Category Archives: Addiction

Cannabidiol disrupts the reconsolidation of contextual drug-associated memories in Wistar rats.

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“In addicts, craving and relapse are frequently induced by the recall of memories related to a drug experience. Several studies have demonstrated that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to the pathological cycle of addiction.

Here we used drug-induced conditioned place preference (CPP) to investigate whether cannabidiol (CBD), a phytocannabinoid, given just after reactivation sessions, would affect reconsolidation of drug-reward memory, reinstatement of morphine-CPP, or conditioned place aversion precipitated by naltrexone in Wistar rats.

We found that CBD impaired the reconsolidation of preference for the environment previously paired with both morphine and cocaine. This disruption seems to be persistent, as the preference did not return after further reinstatement induced by priming drug and stress reinstatement.

Moreover, in an established morphine-CPP, an injection of CBD after the exposure to a conditioning session led to a significant reduction of both morphine-CPP and subsequent conditioned place aversion precipitated by naltrexone in the same context.

Thus, established memories induced by a drug of abuse can be blocked after reactivation of the drug experience.

Taken together, these results provide evidence for the disruptive effect of CBD on reconsolidation of contextual drug-related memories and highlight its therapeutic potential to attenuate contextual memories associated with drugs of abuse and consequently to reduce the risk of relapse.”

http://www.ncbi.nlm.nih.gov/pubmed/26833888

Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

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“In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction.

In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization.

Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could contribute to the specifically increased GluN1 expression observed in the hippocampus of cocaine-sensitized mice.”

http://www.ncbi.nlm.nih.gov/pubmed/26811312

http://www.thctotalhealthcare.com/category/addiction/

Opposite regulation of cannabinoid CB1 and CB2 receptors in the prefrontal cortex of rats treated with cocaine during adolescence.

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“The endocannabinoid system is implicated in the neurobiology of cocaine addiction, although it is not clear how cocaine regulates brain CB1 and CB2receptors, especially during adolescence, a critical moment for shaping adult response to drug use.

This study evaluated CB1 and CB2 protein levels in prefrontal cortex (PFC) and hippocampus (HC) by western blot analysis with specific and validated antibodies: (1) basally during adolescence (post-natal day PND 40, PND 47, PND 54), (2) by a sensitizing regimen of cocaine (15mg/kg, 7 d, i.p.) during different windows of adolescence vulnerability (PND 33-39, PND 40-46, PND 47-53), and (3) following repeated cocaine administration during adolescence (PND 33-39) in adulthood (PND 64).

The results demonstrated a dynamic and opposite basal modulation of CB1 and CB2 receptors in PFC and HC during adolescence. CB1 receptor levels were increased while CB2 receptors were decreased as compared to adulthood with asymptotes values around mid adolescence (PND 47) both in PFC (CB1: +45±22, p<0.05; CB2: -24±6%, p<0.05) and HC (CB1: +53±23, p<0.05; CB2: -20±8%, p<0.05).

Interestingly, cocaine only altered CB1(+55±10%, p<0.05) and CB2 (-25±10%, p<0.05) receptors when administered during early adolescence and only in PFC. However, the changes observed in PFC by repeated cocaine administration in adolescence were transient and did not endure into adulthood.

These results identified a period of vulnerability during adolescence at which cocaine dysregulated the content of CB receptors in PFC, suggesting an opposite role for these receptors in the effects mediated by cocaine.“

Prevention of drug priming- and cue-induced reinstatement of MDMA-seeking behaviors by the CB1 cannabinoid receptor antagonist AM251.

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“3,4-Methylenedioxymethamphetamine (MDMA), a methamphetamine (METH) derivative, exhibits METH-like actions at monoamine transporters and positive reinforcing effects in rodents and primates.
The purposes of the present study were to determine whether cross-reinstatement would be observed between MDMA and METH and if the cannabinoid receptor, a receptor known to play critical roles in the brain reward system, could modulate MDMA craving…
These findings show that MDMA has obvious addictive potential for reinstating drug-seeking behavior and that METH can be an effective stimulus for reinstating MDMA-seeking behaviors.
Furthermore, based on the attenuating effect of AM251 in the reinstatement of MDMA-seeking behaviors, drugs that suppress CB1 receptors may be used in treatment of MDMA dependence.”

Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala.

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“The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse.

The endogenouscannabinoid/type 1 cannabinoid receptor (eCB/CB1 ) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis.

Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats.

Here, we investigated the potential disruption of eCB/CB1signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2-3 weeks intermittent ethanol.

In the naïve rat BLA, the CB1agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity.

This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system.

In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms.

Notably, CB1 activation impaired ethanol’s facilitation of GABAergic transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action.

Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.”

Marijuana: A Fifty-Year Personal Addiction Medicine Perspective.

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“As of September 2015, the cultivation, possession, and/or use of marijuana is illegal under U.S. federal law as a Schedule I narcotic; however, it is legal in four states and Washington, D.C. Forty-six states allow some form of medicinal marijuana or decriminalization.

Marijuana has been used medicinally for thousands of years; Marijuana’s regulation by law enforcement in the U.S., rather than the medical community, led to an almost complete halt to academic and scientific research after the 1930s.

The late 1960s saw an upsurge in recreational marijuana use by middle-class youth, the majority of whom experienced minimal adverse effects aside from arrest and attendant legal complications.

Since the mid-1990s, the use of medicinal marijuana for certain conditions has gained increasing acceptance.

In the East, the feeling is primarily that marijuana continue to be proscribed. In the West, where clinicians must face the realities of medicalization, decriminalization, and/or legalization, as well as widespread recreational use, there is more of a movement to minimize adverse effects, particularly on youth.”

http://www.ncbi.nlm.nih.gov/pubmed/26757396

Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives.

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“Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids.

CONCLUSIONS:

Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/26728894

Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.

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“Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation.

Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson’s disease.

From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively.

Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection.

Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs.

Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output.

The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction.”

http://www.ncbi.nlm.nih.gov/pubmed/26638769

The prescription of medical cannabis by a transitional pain service to wean a patient with complex pain from opioid use following liver transplantation: a case report.

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Canadian Journal of Anesthesia/Journal canadien d'anesthésie

“The purpose of this case report is to describe a patient with a preoperative complex pain syndrome who underwent liver transplantation and was able to reduce his opioid consumption significantly following the initiation of treatment with medical cannabis.

CLINICAL FEATURES:

A 57-yr-old male with a history of hepatitis C cirrhosis underwent liver transplantation. Preoperatively, he was taking hydromorphone 2-8 mg⋅day-1 for chronic abdominal pain. Postoperatively, he was given intravenous patient-controlled analgesia through which he received hydromorphone 30 mg⋅day-1. Our multidisciplinary Transitional Pain Service was involved with managing his moderate to severe acute postsurgical pain in hospital and continued with weaning him from opioid medications after discharge. It was difficult to wean the patient from opioids, and he was subsequently given medical cannabis at six weeks postoperatively with remarkable effect. By the fifth postoperative month, his use of opioids had tapered to 6 mg⋅day-1 of hydromorphone, and his functional status was excellent on this regimen.

CONCLUSION:

Reductions in opioid consumption were achieved with the administration of medical cannabis in a patient with acute postoperative pain superimposed on a chronic pain syndrome and receiving high doses of opioids. Concurrent benefits of initiating medical cannabis may include improvements in pain profile and functional status along with reductions in opioid-related side effects. This highlights the potential for medical cannabis as an adjunct medication for weaning patients from opioid use.”

http://www.ncbi.nlm.nih.gov/pubmed/26507533

Addressing the stimulant treatment gap: A call to investigate the therapeutic benefits potential of cannabinoids for crack-cocaine use.

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“Crack-cocaine use is prevalent in numerous countries, yet concentrated primarily – largely within urban contexts – in the Northern and Southern regions of the Americas. It is associated with a variety of behavioral, physical and mental health and social problems which gravely affect users and their environments. Few evidence-based treatments for crack-cocaine use exist and are available to users in the reality of street drug use. Numerous pharmacological treatments have been investigated but with largely disappointing results.

An important therapeutic potential for crack-cocaine use may rest in cannabinoids, which have recently seen a general resurgence for varied possible therapeutic usages for different neurological diseases.

Distinct potential therapeutic benefits for crack-cocaine use and common related adverse symptoms may come specifically from cannabidiol (CBD) – one of the numerous cannabinoid components found in cannabis – with its demonstrated anxiolytic, anti-psychotic, anti-convulsant effects and potential benefits for sleep and appetite problems.

The possible therapeutic prospects of cannabinoids are corroborated by observational studies from different contexts documenting crack-cocaine users’ ‘self-medication’ efforts towards coping with crack-cocaine-related problems, including withdrawal and craving, impulsivity and paranoia. 

Cannabinoid therapeutics offer further benefits of being available in multiple formulations, are low in adverse risk potential, and may easily be offered in community-based settings which may add to their feasibility as interventions for – predominantly marginalized – crack-cocaine user populations.

Supported by the dearth of current therapeutic options for crack-cocaine use, we are advocating for the implementation of a rigorous research program investigating the potential therapeutic benefits of cannabinoids for crack-cocaine use.

Given the high prevalence of this grave substance use problem in the Americas, opportunities for such research should urgently be created and facilitated there.” 

http://www.ncbi.nlm.nih.gov/pubmed/26500166

http://www.thctotalhealthcare.com/category/addiction/