Bramhananda marga
IPUB or BRANMA Clinical pathways
by Dr.Hariharan Ramamurthy
Alcohol and illicit drug use is an escalating and complex global public health burden. In 2010, the global prevalence of alcohol and illicit drug use disorders were 9.6 and 10.9% respectively (1). Mortality rates have risen to epidemic proportions in some countries due to increasing prevalence of opioid use. For example, the United States, which accounts for 25% of global overdose mortality, has experienced an 88% increase in opioid overdose deaths each year from 2013 to 2016 (2, 3). Substance use disorders (SUDs) include cognitive, behavioral, and physiological symptoms. Hallmark signs of SUDs include impaired control, cravings, social impairment, risky use, and withdrawal symptoms. Withdrawal from heavy, prolonged alcohol use can result in life-threatening seizures and autonomic instability in addition to hallucinations, severe agitation, and anxiety. Physiologic response to opioid withdrawal can also be severe, and includes nausea, emesis, diarrhea, myalgias, intractable lacrimation and rhinorrhea, fevers, dysphoria and insomnia. Fear of these withdrawal symptoms is frequently cited as a barrier to treatment and reason for relapse (4).
Despite the high prevalence and substantial societal burden of SUDs, effective pharmacotherapy options are limited. FDA-approved medications for alcohol use disorder include naltrexone (an opioid receptor antagonist) and acamprosate (a GABA-agonist) which have been shown in meta-analyses to modestly reduce rates of return to heavy drinking (5), and disulfiram and nalmefene (approved in the European Union although not FDA-approved in the U.S.) have shown overall Hedge's g effect sizes of 0.58 and 0.33, respectively (6, 7). Treatment options for opioid dependence include full opioid agonists (methadone), partial agonists (buprenorphine) and antagonists (naltrexone). For cannabis and stimulant use disorders, there are no FDA-approved treatments (8). With limited treatment options, a myriad of non-FDA approved medications (e.g., gabapentin, clonidine, bupropion) are tried as standalone pharmacotherapies and in conjunction with behavioral interventions.
Ketamine
How exactly does Ketamine affect memory formation? Scientists have demonstrated that ketamine promotes the growth of new neural connections in the brain which is essential in the process of learning and forming new memories. In people who are depressed or have an alcohol use disorder, it is thought that these processes are impaired. That’s where ketamine comes in. It can help people be more receptive to new information, increase their planning skills and break memories associated with drinking behavior. The best part? All of these effects could then enhance the effects of traditional psychological therapies which work to treat the underlying causes of why the addiction developed in the first place.
Preliminary evidence suggests that ketamine may be effective in addiction.
Potential interacting mechanisms are enhancing neurogenesis and psychological therapies.
Ketamine may reduce depressive symptoms in a risky window for addiction relapse.
Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy.
Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed.
Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs
Results and conclusion: Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research.
Front Psychiatry. 2018; 9: 277.
Published online 2018 Jul 24. doi: 10.3389/fpsyt.2018.00277
PMCID: PMC6094990
PMID: 30140240
Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review
Jennifer L. Jones,1,* Camilo F. Mateus,1 Robert J. Malcolm,1 Kathleen T. Brady,1,2 and Sudie E. Back1,2
Neurotox Res. 2017 Jul;32(1):121-133. doi: 10.1007/s12640-017-9718-9. Epub 2017 Apr 18.
Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia.
Abstract
Ketamine may prove to be a potential candidate in treating the widespread drug addiction/substance abuse epidemic among patients with schizophrenia. Clinical studies have shown ketamine to reduce cocaine and heroin cravings. However, the use of ketamine remains controversial as it may exacerbate the symptoms of schizophrenia. Therefore, the aim of this study is to characterize the effects of ketamine on drug addiction in schizophrenia using the methylazoxymethanol (MAM) acetate rat model on operant IV methamphetamine (METH) self-administration. MAM was administered intraperitoneally (22 mg/kg) on gestational day 17. Locomotor activity test and later IV self-administration (IVSA) were then performed in the male offspring followed by a period of forced abstinence and relapse of METH taking. After reaching stable intakes in the relapse phase, ketamine (5 mg/kg) was administered intraperitoneally 30 min prior to the self-administration session. As documented previously, the MAM rats showed a lack of habituation in the locomotor activity test but developed stable maintenance of METH self-administration with no difference in operant behaviour to control animals. Results show that ketamine treatment significantly reduced the METH intake in the control animals but not in MAM animals. Ketamine effect on METH self-administration may be explained by increased glutamatergic signalling in the prefrontal cortex caused by the N-methyl-D-aspartate antagonism and disinhibition of GABA interneurons which was shown to be impaired in the MAM rats. This mechanism may at least partly explain the clinically proven anti-craving potential of ketamine and allow development of more specific anti-craving medications with fewer risks.
Ketamine has been shown to enhance synaptogenesis at rest (independent of glutamate
activation) through 1) inhibition of eukaryotic elongation factor 2 (eEF2) kinase, 2) desuppression of eEF2, and 3) increased BDNF translation.[41] Additionally, selective genetic
deletion of pyramidal neurons’ GluN2B subunits – which are abundant in extrasynaptic
Abdallah et al. Page 4
Depress Anxiety. Author manuscript; available in PMC 2017 August 01.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
NMDA receptors – mimics the antidepressant and synaptic effects of ketamine.[53]
Together, these neuroplasticity-related processes culminate in increases in AMPA receptors,
synaptic strength, and synaptogenesis (Figure 2); leading to a rapid reversal of stress and
depression-induced neuronal atrophy.
AnadamideUltra low dose naloxone
CBD/THC
Herbal mix
Ibogaine
Ayahuasca
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