Category Archives: Addiction

Therapeutic potential of endocannabinoid system activation in opioid use disorder and pain

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“Introduction: Opioid use disorder (OUD) and chronic pain remain major global health challenges. Although opioid-based therapies provide effective analgesia, their long-term use is limited by safety concerns, dependence, and variable efficacy. Modulation of the endocannabinoid system (ECS) has emerged as a promising therapeutic strategy for pain management and opioid-related disorders.

Areas covered: This narrative review summarizes current evidence on ECS-targeted interventions for OUD, chronic non-cancer pain, and cancer-related pain. Relevant literature was identified through PubMed using search terms related to the ECS, cannabinoid receptors (CB1 and CB2), phytocannabinoids (Δ9 -tetrahydrocannabinol [THC] and cannabidiol [CBD]), synthetic cannabinoids, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors, and opioid – cannabinoid interactions. Particular emphasis is placed on mechanistic interactions between ECS and opioid signaling pathways, as well as evidence from preclinical and clinical studies evaluating therapeutic efficacy and safety.

Expert opinion: ECS modulation may alleviate pain, reduce opioid withdrawal symptoms, and improve affective outcomes. Interactions between cannabinoid and opioid receptors may produce synergistic analgesic effects while potentially mitigating opioid tolerance and dependence. However, clinical translation remains limited by small sample sizes, heterogeneous study populations, and variability in trial design. Well-controlled clinical trials are needed to establish optimal dosing strategies, evaluate long-term safety, and clarify the therapeutic role of ECS-targeted interventions in OUD and pain management.”

https://pubmed.ncbi.nlm.nih.gov/42295097

“The endocannabinoid system (ECS) represents a promising therapeutic target for opioid use disorder (OUD), chronic non-cancer pain, and cancer-related pain.”

“Cannabinoids (e.g., CBD and Δ9 -THC) exert analgesic and anti-inflammatory effects through CB1-mediated central mechanisms and CB2-mediated peripheral mechanisms.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2026.2690138

Selective opioid-sparing effects of cannabidiol on opioid analgesia in rats

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“Cannabidiol, a major non-psychoactive constituent of cannabis, has generated interest as a novel therapeutic for managing several pathological conditions including chronic pain and opioid use disorder.

Here, we evaluated the effects of cannabidiol (3.2 or 10.0 mg/kg) on the antinociceptive and the reward-related effects of the opioid analgesic oxycodone (0.56 mg/kg) in rats (male and female Sprague-Dawley) using an operant facial pain assay, locomotor activity monitoring, and the conditioned place preference paradigm.

Cannabidiol enhanced the antinociceptive effect of oxycodone without affecting oxycodone-induced rearing behavior, or the acquisition and expression of oxycodone conditioned place preference under the conditions tested.

Together, these findings suggest that cannabidiol potentiates the analgesic effects of oxycodone without affecting its reward-related properties. These results support the potential of cannabidiol as an adjunctive, opioid-sparing agent in pain management.

PERSPECTIVE: Opioids remain important for treating moderate to severe pain, but adverse effects and misuse liability limit their use. These preclinical findings suggest cannabidiol may enhance oxycodone antinociception under acute painful conditions, without increasing abuse-relevant effects under the conditions tested, supporting further study as an opioid-sparing adjunct.”

https://pubmed.ncbi.nlm.nih.gov/42219047

https://www.jpain.org/article/S1526-5900(26)00156-2/abstract

Medical Cannabis as an Opiate Alternative: A Prospective Observational Cohort Study

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“Opioid use for chronic pain has contributed to an epidemic of overdoses and deaths in the United States.

Some clinical studies suggest that medical cannabis may help alleviate pain and improve quality of life. However, cost can be a barrier to patients accessing medical cannabis.

This is the first prospective observational study evaluating medical cannabis as an alternative to opioids in a setting where cost was removed as a major barrier.

Methods: Twenty-nine patients were recruited from a university-based outpatient chronic pain clinic. Each patient underwent monthly pain assessments using the Numeric Pain Rating Scale (NRS). Daily opioid use, measured in morphine milligram equivalents (MMEs), was recorded and monitored over five months. Pain-related quality of life was assessed using the SF-36 Health Survey at baseline, and again at two and five months.

Results: Daily opioid use decreased from baseline to one month (from 46.8 MMEs to 16.2 MMEs, a 65% reduction), and this reduction was maintained through five months. The mean NRS score decreased by two points from baseline to one month (from 7.03 to 5.07; p < 0.0001), and this improvement was sustained at five months. The SF-36 Physical Functioning score increased from 15.3 at baseline to 21.4 at one month and was maintained at five months (p < 0.03 for both comparisons).

Conclusion: These results suggest that medical cannabis may be a useful adjunct therapy for reducing opioid use, relieving chronic pain, and improving health-related quality of life.”

https://pubmed.ncbi.nlm.nih.gov/42153072

“Opioids are associated with serious adverse events, including death, particularly at higher dosages or when used in combination with benzodiazepines.

In contrast, medical cannabis has not been associated with mortality from overdose. When used under appropriate medical supervision, medical cannabis may represent an effective adjunctive strategy for reducing opioid use among patients receiving long-term opioid therapy.

“Although cannabis has historically been characterized as a potential “gateway drug,” it may also serve as a harm-reduction tool for some patients seeking to reduce reliance on higher-risk opioid medications.”

https://www.cureus.com/articles/432327-medical-cannabis-as-an-opiate-alternative-a-prospective-observational-cohort-study#!

Cannabis for Harm Reduction: Exploring Mental Health and Other Motivational Factors among Adults at Risk for Alcohol Use Disorder in Florida

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“Background: Prior research has suggested that cannabis may serve as a safer alternative to alcohol, this study examined “marijuana” (THC-dominant cannabis) and cannabidiol (CBD) use as strategies to reduce alcohol consumption among adults who report harmful levels of drinking.

Method: Online surveys were distributed to 451 Florida adults (≥18 years) who consumed ≥5 alcoholic drinks weekly and reported any lifetime cannabis use. Measures included comorbid health conditions, alcohol use severity (Alcohol Use Disorder Identification Test [AUDIT]), depressive symptoms (PHQ-8), anxiety (GAD-7), post-traumatic stress symptoms (primary care post-traumatic stress disorder [PC-PTSD]), childhood trauma (Adverse Childhood Experience Questionnaire [ACE-Q]), and readiness to change (Readiness to Change Questionnaire [RCQ-12]). Chi-square and ANOVA examined differences across alcohol use risk groups; logistic regression identified factors associated with marijuana and CBD use for alcohol reduction.

Results: High (AUDIT scores ≥16) were found in 61.4% of males and 40.9% of females. Higher alcohol use risk was significantly associated with younger age, higher PHQ-8 and GAD-7 scores, greater ACE-Q scores, PTSD positivity, more health conditions, and higher readiness to change (p < 0.001). Marijuana (37.9%) and CBD (32.2%) were the most frequently reported alcohol-reduction strategies; higher alcohol use severity was linked to greater perceived effectiveness. Factors associated with marijuana use for alcohol reduction included higher PTSD scores (OR = 1.76), more comorbid conditions (OR = 1.17), action-stage readiness to change (OR = 1.47), and higher AUDIT scores (OR = 1.83). Factors associated with CBD use for alcohol reduction included higher ACE-Q scores (OR = 1.14), more comorbid conditions (OR = 1.18), action-stage readiness (OR = 1.50), and higher AUDIT scores (OR = 1.95).

Conclusion: These findings identify key clinical and motivational correlates of cannabis use for alcohol harm reduction, informing future intervention development.

Plain language summary

“This study found that individuals with severe alcohol problems, especially those with trauma and mental health conditions, frequently use cannabis to reduce drinking. Many perceive these strategies as effective, particularly when traditional treatments are inadequate or inaccessible. Public health efforts should recognize this growing interest in cannabis-based harm reduction and address the unmet needs of individuals who wish to reduce alcohol consumption, exploring alternative, evidence-based strategies to improve outcomes for high-risk groups and reduce the broader burden of alcohol-related harm.”

https://www.tandfonline.com/doi/full/10.1080/10826084.2026.2670620

Associations of Low-Level Prenatal Alcohol and Cannabis Exposure With Adolescent Cognitive Trajectories

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“Background: No studies have examined the differential and combined effects of prenatal alcohol and cannabis exposure (PAE/PCE) on longitudinal trajectories of adolescent cognitive development. Further, previous alcohol research is mixed, with some evidence for negative PAE effects on cognition and other studies reporting null or positive associations. This study examined associations between PAE, PCE, and growth trajectories of adolescent cognition in a large, diverse sample.

Methods: N = 11,029 adolescents from the Adolescent Brain Cognitive Development℠ Study completed the NIH Toolbox cognitive battery at baseline (Mage = 9.95), two-year follow-up (Mage = 11.95), and four-year follow-up (Mage = 14.07). Retrospective parent report of PAE and PCE was assessed at baseline. Univariate growth trajectories were estimated for cognitive measures: Pattern Comparison, Picture Sequence Memory, Oral Reading, Flanker Task, and Picture Vocabulary. Cross-product terms for PAE and PCE tested combined use.

Results: Most mothers reported no prenatal alcohol (n = 8257; 74%) or cannabis (n = 10,812; 94%) use. Overall, use was low: across pregnancy, women reporting any alcohol use averaged 33.31 drinks, and those reporting any cannabis use averaged 33.00 use occasions. Before including covariates, there were negative main effects of PCE and positive main effects of PAE on intercepts for all five cognitive domains. There was little evidence for PCE/PAE effects on slopes for cognition. After adding covariates, no negative effects of PCE remained. Small positive PAE effects on intercepts for multiple domains persisted. Cross-product terms for combined exposure were not significant.

Conclusions: Little evidence emerged for negative effects of low PAE, PCE, or combined exposure on adolescents’ cognitive development after accounting for sociodemographic factors. Light drinking in families with social features positively associated with cognitive ability may result in few negative consequences. This study is the first to demonstrate weak evidence for adverse differential and combined low-level PAE and PCE effects on the development of adolescent cognition.”

https://pubmed.ncbi.nlm.nih.gov/41947378

“Little evidence emerged for negative effects of low level prenatal alcohol, cannabis, or combined exposure on adolescents’ cognitive development after accounting for sociodemographic factors.”

https://onlinelibrary.wiley.com/doi/10.1111/acer.70297

Effect of cannabinol, tetrahydrocannabivarin and cannabidiol on voluntary alcohol consumption

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“Aims: Previous studies have demonstrated that the endocannabinoid system plays a significant role in the development of alcohol use disorder (AUD), and CB1 receptor antagonists/inverse agonists show promise as a novel AUD pharmacotherapy. However, these compounds failed in clinical trials due to the severe psychiatric side effects. Non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat AUD. The aim of this study was to test the potential of three phytocannabinoids in reducing alcohol consumption: CB1 receptor partial agonist cannabinol (CBN), neutral antagonist tetrahydrocannabivarin (THCV) and negative allosteric modulator cannabidiol (CBD).

Methods: Male Wistar rats were subjected to a long-term voluntary alcohol drinking procedure that lasted for several months. Thereafter, rats were given three once daily administrations of CBN, THCV, or CBD. Their side-effect profile was examined by recording changes in water consumption, body weight and locomotor activity. Ultrasonic vocalisations were recorded in alcohol-naïve group-housed rats to monitor if treatment induced discomfort, distress, or other changes in emotional states.

Results: Our data demonstrated that all phytocannabinoids reduced voluntary alcohol consumption; however, the compounds differed in their effectiveness and side-effect profile. Treatment with CBN and THCV reduced alcohol intake and alcohol preference and had a mild sedative effect. CBD had a minor effect on alcohol consumption, did not affect alcohol preference, reduced the locomotor activity and lowered the positive emotional states of rats. None of the compounds caused discomfort or distress.

Conclusions: We conclude that CBN and THCV may have potential in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/41947574

“Cannabis plants have long been used both medicinally and recreationally, mainly due to the psychoactive compound delta9-tetrahydrocannabinol (THC, a partial agonist of the CB1 receptor). However, the health benefits of these plants may be attributable to over a hundred of other, non-psychoactive compounds or their metabolites, collectively termed phytocannabinoids.”

“In summary, the present study demonstrated that CBN and THCV were more effective in reducing the maintenance of voluntary alcohol consumption and had a better safety profile compared to CBD. The effect of all three phytocannabinoids on alcohol consumption may be related to their action on the CB1 receptor.”

https://academic.oup.com/alcalc/article/61/3/agag019/8607733

Inhibitory effects of Δ8-tetrahydrocannabinol on nicotine metabolism and implications as a smoking cessation agent

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“Tobacco use remains the leading cause of preventable death worldwide. The major metabolic pathway for nicotine, the addictive component in tobacco, is via cytochrome P450 (CYP) 2A6-mediated metabolism to cotinine.

Cannabidiol has been shown to reduce cigarette consumption in vivo and inhibit CYP2A6-mediated nicotine metabolism in vitro. In the present study, Δ-8-tetrahydrocannabinol (Δ8-THC), an isomer of Δ-9-tetrahydrocannabinol, was examined as a potential inhibitor of CYP2A6-mediated nicotine metabolism.

While Δ-9-tetrahydrocannabinol showed no significant inhibition of nicotine metabolism to cotinine, Δ8-THC demonstrated unbound IC50 values of 0.57 ± 0.04 μM in microsomes from recombinant wild-type CYP2A6 overexpressing human embryonic kidney 293 cells and 0.70 ± 0.16 μM in human liver microsomes (HLMs). A similar unbound IC50 value was observed for recombinant CYP2A6∗5 microsomes (0.52 ± 0.17 μM) and was modestly elevated in recombinant CYP2A6∗2 microsomes (1.00 ± 0.12 μM). IC50 shift experiments were consistent across pooled HLM (5.3-fold) and microsomes from liver specimens exhibiting the CYP2A6 (∗2/∗2) and (∗9/∗9) genotypes (6.1- and 4.0-fold, respectively) but were reduced in CYP2A6 (∗35/∗35) microsomes (1.0-fold). Irreversible inhibition kinetics in pooled HLMs by Δ8-THC yielded a kinact value of 0.022 ± 0.001 min-1 and an unbound KI value of 0.232 ± 0.062 μM. Static modeling predicted that oral dosing with 10 mg Δ8-THC increased the nicotine plasma area under the curve by 189%, with further increases observed at 20 mg and 40 mg; interactions were also observed with inhalation doses ≥70 mg.

These findings suggest that, based on CYP2A6 genotype, Δ8-THC could be a candidate for smoking cessation therapy.

SIGNIFICANCE STATEMENT: This study is the first, to the best of our knowledge, to identify Δ-8-tetrahydrocannabinol as a potent and irreversible inhibitor of nicotine metabolism to cotinine. The extent of inhibition is modulated by genetic variation in cytochrome P450 2A6. These findings suggest that further investigations focusing on Δ-8-tetrahydrocannabinol and its potential as a candidate for smoking cessation therapy are warranted.”

https://pubmed.ncbi.nlm.nih.gov/41830876

“In conclusion, the present study is, to our knowledge, the first to demonstrate the irreversible inhibition of nicotine metabolism by Δ8-THC in vitro, highlighting its potential as a smoking cessation agent.”

https://dmd.aspetjournals.org/article/S0090-9556(26)00004-8/fulltext

Alcohol as a Novel Trigger for Cannabis Hyperemesis Syndrome

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“Cannabis hyperemesis syndrome (CHS) is a paradoxical condition occurring in chronic cannabis users, characterized by cyclic nausea, vomiting, and abdominal pain. While the primary trigger is cannabis itself, other precipitants remain poorly defined.

We present the case of a 52-year-old male with recurrent CHS who experienced five distinct hyperemetic episodes, each occurring approximately one week after ingesting a single dose of alcohol. His most recent presentation was complicated by severe, life-threatening hyponatremia requiring intensive care unit management. Diagnostic workup confirmed CHS and excluded other pathologies.

The consistent temporal pattern observed across multiple episodes suggests that a single dose of alcohol may be a novel and specific trigger for CHS. This case highlights a previously underreported precipitant and underscores the syndrome’s potential for severe metabolic complications. Clinicians should consider inquiring about alcohol use in patients with recurrent CHS, as its identification could be pivotal for prevention strategies and patient counseling.”

https://pubmed.ncbi.nlm.nih.gov/41769444

“This case provides critical clinical insights by identifying a single dose of alcohol as a potential novel trigger for CHS, expanding the known spectrum of precipitants. It underscores the serious morbidity of CHS, which can progress to life-threatening complications like severe hyponatremia necessitating intensive care.”

https://www.cureus.com/articles/434462-alcohol-as-a-novel-trigger-for-cannabis-hyperemesis-syndrome#!

“Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC5742761

Potential effects of cannabidiol on formalin-induced inflammatory pain in morphine-dependent rats

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“Chronic morphine exposure leads to tolerance and dependence, complicating pain management and reducing the efficacy of opioid analgesics.

Cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has been recognized for its anti-inflammatory and analgesic potential.

This study examined the effects of CBD on acute and inflammatory phases of formalin-induced nociception in morphine-dependent and non-dependent rats.

Eighty-four male Wistar rats were divided into the control (non-dependent) and dependent groups. Morphine dependence was induced through an oral escalating-dose regimen in drinking water containing 3% sucrose (to mask bitterness) for 14 days, while controls received only sucrose. CBD (25-200μg/5 μL, ICV) was administered prior to the formalin test. Formalin injection produced a clear biphasic nociceptive response (P < 0.001 in both phases), confirming the model’s validity.

Morphine dependence alone did not significantly affect baseline pain responses (P > 0.05). However, CBD produced a significant, dose-dependent reduction in pain behaviors during both the early (0-5 min) and the late (20-50 min) phases (P<0.001 vs. vehicle). The 100 μg/5 μL and 200 μg/5 μL doses showed the most robust and consistent antinociceptive effect.

CBD produced robust antinociceptive effects in both morphine-treated and non-treated rats, with no statistically significant difference between groups. Open-field results indicated no significant differences in locomotor activity, confirming that the observed analgesia was not related to motor impairment.

These findings demonstrate that CBD effectively attenuates both acute and inflammatory pain. Moreover, it maintains its effectiveness in animals treated with morphine. This highlights its potential as a non-opioid supplementary therapy for managing pain in individuals with opioid dependence.”

https://pubmed.ncbi.nlm.nih.gov/41747636

https://www.sciencedirect.com/science/article/abs/pii/S0022395626001263?via%3Dihub

A CBD-rich hemp extract is superior to CBD alone in reducing relapse to methamphetamine-seeking in rats

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“In preclinical models, the non-intoxicating cannabis component cannabidiol (CBD) reduces relapse to methamphetamine (Meth)-seeking and Meth-induced hyperactivity in rats.

Cannabis products containing multiple cannabinoids (“full spectrum”) may offer greater therapeutic potential than single cannabinoid (“isolate”) products.

However, few studies tested this. This study examined whether a hemp extract (HE) containing multiple cannabinoids might be superior to CBD alone in reducing Meth-induced behavioural sensitisation and relapse, and whether serotonin 1 A receptors (5-HT1A) are involved.

Male Sprague-Dawley rats self-administered either Meth or sucrose via lever press, followed by extinction and reinstatement by Meth injection (1 mg/kg; i.p.) or sucrose access. Rats received vehicle, CBD isolate (80 mg/kg), HE (containing 2.5 mg/kg of CBD and other phytocannabinoids), or HE with CBD added to match the 80 mg/kg amount of the CBD isolate (CBD + HE condition). The 5-HT1A antagonist WAY-100635 was co-administered to assess receptor involvement. Separate rats were tested for conditioned place preference (CPP) to assess possible intrinsic rewarding properties of the cannabinoids. A final group was tested for Meth-induced behavioural sensitisation.

All CBD containing treatments reduced Meth-primed reinstatement, with HE and CBD + HE more effective than CBD isolate.

There was no effect of any treatment on reacquisition of sucrose seeking. WAY-100635 did not block the effects of any treatment. Neither cannabinoid treatment produced CPP. All treatments reduced the expression of Meth-induced sensitised hyperactivity with CBD + HE showing some superiority over CBD or HE alone.

This study suggests that CBD + HE may be more effective than CBD in reducing Meth relapse-like behaviour.”

https://pubmed.ncbi.nlm.nih.gov/41605363

“CBD-rich hemp extract surpasses CBD alone in reducing relapse to Meth-seeking.”

https://www.sciencedirect.com/science/article/pii/S0278584626000254?via%3Dihub