Category Archives: Addiction

Acute cannabidiol administration reduces alcohol craving and cue-induced nucleus accumbens activation in individuals with alcohol use disorder: the double-blind randomized controlled ICONIC trial

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“Although alcohol use disorder (AUD) is highly prevalent, only a few medications are approved for its treatment leaving much room for improvement. Cannabidiol (CBD) might be a particularly promising candidate, with preclinical data suggesting that CBD is effective in targeting AUD symptoms and disease processes that drive alcohol use and relapse, due to its anti-craving, stress-reducing, and anti-compulsive effects.

Here we report data from the double-blind randomized controlled ICONIC trial that compared the effects of a single dose of 800 mg cannabidiol against placebo (PLC) in N = 28 individuals with AUD. Cue-induced nucleus accumbens (NAc) activation, alcohol craving during a combined stress- and alcohol cue exposure session, as well as craving during an fMRI alcohol cue-reactivity task and CBD plasma levels served as outcomes.

Individuals receiving CBD showed lower bilateral cue-induced NAc activation (tleft_NAc(23) = 4.906, p < 0.001, d = 1.15; tright_NAc (23) = 4.873, p < 0.001, d = 1.13) and reported significantly lower alcohol craving after a combined stress- and alcohol cue exposure session (Fgroup(1,26) = 4.516, p = 0.043, eta2 = 0.15) and during the fMRI cue-reactivity task (Fgroup(1,24) = 6.665, p = 0.015, eta2 = 0.23). CBD levels were significantly higher in the CBD group (t(25) = 3.808, p < 0.001, d = 1.47) and showed a significant negative association with alcohol craving during the cue exposure experiment (r = -0.394, pFDR = 0.030) and during fMRI (r = -0.389, pFDR = 0.030), and with left and right NAc activation (rleft_NAc = -0.459, pFDR = 0.030; rright_NAc = -0.405, pFDR = 0.030).

CBD’s capacity to reduce stress- and cue-induced alcohol craving and to normalize NAc activation – a region critical to the pathophysiology of AUD – contribute to understanding the neurobiological basis of its clinical effects and support its potential as a treatment option for AUD.”

https://pubmed.ncbi.nlm.nih.gov/39668256/

“In summary, the observed potential of CBD to reduce cue-induced NAc activity and alcohol craving, together with its good safety profile, supports the potential of CBD to treat individuals with AUD. New pharmacological treatment options that target central neurobiological disease mechanisms and core symptoms of AUD, such as craving, could complement existing treatment options and reduce relapse risk and the enormous disease burden inflicted by AUD.”

https://www.nature.com/articles/s41380-024-02869-y

Cannabinoid for alcohol use disorder

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“Several pieces of evidence have implicated the endocannabinoid system on dopaminergic mesolimbic brain reward, as well as the potential role of cannabinoid receptors CB1 and CB2 on modulation of reinforced properties of drug abuse and consequently to the treatment of substance use disorder, including alcoholism.

Moreover, growing evidence has been proposed that cannabis or cannabinoid compounds may be helpful to treat alcohol use disorder (AUD).

Cannabis is prevalent among individuals who also consume alcohol. While some authors reported that cannabis may be a promising candidate as a substitute medication for AUD, some studies have demonstrated that concomitant use of alcohol and cannabis may increase the risk of adverse outcomes.

Considering that advances in the legalization and decriminalization movements regarding cannabis have led to increased availability worldwide, the current chapter aims to provide evidence on the benefits and risks of combining alcohol and cannabis, as well as the potential therapeutic use of cannabinoid compounds in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/39523058/

“Growing studies have indicated that medicinal cannabis could be reasoned as a substitute therapy for alcohol, especially among individuals who are trying to reduce drinking behavior. Based on these premises, medicinal cannabis might be safer and also produce less social harms, for this reason some studies have been pointed as a good candidate for substitute medication for alcohol.”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224001089?via%3Dihub

Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review

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“Interest in cannabinoids’ therapeutic potential in mental health is growing, supported by evidence of the involvement of the endocannabinoid system in psychiatric disorders such as anxiety, depression, and addiction.

While the major cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have been more extensively researched, approximately 120 minor cannabinoids from the cannabis plant have been identified. Although some displayed promising pharmacological profiles, research on their application for psychiatric disorders is fragmented.

This systematic review evaluates, for the first time, both preclinical and clinical studies exploring minor cannabinoids’ therapeutic potential in psychiatric disorders. 22 preclinical studies and one clinical study were included, investigating various minor cannabinoids in substance use disorders, anxiety disorders, depressive disorders, trauma and stressor-related disorders, psychotic disorders, neurodevelopmental disorders, and eating disorders. Despite the heterogeneous results and the moderate to high risk of bias in several articles, certain compounds demonstrate promise for further investigation.

Δ8-tetrahydrocannabidivarin (Δ8-THCV) exhibited potential for nicotine addiction; Δ9-tetrahydrocannabidivarin (Δ9-THCV) for psychotic-like symptoms; cannabidiolic acid methyl ester (CBDA-ME) alleviated anxiety and depression-like symptoms, and cannabidivarin (CBDV) autism spectrum disorder-like symptoms.”

https://pubmed.ncbi.nlm.nih.gov/39541799/

https://www.sciencedirect.com/science/article/pii/S0924977X24007508?via%3Dihub

Effect of cannabis use history on postoperative opioid utilization in lumbar fusion patients: an American retrospective study

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“Study design: A retrospective cohort study.

Purpose: To examine the effect of cannabis use history on postoperative opioid utilization in patients undergoing one- to three-level lumbar fusion for degenerative spine disease.

Overview of literature: Strategies to minimize dosing and chronic opioid use are needed for spine surgery given their widespread prescription for postsurgical pain management.

Methods: In this database study, medical coding was used to identify patients who had undergone one- to three-level lumbar fusions between 2012 and 2021. Propensity score matching was used to create two equal cohorts with respect to cannabis use history. Opioid utilization rates (morphine milligram equivalents [MME]/day) and overuse rates at 6 months post-index procedure were assessed. All pvalues <0.05 were considered statistically significant.

Results: Following examination of 153,500 patient records, 1,216 patients were matched into cannabis user and non-cannabis user cohorts. Cannabis users had lower rates of opioid utilization compared to non-cannabis users as early as 2 months after fusion (47.7% vs. 41.1%, p <0.05), a relationship which persisted at 6 months (46.2% vs. 37.7%, p <0.01). Additionally, cannabis users had lower rates of high-dose opioid utilization (≥100 MME per day) during the initial 14-30 days following surgery (6.91% vs. 3.79%, p <0.05).

Conclusions: Patients with a history of cannabis use were less likely to be using opioids as early as 2 months postoperatively and had lower rates of high-dose opioid utilization in the immediate postoperative period. Physicians operating on these patients should consider their cannabis use patterns to provide appropriate titration of pain medication over time.”

https://pubmed.ncbi.nlm.nih.gov/39434224/

https://www.asianspinejournal.org/journal/view.php?doi=10.31616/asj.2024.0194

Proof of Concept for High-Dose Cannabidiol Pretreatment to Antagonize Opioid Induced Persistent Apnea

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“Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities.

CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone.

The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.”

https://pubmed.ncbi.nlm.nih.gov/39314412/

https://www.biorxiv.org/content/10.1101/2024.09.13.612358v1

“Naloxone is a life-saving medication that can reverse an overdose from opioids—including heroin, fentanyl, and prescription opioid medications—when given in time.”

https://www.cdc.gov/stop-overdose/caring/naloxone.html#:~:text=What%20is%20naloxone%3F,use%20and%20small%20to%20carry.

Cannabidiol Modulation of Nicotine-Induced Toxicity: Assessing Effects on Behavior, Brain-Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice

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“High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds’ potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward.

Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice.

In this context, the open-field behavioral test was specially conducted to assess CBD’s effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood’s metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function.

Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue’s systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).”

https://pubmed.ncbi.nlm.nih.gov/39297526/

https://onlinelibrary.wiley.com/doi/10.1002/jnr.25384

Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness

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“Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field.

The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs.

Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.”

https://pubmed.ncbi.nlm.nih.gov/39273354/

https://www.mdpi.com/1422-0067/25/17/9407

The neurobehavioural effects of cannabidiol in alcohol use disorder: Study protocol for a double-blind, randomised, cross over, placebo-controlled trial

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“Current treatments for alcohol use disorders (AUD) have limited efficacy. Recently, Cannabidiol (CBD) has been examined in a multitude of clinical settings. Preclinical and clinical results suggest that CBD might be particularly well suited for the treatment of AUD and may reduce alcohol cue and stress-induced craving and alcohol seeking. This study aims to investigate this new pharmacotherapy with a particular focus on neurobiological and physiological indicators of craving.

Methods: In this double-blind, within-subject, randomised, placebo-controlled, cross-over study, non-treatment seekers will be randomly allocated to three days of four 200 mg CBD gel capsules (800 mg/day) or placebo, with an 18-day washout period. Cognitive, clinical, and neuroimaging assessments will be completed during these three days. The CBD and placebo assessments will be compared.

The primary outcomes are i) BOLD signal as a proxy for regional activity during a cue reactivity and a fear response task measured with functional magnetic resonance imaging (fMRI), ii) heart rate variability and skin conductance levels as a proxy for psychophysiological responses to alcohol stimuli. The secondary outcomes are: i) neurometabolite levels (γ-Aminobutyric acid, ethanol, glutathione, and glutamate + glutamine (combined signal)) using magnetic resonance spectroscopy (MRS); ii) functional connectivity using resting state fMRI (rsfMRI); iii) executive functioning task results; iv) clinical outcomes such as craving, anxiety, and sleep. 

Discussion: This study will improve the understanding of the mechanisms of action of CBD and provide early signals of efficacy regarding the therapeutic potential of CBD in the treatment of alcohol use disorder.”

https://pubmed.ncbi.nlm.nih.gov/39252861/

“CBD could reduce alcohol craving and seeking due to moderating responses to alcohol and stress cues, normalising dysregulated neurobiological systems and/or improving relevant clinical characteristics that lead to relapse such as sleep and mood disturbances. Compared to other medications used for the management of addiction, CBD has been demonstrated to be particularly safe with less severe side effects and few contraindications which may lead to better treatment adherence. CBD may also offer potential protection from alcohol-related liver and brain damage due to anti-inflammatory and antioxidant properties. “

https://www.sciencedirect.com/science/article/pii/S2451865424000887?via%3Dihub

Alcohol Activates Cannabinoid Receptor 1 and 2 in a Model of Pathogen Induced Pulmonary Inflammation

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“Alcohol use disorder (AUD) is defined as patterns of alcohol misuse and affects over 30 million people in the US. AUD is a systemic disease with the epidemiology of acute lung injury and excessive alcohol use established in the literature. However, the distinct mechanisms by which alcohol induces the risk of pulmonary inflammation are less clear.

A compelling body of evidence shows that cannabinoid receptors (CB1R and CB2R) play a relevant role in AUD. For this study, we investigated the role of CBR signaling in pulmonary immune activation.

Using a human macrophage cell line, we evaluated the expression of CBR1 and CBR2 after cells were exposed to EtOH, +/- cannabinoid agonists and antagonists by flow cytometry. We also evaluated the expression of cannabinoid receptors from the lungs of adolescent mice exposed to acute binge EtOH +/- cannabinoid agonists and antagonists at both resting state and after microbial challenge via western blot, rt-PCR, cytokine analysis, and histology.

Our results suggest that EtOH exposure modulates the expression of CBR1 and CBR2. Second, EtOH may contribute to the release of DAMPs and other proinflammatory cytokines, Finally, microbial challenge induces pulmonary inflammation in acute binge EtOH-exposed mice, and this observed immune activation may be CBR-dependent.

We have shown that adolescent binge drinking primes the lung to subsequent microbial infection in adulthood and this response can be mitigated with cannabinoid antagonists. These novel findings may provide a framework for developing potential novel therapeutics in AUD research.”

https://pubmed.ncbi.nlm.nih.gov/39251147/

  • “Acute binge alcohol modulates the levels of cannabinoid receptor expression in the lung.
  • •Microbial challenge induces pulmonary inflammation in mice previously exposed to binge alcohol
  • •Excessive alcohol paired with microbial challenge contributes to the release of proinflammatory cytokines in the lung
  • •Cannabinoid receptor antagonists block alcohol-induced pulmonary inflammation”

https://www.sciencedirect.com/science/article/abs/pii/S0378427424010981?via%3Dihub


Multi-level therapeutic actions of cannabidiol in ketamine-induced schizophrenia psychopathology in male rats

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“Repeated administration of ketamine (KET) has been used to model schizophrenia-like symptomatology in rodents, but the psychotomimetic neurobiological and neuroanatomical underpinnings remain elusive. In parallel, the unmet need for a better treatment of schizophrenia requires the development of novel therapeutic strategies.

Cannabidiol (CBD), a major non-addictive phytocannabinoid has been linked to antipsychotic effects with unclear mechanistic basis. Therefore, this study aims to clarify the neurobiological substrate of repeated KET administration model and to evaluate CBD’s antipsychotic potential and neurobiological basis.

CBD-treated male rats with and without prior repeated KET administration underwent behavioral analyses, followed by multilevel analysis of different brain areas including dopaminergic and glutamatergic activity, synaptic signaling, as well as electrophysiological recordings for the assessment of corticohippocampal and corticostriatal network activity.

Repeated KET model is characterized by schizophrenia-like symptomatology and alterations in glutamatergic and dopaminergic activity mainly in the PFC and the dorsomedial striatum (DMS), through a bi-directional pattern. These observations are accompanied by glutamatergic/GABAergic deviations paralleled to impaired function of parvalbumin- and cholecystokinin-positive interneurons, indicative of excitation/inhibition (E/I) imbalance.

Moreover, CBD counteracted the schizophrenia-like behavioral phenotype as well as reverted prefrontal abnormalities and ventral hippocampal E/I deficits, while partially modulated dorsostriatal dysregulations.

This study adds novel insights to our understanding of the KET-induced schizophrenia-related brain pathology, as well as the CBD antipsychotic action through a region-specific set of modulations in the corticohippocampal and costicostrtiatal circuitry of KET-induced profile contributing to the development of novel therapeutic strategies focused on the ECS and E/I imbalance restoration.”

https://pubmed.ncbi.nlm.nih.gov/39242923/

https://www.nature.com/articles/s41386-024-01977-1