Disclosures: Dr. Ross reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Stephen Ross, MD, 104 E 40th St, Suite 802, New York, NY, 10016; Tel: 212-562-4097; Fax: 212-562-2041; E-mail:stephen.ross@nyumc.org.
Abstract
Ketamine is a schedule III drug with a well-established safety profile that has been used extensively as an anesthetic for close to 4 decades. It has long been described as a drug of abuse and has become known as one of the “club drugs,” used by adolescents and young adults in rave and circuit party settings. Ketamine is a congener of phencyclidine and acts as a noncompetitive N-methyl-d-aspartate (NMDA) antagonist. Through a complicated and not completely understood process, NMDA antagonism increases dopamine levels in reward-related areas such as the ventral tegmental area and the nucleus accumbens. In addition to its addictive liability, there is also evidence to suggest that ketamine might have anti-addictive properties when used as an adjunct to psychotherapy that takes advantage of its ability to produce spiritually oriented altered states of consciousness. This technique has been applied to patients with alcohol and opiate use disorders. Ketamine’s potential anti-addictive properties can be understood by looking at biologic and psycho-spiritual models.
Introduction
Ketamine is a commonly used, safe, effective and well-known anesthetic agent that has been available as a schedule III agent for close to 4 decades. It has been known as a drug of abuse since its discovery and introduction as a medicine and has most recently become associated as a “club drug” used primarily by adolescents, young adults, and gay men at “raves” and “circuit parties.”1 It is primarily thought of as a drug of abuse; however, it is also starting to find its way into the pharmacopoeia of agents used to treat addictive disorders by taking advantage of its ability to be used as an adjunct to psychotherapy, where its ability to produce psychedelic and spiritual states of consciousness has been successfully applied to induce sobriety in addicted individuals, mostly in Russia.2 It is worth trying to understand this contradictory phenomenon. This can be addressed by looking at biologic and psycho-spiritual etiologic models. This article includes a brief historic review of research and use of ketamine for a variety of medical and psychiatric conditions, addictive liability of ketamine including biologic mechanisms, and potential anti-addictive properties of ketamine with an exploration of biologic and psycho-spiritual mechanisms of action.
History of Research and Current Use Practices of Ketamine
Ketamine was synthesized by the American chemist Calvin Stevens in 1962 at the University of Michigan for use as a novel anesthetic agent after phencyclidine (PCP) was discovered to be too psychotigenic when used as an anesthetic.1 In 1965, Domino coined the term “dissociative anesthetic”3 to describe its properties of disconnecting mind from body unlike conventional anesthetics that completely suppressed consciousness. It was patented in 1966 by Parke-Davis and in 1970 the Food and Drug Administration approved its use for anesthesia in children, adults, and the elderly. Since then, it has been used extensively for this purpose as a result of the properties of rapid onset, rapid patient recovery, and its ability to suppress conscious experience without altering respiratory and circulatory functioning. It has a well-established biologic safety profile based on >7,000 published reports. There is some evidence it may prevent neurotoxicity from strokes, head trauma, and seizures, likely a result of its antagonist properties at the N-methyl-d-aspartate (NMDA) receptor.2In addition, there is no evidence of long-term neurotoxicity or prolonged adverse psychological effects when used in controlled environments.4-7
In the 1970s and 1980s, ketamine was used and studied as an adjunct to psychotherapy in patients with depressive, anxiety, and psychosomatic spectrum disorders with anecdotal reports suggesting an effect on reducing symptom distress.8-10 Current research with ketamine has strongly suggested a role in treating refractory pain syndromes such as complex regional pain syndrome,11-13 and breakthrough pain in chronic pain syndromes such as that related to advanced cancer.14 Krystal15 has successfully used ketamine as a research tool for over a decade in normal volunteers and schizophrenics to explore the NMDA antagonist hypothesis of schizophrenia. As a serendipitous finding in Krystal’s research, subjects reported acute reductions in depressive symptomatology after ketamine administration.16 This laid the foundation for subsequent work by several investigators where ketamine was found to be the first known agent to effect acute antidepressant properties in patients with major depressive disorder (MDD) in randomized, placebo-controlled trials.17-19 Further research into this effect is actively being pursued at several centers in the country.
Addictive Liability
Illicit use and abuse of ketamine started soon after its introduction in 1970. Soldiers returning from Vietnam who received ketamine as an anesthetic reported vivid hallucinogenic experiences. It became linked with “intellectual hedonism” in the 1970s and 1980s, particularly in the United States, and the first reports of abuse by healthcare workers began to appear.20 Over the past decade, an increase in non-medical use of ketamine in Australia, Great Britain, Sweden, and the US (particularly in New York City) has been reported, with diversion from veterinary supplies a major source of obtaining the drug.1,21 There are two main groups of users, namely those who use in a solitary fashion seeking transcendental, psychedelic experiences and seeking spiritual growth, and those who use ketamine as a ‘“club drug” as part of the rave and circuit party scene. It is difficult to establish the true prevalence of ketamine use disorders as the users remain a mostly hidden group. One study21 in Britain reported that close to 30% of club-goers surveyed reported a lifetime use of ketamine. Another survey22 of mostly gay, Caucasian men who attended a “circuit party” in the New York City area in 1998 found that 86% of the 173 subjects reported drug or alcohol use at the party with ketamine being the second most common drug used (53%) after methylenedioxymethamphetamine (“ecstasy”; 71%). Several converging pieces of data point to ketamine having real addictive liability. These include positron emission tomography studies demonstrating that ketamine leads to increases in dopamine in the ventral tegmental area (VTA) in humans correlating with elevated mood23; ketamine induces increases in dopamine in the nucleus accumbens in humans24; ketamine induces self-administration in animal models25,26; repeated ketamine administration causes behavioral tolerance in animals27,28 and humans21; and heavy, habitual use of ketamine has been described in humans, including in anesthesiologists.29,30
Understanding ketamine’s addictive properties involves considering its mechanism of action. Ketamine is an arylcyclohexylamine and is part of the class of dissociative anesthetics, which also includes PCP (“angel dust”) and dextromethorphan. Its main receptor action is antagonism at the NMDA glutamate receptor complex at the same site as PCP, located inside the calcium channel leading to blockade of calcium influx through the channel.31 This action underlies its analgesic, dissociative, psychotigenic, psycho-spiritual, and neuroprotective properties. Ketamine mainly acts at the pre-frontal cortex (PFC) and limbic system, with the highest density of NMDA receptors being in the PFC and hippocampus.32Alcohol, as one of its several mechanisms of action, also antagonizes the NMDA receptor, and ketamine produces alcohol-like subjective effects in humans.33 In addition, ketamine has opioidergic effects (mu and sigma opiate agonism)16 contributing to its analgesic properties and stimulant-like properties by enhancing monoaminergic transmission (dopamine, norepinephrine, serotonin) through inhibition of re-uptake pumps.34 The above effects have led some to describe ketamine’s subjective state as “alcohol-like intoxication, cocaine-like stimulation, opiate-like calming, and cannabis-like imagery.”35
Next, it is first important to look at the biologic underpinning of the addicted state. Two effects that likely contribute significantly to the addicted state are changes in midbrain dopamine as well as PFC dopamine and glutamate function. Damage to the dopamine system leads to decreased dopamine receptor density and release in the nucleus accumbens and PFC, diminishing the ability of dopamine to signal novel salient events, leading to under-excitability to biologically relevant stimuli.36,37 As addiction progresses, the neurocircuity of the reward pathway becomes corrupted, re-organized, and dysregulated whereby the behavioral system changes from a dopamine-oriented one in the nucleus accumbens (involved in the acute high and the initiation of learning and conditioned responses) to a glutamate-based system in the PFC (especially the anterior cingulate and orbitofrontal cortex) marked by altered glutamatergic transmission in projections from the PFC to the nucleus accumbens.38 Specifically, the system becomes hyperexcitable to drug-conditioned cues and under-excitable to biologically oriented ones. As part of these dopaminergic and glutamatergic changes, pharmacotherapy development of anti-addictive agents is currently focusing on agents that can strengthen the saliency of natural reinforcers, such as enhancing dopamine function, and agents that can alter the dysfunctional response to conditioned cues (either drug related or biologically relevant) by altering glutamatergic transmission.
Along the lines of hyperglutamatergic states being associated with addiction, it is key to consider that subanesthetic doses of NMDA antagonists (ie, ketamine) may actually enhance glutamatergic transmission by disinhibiting glutamate release, shunting glutamate to the other glutamatergic receptors other than NMDA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], kainite, and the metabotropic G protein coupled glutamate receptor) and causing a hyperglutamatergic state.15 One may ask how this is possible and what is its significance. There is some evidence to suggest that NMDA receptor blockers may antagonize γ-aminobutyric acid (GABA) neurons with a greater potency than their inhibition at the NMDA receptor. The NMDA antagonism may therefore diminish activation of GABA inhibitory neurons, with a diminution of cortical extracellular GABA levels,39 which in turn would decrease GABA’s normal inhibition of glutamate neurons, causing a net disinhibition of glutamate neurons and an increase in glutamatergic transmission in non-NMDA glutamate receptors.40 In turn, cortical glutamatergic activation stimulates monoaminergic terminals within the cortex, limbic system, midbrain, and brainstem.15As part of this, extracellular dopamine levels are increased in reward-related areas (ie, VTA and nucleus accumbens) thereby likely explaining ketamine’s addictive liability. Given this, one can ask how we can understand a possible explanation—biologic or otherwise—for ketamine’s putative anti-addictive properties.
Anti-Addictive Properties
Brief History of the Use of Hallucinogens to Treat Addictive Disorders
Ketamine is not the first psychedelic agent to be tested to treat addictive disorders. In the 1950s and 1960s, serotonergic hallucinogens (predominantly d-lysergic acid diethylamide [LSD]; “acid”) were applied to patients with addictive disorders, mostly alcohol dependence and to a lesser degree opiate dependence. The most prominent researcher who studied this application was Humphrey Osmond, MD. He, in conjunction with Abram Hoffer, MD,41 treated >1,000 alcoholics using high-dose LSD. Their initial mechanistic hypothesis was based on aversive counterconditioning where they likened the intense LSD experience to the frightening altered state seen in the delirium tremens, which, in their experience, often served as a transformative, near-death (“bottoming out”) state that led to a sober conversion. However, soon after treating alcoholic patients with LSD in highly controlled environments paying careful attention to set and setting, they changed to a more positivist paradigm where they described that such agents had the capacity to produce a transcendental feeling of unity with the world, personal insights, self-understanding, increased sense of responsibility to self and others, and spiritual enlightenment.41 They reported high success rates including improved rates of abstinence, but the research was methodologically flawed with no randomization, no placebo controls, lack of blind raters, the use of unsophisticated severity measures, inadequate diagnostic specificity, inclusion of co-occurring psychiatric and substance use disorders (SUDs) other than alcohol, inadequate informed consent, and inadequate follow up.
Other studies looking at LSDs effect in alcoholism varied widely from astonishingly positive results to worsening of the alcoholism, depending on the design of the study and the set and setting. Unfortunately, almost all studies were methodologically flawed, leaving others unable to determine what if any effect might have existed.42However, this has laid the groundwork for current studies using these and similar agents (ie, ketamine) to determine if there is a true treatment efficacy signal. The correct methodology would have to include randomization, placebo control, use of specific diagnoses using validated measures (ie, Structured Clinical Interview for theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition), inclusion of severity measures, standardized psychotherapy dose, objective “blind” raters, and having adequate follow up.43
Current Use of Ketamine to Treat Addictive Disorders
The first psychiatrist to rigorously study the potential of ketamine to treat addictive disorders was Evgeny Krupitsky, MD, PhD. In 1985, he developed a technique using ketamine—ketamine psychedelic psychotherapy (KPT)—to treat patients with alcohol use disorders.2 Similar to Osmond, he first conceptualized an aversive counter-conditioning model utilizing preparation and suggestion in combination with the altered state of consciousness induced by ketamine to induce and amplify a negative psychological state paired with the continued negative consequences of alcoholism. It is worth considering a model of a pharmacologically initiated, precipitated or enhanced “hitting of rock bottom.” In the addiction field, we often hear the adage of needing to hit “rock bottom” before the initiation of sobriety. This event may be similar to near-death experiences, which have been described as triggering transformative and positive life changes,44and may serve to initiate a rapid change to a sober state. In Alcoholics Anonymous (AA), it is taught that this is what is needed before the individual can really get sober. Although this may be true for some, “rock bottom” for other addicts may be death. Rather than disengaging from the patient and waiting for this to happen, one may wonder if it could be possible to chemically induce or enhance this phenomenon, thereby speeding up the process to recovery initiation.
From an adverse psychiatric perspective, ketamine can induce frank psychotic states (with both positive and negative symptoms), dissociation, and cognitive impairment (including impaired attention, memory, and performance).21 However, this does not capture the phenomenology of the profound psychological, mystical, and spiritually oriented altered state of consciousness induced by ketamine. It is useful to define what is meant by “spirituality,” a broad construct that encompasses both faith and meaning.45,46 Faith can be defined as the belief in and relationship with a transcendent higher power, which does not have to be identified as “God” and does not have to occur through participation in traditional organized religion, while meaning can include feeling that one has a unique purpose in life and can achieve a sense of fulfillment and “even transcendence through connectedness with something greater than one’s self.”47 The spiritual types of experiences induced by ketamine, separate from its dissociative properties (ie, out of body experiences) and perhaps overlapping with and traditionally understood as psychotic phenomenon, can include feelings of ego dissolution and loss of identity; experience of psychological death and re-birth; emotionally intense visions and dream-like states; enhanced insight/self-reflection and meaning in life; and feelings of unity with humanity, nature, the universe and God.2 These effects led Krupitsky to change his model from an aversive one to an existential, spiritual model within a positivist framework with the goal of inducing peak/transcendental states to effect conversion to a sober state in addicted patients. He extended his research to include patients with opiate addiction, and from 1985 until 2002 treated >1,000 patients with addictive disorders using KPT.2 KPT includes three stages, namely, preparation, administration, and integration. The preparatory phase includes 5–10 hours of suggestive psychotherapy where the patient is told the ketamine experience may induce important insights related to personal problems, value systems, and the meaning of their lives and that these insights may lead to changes associated with sobriety. During administration, the patients receive 2–2.5 mg/kg intramuscular (IM) of ketamine with onset of action in 10 minutes and the duration of the experience lasting approximately 1 hour. Patients are told they will enter an altered state and to surrender to the experience. They lie supine with eyeshades and headphones, hearing pre-selected music. In the integration phase, a combination of individual and group psychotherapy is administered over time to help subjects interpret and integrate the ketamine experience with the goal of leveraging the experience to effect behavioral changes associated with abstinence. The therapist assists in the integration of the spiritual transformation.2
In a controlled trial48 of patients with alcohol dependence, a one-time dose of ketamine as part of KPT (added to standard psychosocial care for patients with alcohol dependence in Krupitsky’s treatment center) added considerable benefit to the standard treatment. Total abstinence from alcohol for >1 year was reported in approximately 66% (73 out of 111) of alcoholic subjects in the KPT group compared to 24% (24 out of 100) in the conventional treatment control group (P<.01). In addition, based on psychological measures administered in the study, the group receiving KPT had positive changes in their emotions and perception of themselves and others, positive changes in life values and purposes, important insights into the meaning of life, and increased spiritual development compared to the placebo group. Krupitsky further tested the use of KPT in patients with heroin dependence in a double-blind placebo-controlled, randomized trial49 where 70 detoxified heroin-dependent subjects were randomly assigned to two groups—one with a one-time hallucinogenic dose of ketamine (2 mg/kg IM), versus one group with a control, non-hallucinogenic dose (0.2 mg/kg IM). All patients received the same standardized dose of psychotherapy during the preparatory and integration phases. The experimental group had significantly higher rates of abstinence at multiple prospective points in time out until 2 years follow-up, compared to the active placebo group (Table 1).49 As with the above alcohol studies, compared to the control group, the experimental group also displayed improvements in other dimensions of psychological well being including decreased levels of anxiety/depression, enhanced understanding of the meaning and purpose of life, and increased spiritual development. In this study,49 there were no significant adverse physiologic or psychological events and no subjects became addicted to ketamine.
In these studies, it is unclear as to the exact nature of the pharmacologic or psychosocial component of substance abuse treatment before receiving KPT and especially following the administration stage. For example, in the above study with heroin dependent subjects,49 the integration phase appears to only consist of 5 hours of psychotherapy “carried out within several days after the KPT session” to help “integrate the insights from the ketamine session into everyday life.”49 It is not clear as to exactly what this entails and how such a brief “existentially oriented psychotherapy” intervention could promote long-term abstinence up to 2 years follow up. The follow-up treatment is not described in any detail and it is unknown if these patients received standard evidence-based addiction pharmacologic treatments, such as naltrexone (opiate agonist or partial agonist treatment is banned in Russia), or psychosocial ones, such as motivational interviewing, relapse prevention, contingency management, community reinforcement, or coercion. Furthermore, this was described as a double-blind study. However, there is no description of the integrity of the blinding procedures in terms of any reporting of the percentage of accurate identification, by either subjects or experimenters, of whether the experimental or placebo dose of ketamine was administered. A complete hallucinogenic or psychedelic ketamine experience would seem easily discernible from one that is sub-hallucinogenic given the pronounced phenomenology of the experience. Without data on the blinding integrity, it is unknown how much of the treatment effect could be influenced by either subject or experimenter expectancy biases.
Potential Biologic Anti-addictive Mechanisms of Ketamine
Ketamine, Alcohol Dependence, and the NMDA Receptor
In addition to ketamine, there are other examples of NMDA antagonists that have been associated with anti-addictive effects in humans. One such example is memantine, although the studies have had small sample sizes and the efficacy data has been mixed. For example, in a study50 of frequent cocaine smokers, memantine failed to attenuate the subjective or reinforcing properties of cocaine use and was even associated with significant increases in the subjective effects of smoked cocaine. Regarding alcohol use in humans, memantine has been associated with a reduction in the level of alcohol craving preceding alcohol consumption in moderate drinkers but without diminishing the increase in craving following alcohol use.51
In a study52 of abstinent subjects with alcohol dependence, memantine diminished alcohol cue-induced craving in a dose-dependent manner. Finally, in a study53 of heroin dependent subjects, memantine was associated with modest reductions in the subjective but not reinforcing effects of heroin administration. It should be noted that memantine does not cause the pronounced altered states of consciousness seen with ketamine and so its anti-addictive properties can likely only be explained by its biologic mechanism. Other examples of anti-glutamatergic agents that have anti-addictive potential in humans include acamprosate (weak direct NMDA antagonism and direct interaction with the metabotropic glutamate receptor type 5, thereby indirectly acting as an inhibitory modulator at the NMDA receptor) for alcoholism,54 ibogaine (NMDA antagonism as one of its many receptor actions, although its exact anti-addictive mechanism remains unknown as 18-methoxycoronaridine, a congener of ibogaine, has anti-addictive properties without appreciably antagonizing the NMDA receptor) for opiate withdrawal,55lamotrigine (a glutamate release inhibitor) for alcoholism,56 and topiramate (AMPA/kainite receptor inhibitor) for alcoholism.57
Regarding alcohol use disorders in particular, ketamine’s action as an NMDA antagonist might be helpful at various stages of the illness. For one, we know that neurotoxicity associated with alcohol withdrawal such as seizures and the delirium tremens, are likely mediated by hyperglutamatergic states from both upregulation at the NMDA receptor and increase glutamate release.58,59Theoretically, it would make sense that administering an NMDA antagonist would suppress withdrawal by replacing the NMDA antagonist effect previously provided by alcohol, and acting like a replacement therapy. There is a growing literature to support the use of anti-glutamatergic agents to treat acute alcohol withdrawal.60Protracted withdrawal is another stage of illness that might benefit from modulation at the NMDA receptor. Acamprosate is an example of a pharmacotherapy for alcoholism that weakly suppresses acute alcohol withdrawal in humans61 but seems more effective when given in the time period initially following the cessation of acute withdrawal.62
Another strategy in alcoholism pharmacotherapy is prevention of disease progression, such as preventing the expression of ethanol abuse or dependence in those at high risk (ie, strongly positive family history); preventing the transition from alcohol abuse (ie, heavy social drinkers) to alcohol dependence, or preventing relapse in newly abstinent patients. There is evidence to suggest that alcohol’s NMDA antagonist properties mediate negative physiologic, subjective, and cognitive effects associated with high-dose ethanol intoxication that would normally relay an inhibitory feedback signal to stop drinking.60Furthermore, there is some evidence to suggest that healthy, at-risk individuals for alcoholism with positive family histories63and alcoholics in early recovery64demonstrate diminished sensitivity to biologic markers of heavy alcohol ingestion, which may constitute a deficit in the inhibitory feedback signal that would normally halt the progression to heavy drinking. Thus, an NMDA antagonist might theoretically be used to substitute, restore, or maintain the deficient inhibitory feedback signal.60 Ketamine administration to patients with alcohol dependence has been associated with pronounced cognitive impairment and sedation similar subjectively to heavy (ie, ≥8 standard drinks) alcohol ingestion and without causing craving for alcohol.65,66 Taken together, this suggests that the intoxicated state from ketamine’s NMDA antagonism might serve as an inhibitory feedback signal on drinking behavior in humans. This may serve as an aversive stimuli for preventing alcohol use disorders in vulnerable, at-risk populations; interrupting the transition from abuse to dependence; and preventing relapse in those in early recovery.
Ketamine, the NMDA Receptor, and Other Drugs of Abuse
Regarding the above data suggesting the efficacy of ketamine in an opiate-dependent patient population, it is worth considering ketamine’s action as a mu opiate agonist, even though its affinity for the receptor is only 20% compared to its affinity for the NMDA receptor.67 Furthermore, ketamine, like d-methadone (NMDA antagonist properties) can inhibit the development of opiate tolerance and dependence in animals.68 How this translates clinically in humans is unclear. It is possible that this effect might prevent the expression of opiate dependence in vulnerable individuals and those with opiate abuse. However, it is unclear how this might constitute an anti-addictive effect in actively using opiate-dependent patients or how a one-time dose of ketamine (as in the above-mentioned ketamine study in heroin addicts49 could lead to higher abstinence rates relative to placebo up to 2 years follow up.
To try and understand more broadly how ketamine might have anti-addictive properties, one possibility is to consider the level of the reward system activated. For example, NMDA antagonists are reinforcing when injected into the PFC and nucleus accumbens in lab animals but not the VTA where they block the rewarding effects of direct electrical stimulation.69 Thus, the relative degree and variability by which ketamine might be acting in the critical neuroanatomic reward substrates in a given individual might make the difference in determining its relative addictive liability. Another factor might relate to dose. It may be that there is an optimal dose range that confers anti-addictive properties and, above this, the addictive properties start to predominate. Those who become addicted to ketamine tend to continue to escalate their dose and in general use higher doses than those who use it intermittently (ie, occasional use for spiritual enhancement). It may be that higher doses of ketamine lead to a greater relative increase in glutamate transmission compared to lower doses and as stated previously enhanced cortical glutamatergic activation causes dopamine elevation in the VTA and nucleus accumbens, a property associated with addictive liability. One simplistic heuristic divide might be that antagonist effects at the NMDA receptor might confer the relative anti-addictive properties of ketamine and its hyperglutamatergic effects may confer its addictive liability. Thus, the relative balance or ratio of NMDA blockade to enhanced glutamate transmission (which may be a function of dose, route of administration, relative potency at the NMDA receptor, and pharmacokinetic/pharmacodynamic inter-individual variation) may explain why some NMDA antagonists are more reinforcing than others and why some may have greater anti-addictive properties.
Indirect Mechanism: Antidepressant Effects of Ketamine
Rather than a direct anti-addictive effect of ketamine on substance abuse behavior, it may be that ketamine indirectly diminishes addiction by its acute antidepressant properties. As described above, ketamine is emerging as a promising and novel treatment for depressive spectrum disorders.17-19 In the above study49 utilizing KPT in heroin-dependent patients, both high- and low-dose ketamine groups reported significant reductions in depressive symptomatology. There is some evidence to suggest that in patients with depression and co-occurring SUDs, improvements in depression with anti-depressant treatment can be associated with decreased substance abuse. For example, in a 12-week, placebo-controlled trial of imipramine treatment in a cohort of actively drinking patients with alcohol dependence and comorbid depression, McGrath and colleagues70 reported that although imipramine did not have a direct effect on drinking behavior, it was associated with a decrease in depressive symptoms, and the patients with improved mood demonstrated a more pronounced reduction in alcohol intake. In addition, it has been reported that elevated depressive symptoms in patients with heroin dependence may serve as a trigger for relapse in abstinent individuals.71Further research would be necessary to discern if ketamine’s effects on addictive behavior is independent of its effects on depression.
Putative Psycho-Spiritual Anti-Addictive Mechanisms
Perhaps ketamine’s anti-addictive properties have little or nothing to do with its biologic properties and everything to do with its pronounced psychological and spiritual (psycho-spiritual) effects. Alternatively, it may be that its biologic reinforcing properties may be countered by anti-addictive psycho-spiritual effects.
In Krupitsky’s work he lists several psycho-spiritual effects, induced by ketamine’s altered state, that might underlie its anti-addictive properties including…
…important insights into existential problems and the meaning of life, transformation of one’s life value system, a change of view of one’s self and the world around, insight into life and death, enhancing personal growth and self-awareness, increase in creative activities, stabilizing positive psychological changes, broadening of spiritual horizons, and harmonization of a person’s relationship with the world and other people.2
Although this is highly speculative, several aspects here are worth exploring in some detail. For one, the added capacity for insight, self reflection, and learning as it relates to changing addictive behavior are important because these are factors we seek to change in addiction psychotherapy especially in addressing resistance and denial. Another potential factor relates to the phenomenon of ego dissolution or death and then re-birth. There are similarities to this substance-induced state and reports of “near death” experiences, which can be frightening but are usually marked by feelings of calm and peace; transcendent spiritual states are common in these experiences, with past memories often organized into a life review, including important figures from one’s past, and archetypal images of God often experienced as an “ocean of luminescent white light.”2As mentioned above, these near-death experiences often trigger transformative and positive life changes.44 This death-re-birth experience in the context of enhanced spirituality has some parallels to the core treatment philosophy inherent in AA and other 12-step treatments whereby addicts undergo a spiritual conversion with a concomitant and rapid transformation in identity from an “addict” to one in “recovery.” In fact, Bill Wilson, one of the founders of AA, underwent several sessions of LSD psychotherapy in the 1950s and likened the experience to his spiritually redemptive experiences that led him to sobriety and to form AA.72 He felt so strongly about this, he attempted to introduce LSD use into the bylaws of AA, an attempt rejected by the board at the time. Predating this, both James and Jung recognized the importance of spiritual factors in treating addiction. James famously commented, “the best cure for dipsomania is religiomania” and Jung stated “Spiritus contra spiritum” (ie, spirituality combats alcoholism).72
The idea that spirituality can be a useful anti-addictive tool, as seen in AA, is worth considering in the two instances in the US where a particular religious group is legally allowed to use a schedule I serotonergic hallucinogen or sacrament—the use of peyote in the Native American Church (NAC) and the use of ayahuasca (dimethyltryptamine as the psychoactive compound) in the Brazilian syncretic religion, the Uniao do Vegetal (UDV). These religious groups have similarities to AA (although in AA the spiritual state is not drug induced), where spirituality is combined with social factors such as group cohesion and coercion to effect sobriety.73 There are anecdotal reports of low rates of addiction in the NAC and UDV, where substances (ie, alcohol, nicotine, illicit drugs), other than their respective sacramental hallucinogens, are prohibited.74 Formal epidemiologic study of the prevalence of substance use disorders in these two groups would be an important starting point. If the NAC and UDV were found to have significantly lower rates of addiction compared to the general population or some appropriate comparison group (ie, the NAC versus other Native American groups), one could then speculate on possible etiologies such as biologic effects of the prescribed sacramental hallucinogens; psychosocial factors, such as group cohort effects (ie, proscribed alcohol/drug abuse, cohesion, shared sober identity formation/maintenance, enhanced spiritual or religious affiliation); or some combination of factors.
It would be naïve to think that a one-time experience with ketamine, however profound, could effect long-term sobriety, especially without linkage to after-care and psychosocial treatment. For some addicts, a spiritual conversion experience can last a lifetime. However, for the vast majority, they need multiple repeated attempts included with 12-step treatment. Thus, it may be that repeated dosing is necessary, similar to an electroconvulsive therapy type model. Biologically, it would seem that if ketamine can truly have anti-addictive properties by optimally modulating or re-altering glutamatergic imbalance in the addicted state, it would need to be dosed repeatedly. It may be that in the use of ketamine to treat addictive disorders, multiple sessions are needed, especially for treatment refractory patients. There is some evidence to support this. In a randomized trial of 59 detoxified heroin dependent subjects, subjects who received three sessions of ketamine administration as part of KPT, at monthly intervals had higher abstinence rates at 1-year follow up compared to those who only had one initial ketamine experience, this amounting to 50% versus 22% (P<.05).75 It has been reported that after the use of certain hallucinogens (both serotonergic and NMDA antagonist types), there is a “psychedelic afterglow” inducing positive psychological changes that can last for days to weeks.76 It may be necessary to repeat the experience in a controlled carefully prepared environment to consolidate the new changes/learning. Furthermore, the dose of the experience needs to be sufficiently intense or of a “peak” quality to have a higher likelihood of effecting change. Prior and current research with serotonergic hallucinogens has shown a clear relationship between attaining “peak” or “transcendental mystical” states and resulting in positive and lasting changes.77,78
Conclusion
In the US, ketamine administration in humans has almost exclusively been used in psychiatric research as a psychopharmacologic probe to understand the neurobiology of psychiatric disorders, in particular the glutamate hypothesis of schizophrenia, and the effects of drugs of abuse, in particular alcohol. A unique aspect of ketamine, unlike all of the serotonergic hallucinogens, is that it is a schedule III drug, currently available for off-label purposes other than for anesthesia (Table 2). As such, it is currently available in the US for legal use in the treatment of addiction, pain syndromes, and MDD where its ability to induce immediate antidepressant effects seems most promising and may constitute a truly novel psychopharmacologic property.79However, the data to support the use of ketamine to treat addictive disorders does not currently rise to the level of unequivocally justifying its use as off-label treatment in clinical settings. More research would be needed, ultimately with phase III trials, demonstrating a clear and sufficient treatment effect. Its use would be similar to the current use of g-hydroxybutyrate, another schedule III “club drug” with addictive liability but one with therapeutic utility—treatment of cataplexy associated with narcolepsy and other sleep disorders in this case.1 If the application of ketamine, in conjunction with addiction psychotherapy, turns out to be an effective and reliable treatment for SUDs, it would constitute a novel psychopharmacologic/psychosocial paradigm of care for addicted individuals, although one where the risks of addiction to the substance itself would have to be carefully considered. PP
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