CANNABIS AS AN EXIT DRUG

As part of its official religion, alcohol has been protected in Slovenia, and users wishing to transition to a safer drug have been told the cure is illegal and immoral or something, stigmatised, criminalised, and used as a cash cow by the judiciary, in the way alcoholics tend to see the economy.

Typically, Slovenia has not noticed anything non-economic about cannabis. To Slovenia, a suicide is not a wasted life, but a waste of educational resources. But it has been observed that alcohol and cannabis are substitutes when it comes to user expenditure.
https://www.tandfonline.com/doi/full/10.1080/1331677X.2018.1561321 [806]

"L'alcoolisme a conduit 2 membres de ma famille au suicide. Le cannabis a permis 2 autres d'arrter l'alcool."
https://twitter.com/ConradMaj [808]

According to Tod H Mikuriya (2004):

"No clinical trials of the efficacy of cannabis as a substitute for alcohol are reported in the literature, and there are no papers directly on point prior to my own account (Mikuriya 1970) of a patient who used cannabis consciously and successfully to discontinue her problematic drinking. There are ample references, however, to the use of cannabis as a substitute for opiates (Birch 1889) and as a treatment for delirium tremens (Clendinning 1843; Moreau 1845), which were among the first uses by European physicians. The 1873 Indian Government Finance Department Resolution recommended against suppressing cannabis use for fear that people (p. 1395) 'would in all probability have recourse to some other stimulant such as alcohol.'

"The Indian Hemp Drugs Commission Report of (1893-1894) articulated the same concern (p. 359): '. . . driving the consumers to have recourse to other stimulants or narcotics which may be more deleterious.

"Birch (1889) described a patient weaned off alcohol by use of opiates who then became addicted and was weaned off opiates by use of cannabis. He noted (p. 625), 'Ability to take food returned. He began to sleep well; his pulse exhibited some volume; and after three weeks he was able to take a turn on the verandah with the aid of a stick. After six weeks he spoke of returning to his post, and I never saw him again.'"

Reviewing his own 92 patients using cannabis as an alcohol substitute:

"All patients reported benefit, indicating that for at least a subset of alcoholics, cannabis use is associated with reduced drinking."
https://hams.cc/mikuriya.pdf [3822]

In "Reductions in alcohol use following medical cannabis initiation: results from a large cross-sectional survey of medical cannabis patients in Canada", Lucas et al (2020) found the same, rather obvious, thing, publishing their results almost 21 years after the ZPPPD in the International Journal of Drug Policy:

"Background: Evidence details how cannabis can influence the use of other psychoactive substances, including prescription medications, alcohol, tobacco and illicit drugs, but very little research has examined the factors associated with these changes in substance use patterns. This paper explores the self-reported use of cannabis as a substitute for alcohol among a Canadian medical cannabis patient population.

"Methods: Data was derived from a survey of 2102 people enrolled in the Canadian medical cannabis program. We included 973 (44%) respondents who reported using alcohol on at least 10 occasions over a 12 month period prior to initiating medical cannabis, and then used retrospective data on the frequency and amount of alcohol use pre-and post medical cannabis initiation to determine which participant characteristics and other variables were associated with reductions and/or cessation of alcohol use.

"Results: Overall, 419 (44%) participants reported decreases in alcohol usage frequency over 30 days, 323 (34%) decreased the number of standard drinks they had per week, and 76 (8%) reported no alcohol use at all in the 30 days prior to the survey. Being below 55 years of age and reporting higher rates of alcohol use in the pre-period were both associated with greater odds of reducing alcohol use, and an intention to use medical cannabis to reduce alcohol consumption was associated with significantly greater odds of both reducing and ceasing alcohol use altogether.

"Conclusions: Our findings suggest that medical cannabis initiation may be associated with self-reported reductions and cessation of alcohol use among medical cannabis patients. Since alcohol is the most prevalent recreational substance in North America, and its use results in significant rates of criminality, morbidity and mortality, these findings may result in improved health outcomes for medical cannabis patients, as well as overall improvements in public health and safety."
https://www.sciencedirect.com/science/article/abs/pii/S0955395920303017?via%3Dihub [399]

Pince et al (2025) found similar support for substitution:

"We investigated the effects of legal-market cannabis on alcohol self-administration and craving using a within-subjects human laboratory drug administration paradigm. We tested whether cannabis serves as a substitute for alcohol (i.e., attenuating alcohol consumption and craving) in a sample of community adults who drink heavily and use cannabis regularly. Consistent with our hypothesis, we found that across the entire sample, self-administering cannabis before alcohol significantly reduced alcohol consumption compared to when alcohol was offered without cannabis. Furthermore, we found that cannabis and alcohol co-administration was associated with significant acute reduction in alcohol craving compared to alcohol administration alone."

In "the first study to test effects of legal-market cannabis on alcohol intake...Cannabis use was associated with a reduction in alcohol intake...Those who drank less after cannabis reported greater decreases in alcohol craving" reported Pince et al (2025):

"While human laboratory studies are comparatively limited, Mello and colleagues instructed participants to complete a basic operant task wherein they could earn cannabis or money after 30 min of work and alcohol after 15 min, and found that individuals self-administered less alcohol when cannabis was concurrently available (Mello et al., 1978). Later, Ballard and DeWitt found that co-administration of low doses of THC and alcohol reduced alcohol craving (Ballard and de Wit, 2011). An unpublished laboratory study also observed that cannabis use was associated with acute reductions in alcohol intake and some measures of craving in a within-subjects design with individuals who engage in heavy drinking (Metrik et al., unpublished). Other observational studies have reported similar reductions in alcohol consumption when cannabis was used before alcohol (Gunn et al., 2021; Karoly et al., 2023, Karoly et al., 2024; Rootman, 2020). The effects of cannabis on alcohol craving and consumption during simultaneous use may be mediated in part by subjective effects (i.e., relaxation versus stimulation), as simultaneous use predicted discontinuation of drinking via increased relaxation and decreased alcohol craving at the event-level in an ecological momentary assessment study (Waddell et al., 2024). Together, these findings suggest the potential for cannabis to act as a substitute for alcohol. Further research is needed to elucidate variables that may predict such substitution behavior."
https://www.sciencedirect.com/science/article/abs/pii/S0376871625003138 [4933]

Gunn et al (2025) think "Working memory capacity predicts cannabis-induced effects on alcohol urge":

"Participants aged 21 to 44 (N = 125, 32 % female) reporting heavy alcohol use and cannabis use ≥ twice weekly completed a laboratory protocol across three days where they smoked a placebo, 3.1 % delta-9 tetrahydrocannabinol (THC), and 7.2 % THC cannabis cigarette. Participants were asked to rate their alcohol urge pre and post smoking. Prior to the experimental sessions, participants completed WMC measures including the n-back and the complex span tasks, operation span (OS) and symmetry span (SS).

"Results
Those with higher WMC, as assessed via the SS task, reported significantly lower alcohol urge after smoking the 7.2 %, but not the 3.1 %, THC dose, relative to placebo. Performance on the OS task was not associated with alcohol urge. Lower WMC as determined via n-back scores was associated with higher alcohol urge overall, but n-back scores did not moderate the impact of cannabis on alcohol urge.

"Conclusion
Findings suggest individuals with higher but not lower working memory experience lower alcohol urge under acute effects of cannabis. Although cannabis is increasingly perceived as a substitute for alcohol, individuals with lower working memory may be less likely to experience such benefits when attempting to reduce their drinking."
https://www.sciencedirect.com/science/article/pii/S030646032500334X?via%3Dihub [5664]

In "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" and using CBD only, Zimmermann et al (2024) were able to confirm the effect of cannabis on craving found in alcoholism and addiction in general [see 2978].

"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). CBDs 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://www.nature.com/articles/s41380-024-02869-y [3787]

Pince et al (2026) are researching "Behavioral phenotypes associated with cannabis and alcohol substitution":

"This study is an exploratory analysis of data from a within-subjects, crossover laboratory study on alcohol and cannabis co-administration. Participants completed two sessions: one in which they self-administered alcohol after using cannabis, and one in which they self-administered alcohol but did not use cannabis. We aim to compare behavioral phenotypes of individuals who self-administered less alcohol after cannabis ('substituters'; n = 23), more alcohol after cannabis ('complementers'; n = 7), or the same amount of alcohol regardless of whether cannabis was used ('non-substituters'; n = 16). We utilized Welch's ANOVAs and Kruskal-Wallis tests to compare baseline group differences, drawing on domains from the Addictions Neuroclinical Assessment (ANA) framework. Wilcoxon tests were employed to test differences in laboratory self-administration measures between sessions for each group.

"Results
Substituters had significantly lower scores on measures corresponding to ANA domains of negative emotionality (BDI-II, DASS-Depression) and executive function (UPPS-P Lack of Premeditation) than non-substituters. Substituters endorsed higher positive cannabis expectancies than non-substituters, though expectancy differences did not reach significance.

"Conclusions
Individuals who use cannabis and alcohol and have lower levels of negative emotionality and impulsivity may be more likely to substitute cannabis for alcohol. Future research is needed to explore long-term outcomes of cannabis substitution."
https://link.springer.com/article/10.1186/s12954-026-01432-y [6002]

CBD was an exit drug for fruit flies in "Long term exposure to dietary cannabinoids inhibits rapid functional tolerance to ethanol in Drosophila melanogaster adults" by Vidal et al (2025):

"Given that CBD acts as a natural antagonist of CB1R, and CB1R antagonists have been shown to reduce the self-administration and appetitive value of ethanol in rodent models (Arnone et al., 1997; Economidou et al., 2006), as well as inhibit the development of rapid tolerance to ethanol in rats (Lemos et al., 2007), CBD had long been viewed as a promising pharmacotherapy candidate to treat alcohol used disorders (AUD). Accordingly, CBD treatment was shown to inhibit the context-dependent relapse into alcohol seeking in rats with a history of alcohol consumption (Gonzalez-Cuevas et al., 2018), and their ability to develop tolerance to sedation by alcohol following re-exposure (Szulc et al., 2023). Not surprisingly, most previous work has focused on the potential role of CB1/2R-dependent signaling in the cross-talk between ethanol and CBD. Notably, Viudez-Martinez and colleagues showed that a 5HT1A serotonin receptor antagonist could block the reduction in alcohol self-administration triggered by the combined treatment with CBD and naltrexone (Viudez-Martnez et al., 2018), establishing a precedent for the potential involvement of non-canonical cannabinoid signaling in the cross-talk between CBD and alcohol."
https://www.micropublication.org/journals/biology/micropub-biology-001825 [5816]

In a prelude to their larger 2021 study "Cannabis Significantly Reduces the Use of Prescription Opioids and Improves Quality of Life" [2815] in 2017 Lucas and Walsh published a study in which they surveyed 271 medical cannabis patients in research funded by Tilray.

"Findings include high self-reported use of cannabis as a substitute for prescription drugs (63%), particularly pharmaceutical opioids (30%), benzodiazepines (16%), and antidepressants (12%). Patients also reported substituting cannabis for alcohol (25%), cigarettes/tobacco (12%), and illicit drugs (3%). A significant percentage of patients (42%) reported accessing cannabis from illegal/unregulated sources in addition to access via LPs, and over half (55%) were charged to receive a medical recommendation to use cannabis, with nearly 25% paying $300 or more."
https://www.sciencedirect.com/science/article/abs/pii/S0955395917300130 [3083]

Holman et al

"...conducted an anonymous, cross-sectional online survey in May 2021 for seven days with adult Canadian federally-authorized medical cannabis patients (N = 2697) registered with two global cannabis companies to evaluate patient perceptions of Primary Care Provider (PCP) knowledge of medical cannabis and communication regarding medical cannabis with PCPs, including PCP authorization of licensure and substitution of cannabis for other medications. Overall, 47.1% of participants reported substituting cannabis for pharmaceuticals or other substances (e.g., alcohol, tobacco/nicotine).
https://jcannabisresearch.biomedcentral.com/counter/pdf/10.1186/s42238-022-00141-0.pdf [1826]

Similar results for alcohol came from Kruger et al (2026) at Buffalo University, NY, for whom cannabis is a "novel harm reduction strategy":

"Alcohol consumption is associated with nearly 200 health conditions. As cannabis-infused beverages emerge in the legal market, their potential as a substitute for alcohol is of growing interest. This study investigates whether cannabis beverages may reduce alcohol use.A total of 438 anonymous adults who used cannabis in the past year completed a survey including cannabis use and alcohol consumption items from the Behavioral Risk Factor Surveillance System (BRFSS). Chi-square and t-tests compared alcohol use between cannabis beverage users and non-users, and before vs. after cannabis beverage initiation.About one-third (33.6%) of respondents used cannabis beverages, typically consuming one per session. Users were more likely to report substituting cannabis for alcohol (58.6%) than non-users (47.2%). They also reported fewer weekly alcoholic drinks after starting cannabis beverages (M = 3.35) compared to before (M = 7.02), and binge drank less frequently (80.7% reported less than monthly or never, vs. 47.2% before). Those who cited reducing other substance use were more likely to use cannabis beverages (45.8%).Findings suggest cannabis beverages may support alcohol substitution and reduce alcohol-related harms, offering a promising alternative for individuals seeking to lower alcohol intake."
https://pubmed.ncbi.nlm.nih.gov/41533430/ [5873]

Anderson et al at the National Bureau of Economic Research:

"...find that both state MMLs and RMLs are associated with decreases in teen marijuana consumption, consistent with the hypothesis that selling to minors becomes a relatively risky proposition for licensed marijuana dispensaries. In addition, we find that MMLs are associated with decreases in teen cigarette use."
https://www.nber.org/system/files/working_papers/w26780/w26780.pdf [400]

Raman and Bradford (2022) find "Recreational cannabis legalizations associated with reductions in prescription drug utilization among Medicaid enrollees":

"We use quarterly data for all Medicaid prescriptions from 2011 to 2019 to investigate the effect of state-level RCLs [recreational cannabis laws] on prescription drug utilization. We estimate this effect with a series of two-way fixed effects event study models. We find significant reductions in the volume of prescriptions within the drug classes that align with the medical indications for pain, depression, anxiety, sleep, psychosis, and seizures. Our results suggest substitution away from prescription drugs and potential cost savings for state Medicaid programs.
https://onlinelibrary.wiley.com/doi/10.1002/hec.4519 [1827]

In Canada, Jeddi et al examined "Cost-Effectiveness of Medical Cannabis Versus Opioids for Chronic Noncancer Pain" (in Canadian dollars):

"Total mean annual cost per patient was $1,980 for oral medical cannabis and $1,851 for opioids, a difference of $129 (95% confidence interval [CI]: -$723 to $525). Mean QALYs were 0.582 for both oral medical cannabis and opioids (95% CI: -0.007 to 0.015). Cost-effectiveness acceptability curves showed that oral medical cannabis was cost-effective in 31% of iterations at willingness-to-pay thresholds up to $50,000/QALY gained. Use of opioids is associated with nonfatal and fatal overdose, whereas medical cannabis is not. Discussion: Our findings suggest that medical cannabis as an alternative to opioids for chronic pain may confer similar, but modest, benefits to patients, and reduce the risk of opioid overdose without substantially increasing costs."
https://www.liebertpub.com/doi/10.1089/can.2024.0120?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed [5182]

On this side of the Atlantic, a report by Sapphire Clinics on opioid prescription in the UK found that one in seven (14%) chronic pain patients prescribed opioid medications claim they became dependent or addicted, while strong side effects reportedly stopped one in four (23%) from living a normal life.

57 million prescriptions for opioids such as tramadol, codeine and fentanyl, were issued to UK patients in 2022, an average of one 108 every minute.
https://www.sapphireclinics.com/wp-content/uploads/2023/06/opioid-campaign-whitepaper.pdf [2852]

Marrinan et al (2024) in the UK determined that increasing access to medical cannabis on the NHS for chronic pain could save the state healthcare provider almost 4 billion annually, 729 per patient.

"An early cost-effectiveness model was developed to estimate the impact of prescribing CBMPs alone and/or in addition to analgesics, physiotherapy, and cognitive behavioral therapy for chronic pain in the UK for 1 year.

"Results
Due to their comparative effectiveness, CBMPs were found to be cost saving."
https://www.tandfonline.com/doi/full/10.1080/14737167.2024.2412248 [3629]

In "Perceived Efficacy, Reduced Prescription Drug Use, and Minimal Side Effects of Cannabis in Patients with Chronic Orthopedic Pain" (2022) Greis et al explain:

"Extant inventories for measuring cannabis use were not designed to capture the medically relevant features of cannabis use, but rather were designed to detect problematic use or cannabis use disorder. Thus, we sought to capture the medically relevant features of cannabis use in a population of patients with orthopedic pain and pair these data with objective measures of pain and prescription drug use."

The results show:

"Medical cannabis use was associated with clinical improvements in pain, function, and quality of life with reductions in prescription drug use; 73% either ceased or decreased opioid consumption and 31% discontinued benzodiazepines. This work provides a direct relationship between the initiation of cannabis therapy and objectively fewer opioid and benzodiazepine prescriptions.
https://www.liebertpub.com/doi/10.1089/can.2021.0088 [1828]

In Israel, Aviram et al (2021) found

Patients with chronic pain, licensed to use MC in Israel, reported weekly average pain intensity (primary outcome) and related symptoms before and at 1, 3, 6, 9 and 12 months following MC [medical cannabis] treatment initiation.. 43% of the patients who had been using analgesic medications prior to MC treatment initiation were no longer using them. This was true for all classes of analgesic drugs including over the counter analgesics, non-steroidal anti-inflammatory drugs, anticonvulsants and antidepressants. As for opioid use, 24% and 20% of the participants who had been using weak or strong opioids, respectively, at baseline stopped using them by the time they reached the 12-month follow-up.
https://pubmed.ncbi.nlm.nih.gov/33065768/ [1829]

In "Utilization of medicinal cannabis for pain by individuals with spinal cord injury" Stillman et al found non-users live in a different reality:

"Never users were less likely than current and past users to agree that cannabis should be legalized (CU + PU = 98.00%; NU = 88.10%; χ2 = 10.92, p = .001) (Table 2) and more likely to believe that cannabis is a 'gateway drug' (CU + PU = 7.40%; NU = 22.50%; χ2 = 12.80, p = 0.00), a 'very dangerous' drug (CU + PU = 1.30%; NU = 7.00%; χ2 = 5.90, p = 0.026), and that it is safer to take prescription pain killers than to use MC (CU + PU = 4.00%; NU = 11.80%; χ2 = 5.91, p = 0.021). There was widespread agreement among participants that cannabis could have medicinal effects (CU + PU = 96.00%; NU = 95.30%; χ2 = 0.07, p = 1.00) and that its use carries either no or only slight health risks (CU + PU = 91.20%; NU = 83.60%; χ2 = 3.61, p = 0.067). There were no significant differences in perceptions of social or legal risks between the user groups."

But these authors did not find any difference in pain interference. On the other hand:

"Subjects were asked to select from a list of 33 possible effects that could be ascribed to MC and/or prescription medications and that could be considered either positive, negative, or neutral. On average, MC was assigned 7.6 positive effects while prescription medications were assigned 5.35 (t = 3.9, df = 234; p = .000). Medicinal cannabis was assigned an average of 6.0 negative effects while prescription medications were assigned 9.9 (t = −3.76, df = 203; p = .001).

"When asked to compare the relative efficacy of MC with that of other medications in providing symptom relief (98 CU and 30 PU), 63.3% reported that cannabis works better than prescription medications, 17.20% reported the opposite, and 10.20% answered that only cannabis offered them relief (χ2 = 7.93, p = 0.047). When asked if they suffer or had suffered from symptoms or conditions that had not been helped by MC, 35.20% replied yes (CU = 31.60%; PU = 46.70%; NS) and 64.80% replied no (CU = 68.40%; PU = 53.30%; NS)."

Among our subjects, over 90 percent of CU [cannabis users] and PU [past users] reported a little or great relief from symptoms with MC [medical cannabis] and 61.20 percent claimed that MC had allowed them to reduce or discontinue use of other medications.
https://www.nature.com/articles/s41394-019-0208-6.pdf [1830]

In "The Impact of Isolated Baseline Cannabis Use on Outcomes Following Thoracolumbar Spinal Fusion: A Propensity Score-Matched Analysis" Shah et al write:

"704 patients were identified (n=352 each), with comparable age, sex, race, primary insurance, Charlson/Deyo scores, surgical approach, and levels fused between cohorts (all, p>0.05). Cannabis users (versus non-users) incurred lower 90-day overall and medical complication rates (2.4% vs. 4.8%, p=0.013; 2.0% vs. 4.1%, p=0.018). Cohorts had otherwise comparable complication, revision, and readmission rates (p>0.05). Baseline cannabis use was associated with a lower risk of 90-day medical complications (OR=0.47, p=0.005). Isolated baseline cannabis use was not associated with 90-day surgical complications and readmissions, or two-year revisions.

"Isolated baseline cannabis use, in the absence of any other diagnosed substance abuse disorders, was not associated with increased odds of 90-day surgical complications or readmissions or two-year revisions, though its use was associated with reduced odds of 90-day medical complications when compared to non-users undergoing TLF (thoracolumbar spinal fusion) for ASD (adult spinal deformity)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210439/ [1942]

In 2020's "The impact of cannabis access laws on opioid prescribing", (2020) McMichael et al point out that

"...the number of opioid prescriptions quadrupled in the first fifteen years of the new millennium."

and

"The five specialties that have the highest prescribing rates, as measured by MMEs, reduce their opioid use by 28.3 percent when an RCL is passed and 6.9 percent when an MCL is passed."

"Table A1 reports the means of each of our outcome variables across different cannabis legal regimes for all specialties for which we have at least 2,000 provider-year observations."

"In general, we find consistent evidence that both RCLs and MCLs reduce the use of prescription opioids. These laws reduce the amount of annual MMEs prescribed by individual providers by 6.9 and 6.1 percent, respectively. However, our results are not unique to the MME measure of opioid prescriptions, and both types of cannabis access laws similarly reduce the total days supply of opioids, the number of patients to whom providers prescribe opioids, and the probability that a provider prescribes any opioids. Interestingly, while we find evidence that RCLs and MCLs reduce opioid use across a wide array of medical (and other) specialties, the magnitude of this reduction is not uniform across specialties."

Summary Statistics by Specialty Panel A compares MMEs [morphine milligram equivalents] for All Providers and Providers Not Subject to Any Cannabis Access Law. Only two of the 48 specialties listed - Clinical Nurse Specialist and Physician Assistant - show modestly lower MMEs where there is no cannabis access law, and so 46 were higher.
https://scholarship.law.ua.edu/cgi/viewcontent.cgi?article=1150&context=fac_working_papers [1831]

"Our sample included 888 individuals receiving treatment for chronic pain, of whom 99.4% received treatment with prescription opioids or MC.

"Methods. Problematic use of prescription opioids and MC was assessed using DSM-IV criteria, Portenoys Criteria (PC), and the Current Opioid Misuse Measure (COMM) questionnaire. Additional sociodemographic and clinical correlates of problematic use were also assessed.

"Results. Among individuals treated with prescription opioids, prevalence of problematic use of opioids according to DSM-IV, PC, and COMM was 52.6%, 17.1%, and 28.7%, respectively. Among those treated with MC, prevalence of problematic use of cannabis according to DSM-IV and PC was 21.2% and 10.6%, respectively. Problematic use of opioids and cannabis was more common in individuals using medications for longer periods of time, reporting higher levels of depression and anxiety, and using alcohol or drugs. Problematic use of opioids was associated with higher self-reported levels of pain, and problematic use of cannabis was more common among individuals using larger amounts of MC.

"Conclusions. Problematic use of opioids is common among chronic pain patients treated with prescription opioids and is more prevalent than problematic use of cannabis among those receiving MC. Pain patients should be screened for risk factors for problematic use before initiating long-term treatment for pain-control."
https://academic.oup.com/painmedicine/article-pdf/18/2/294/10452408/pnw134.pdf [1832]

Another medical cannabis study by Lucas et al (2021) focuses

"...on the impacts of cannabis on prescription opioid use and quality of life over a 6-month period."

using 1145 patients and

"...a comprehensive cannabis use inventory, the World Health Organization Quality of Life Short Form (WHOQOL-BREF), and a detailed prescription drug questionnaire."

and

"Participants were 57.6% female, with a median age of 52 years. Baseline opioid use was reported by 28% of participants, dropping to 11% at 6 months. Daily opioid use went from 152 mg morphine milligram equivalent (MME) at baseline to 32.2 mg MME at 6 months, a 78% reduction in mean opioid dosage. Similar reductions were also seen in the other four primary prescription drug classes identified by participants, and statistically significant improvements were reported in all four domains of the WHOQOL-BREF."

and

"The high rate of cannabis use for chronic pain and the subsequent reductions in opioid use suggest that cannabis may play a harm reduction role in the opioid overdose crisis, potentially improving the quality of life of patients and overall public health."

Other pharmaceuticals suffered terribly as well:

"Over 6 months, the percentage of patients using non-opioid pain medications went from 21.6% (n=241) to 7.7% (n=32), use of antidepressants declined from 16.4% (n=183) to 10.1% (n=42), use of antiseizure medications went from 16% (n=178) to 10.6% (n=44), and benzodiazepine use decreased from 6.7% of participants at baseline (n=75) to 3.1% at M6."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971472/ [2815]

Dranitsaris et al (2021) examined opioid prescribing before and after legalisation in Canada:

"Purpose: On 17 October 2018 recreational cannabis became legal in Canada, thereby increasing access and reducing the stigma associated with its use for pain management. This study assessed total opioid prescribing volumes and expenditures prior to and following cannabis legalization.

"Methods: National monthly claims data for public and private payers were obtained from January 2016 to June 2019. The drugs evaluated consisted of morphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, oxycodone, tramadol, and the non-opioids gabapentin and pregabalin. All opioid volumes were converted to a mean morphine equivalent dose (MED)/claim, which is analogous to a prescription from a physician. Gabapentin and pregabalin claims data were analyzed separately from the opioids. Time-series regression modelling was undertaken with dependent variables being mean MED/claim and total monthly spending. The slopes of the time-series curves were then compared pre- versus post-cannabis legalization.

"Results: Over the 42-month period, the mean MED/claim declined within public plans (p < 0.001). However, the decline in MED/claim was 5.4 times greater in the period following legalization (22.3 mg/claim post vs. 4.1 mg/claim pre). Total monthly opioid spending was also reduced to a greater extent post legalization ($Can267,000 vs. $Can95,000 per month). The findings were similar for private drug plans; however, the absolute drop in opioid use was more pronounced (76.9 vs. 30.8 mg/claim). Over the 42-month period, gabapentin and pregabalin usage also declined.

"Conclusions: Our findings support the hypothesis that easier access to cannabis for pain may reduce opioid use for both public and private drug plans."
https://pubmed.ncbi.nlm.nih.gov/33491149/ [2143]

According to Beasley and Dundas (2024) in "Recreational cannabis dispensary access effects on prescription opioid use and mortality", in Oregon:

"Results suggest that communities located closer to recreational dispensaries are associated with lower rates of prescription opioids per capita. We also show that reasonable bounds to our primary specification suggest communities located within a mile from a recreational dispensary have prescription opioid rates per capita that are 1.03.9 percent lower than surrounding communities."

The study acknowledges that while opioid-related mortality rates appeared unaffected by proximity to retail marijuana, its possible that other measures of opioid harms, for example hospitalizations, may nevertheless show an impact.

While mortality rates do not appear to be driven by changes in cannabis access, it says, hospitalizations related to overdoses may be impacted. An extension of this work assessing hospitalizations in lieu of mortalitymay yield further insight.

Authors said in the email to Marijuana Moment that the issue of hospitalizations was raised during peer review of the article and our discussion in the paper on hospitalizations is meant to convey that mortality reduction is just one metric that could be impacted by reduced opioid prescriptions.

For example, it may be possible that the same number of people succumb to opioid misuse, while fewer people are hospitalized, they added.
https://www.sciencedirect.com/science/article/abs/pii/S016604622400067X?via%3Dihub [3128]

In Utah, most patients who reduced opioid prescriptions were using cannabis products with a ratio of 1:0 (64%), a ratio of 1:1 (19%) and 0:1 (16%):



84% showed a decrease in Morphine Milligram Equivalents (MME) per month after starting cannabis use.


https://www.utah.gov/pmn/files/1194859.pdf [3742]

In Israel, Feingold et al examined "Depression and anxiety among chronic pain patients receiving prescription opioids and medical marijuana"...or both:

"Prevalence of depression among patients in the OP (opioids), MM (medical marijuana) and OPMM groups was 57.1%, 22.3% and 51.4%, respectively and rates of anxiety were 48.4%, 21.5% and 38.7%, respectively. Levels of depression and anxiety are higher among chronic pain patients receiving prescription opioids compared to those receiving MM. Findings should be taken into consideration when deciding on the most appropriate treatment modality for chronic pain, particularly among those at risk for depression and anxiety."
https://www.ncbi.nlm.nih.gov/pubmed/28453948 [1833]

Hsu and Kovcs (2021) reported an "Association between county level cannabis dispensary counts and opioid related mortality rates in the United States: panel data study" of 812 counties in the United States in the 23 states that allowed legal forms of cannabis dispensaries to operate by the end of 2017.

"Participants The study used US mortality data from the Centers for Disease Control and Prevention combined with US census data and data from Weedmaps.com on storefront dispensary operations. Data were analyzed at the county level by using panel regression methods.

"Main outcome measure The main outcome measures were the log transformed, age adjusted mortality rates associated with all opioid types combined, and with subcategories of prescription opioids, heroin, and synthetic opioids other than methadone. The associations of medical dispensary and recreational dispensary counts with age adjusted mortality rates were also analyzed.

"Results County level dispensary count (natural logarithm) is negatively related to the log transformed, age adjusted mortality rate associated with all opioid types (β=−0.17, 95% confidence interval −0.23 to −0.11). According to this estimate, an increase from one to two storefront dispensaries in a county is associated with an estimated 17% reduction in all opioid related mortality rates. Dispensary count has a particularly strong negative association with deaths caused by synthetic opioids other than methadone (β=−0.21, 95% confidence interval −0.27 to −0.14), with an estimated 21% reduction in mortality rates associated with an increase from one to two dispensaries. Similar associations were found for medical versus recreational storefront dispensary counts on synthetic (non-methadone) opioid related mortality rates.

"Conclusions Higher medical and recreational storefront dispensary counts are associated with reduced opioid related death rates, particularly deaths associated with synthetic opioids such as fentanyl. While the associations documented cannot be assumed to be causal, they suggest a potential association between increased prevalence of medical and recreational cannabis dispensaries and reduced opioid related mortality rates. This study highlights the importance of considering the complex supply side of related drug markets and how this shapes opioid use and misuse.
https://www.bmj.com/content/372/bmj.m4957 [4778]

Looking at cannabis use for pain management and harm reduction, Kitchen et al (2025) report:

"Between June 2014 and May 2022, 2340 PWUD were initially recruited and of those 1242 PWUD reported chronic pain, use of unregulated opioids and completed at least two follow-up visits. Of these 1242 participants, 764 experienced a cessation event over 1038.2 person-years resulting in a cessation rate of 28.5 per 100 person-years (95% confidence interval [CI] 25.4-31.9). Daily cannabis use was positively associated with opioid cessation (adjusted hazard ratio 1.40, 95% CI 1.08-1.81; p = 0.011). In the sex-stratified sub-analyses, daily cannabis use was significantly associated with increased rates of opioid cessation among males (adjusted hazard ratio 1.50, 95% CI 1.09-2.08; p = 0.014)."
https://pubmed.ncbi.nlm.nih.gov/40011075/ [5174]

Steuart et al (2025) took a long-term look at "Recreational Cannabis Laws and Fills of Pain Prescriptions in the Privately Insured":

"Using data from a national sample of commercially insured adults, we examine the effect of recreational cannabis legalization (through two sequential policies) on prescribing of opioids, NSAIDS, and other pain medications by implementing synthetic control estimations and constructing case-study level counterfactuals for the years 2007-2020.

"Results:
Overall, we find recreational cannabis legalization is associated with a decrease in opioid fills among commercially insured adults in the U.S., and we find evidence of a compositional change in prescriptions of pain medications more broadly. Specifically, we find marginally significant increases in prescribing of non-opioid pain medications after recreational cannabis becomes legal in some states. Once recreational cannabis dispensaries open, we find statistically significant decreases in the rate of opioid prescriptions (13% reduction from baseline, p < .05) and marginally significant decreases in the average daily supply of opioids (6.3% decrease, p < .10) and number of opioid prescriptions per patient (3.5% decrease, p < .10).

"Conclusions:
These results suggest that substitution of cannabis for traditional pain medications increases as the availability of recreational cannabis increases. There appears to be a small shift once recreational cannabis becomes legal, but we see stronger results once users can purchase cannabis at recreational dispensaries. The decrease in opioids and marginal increase in non-opioid pain medication may reflect patients substituting opioids with cannabis and non-opioid pain medications, either separately or concomitantly. Reductions in opioid prescription fills stemming from recreational cannabis legalization may prevent exposure to opioids in patients with pain and lead to decreases in the number of new opioid users, rates of opioid use disorder, and related harms."
https://pmc.ncbi.nlm.nih.gov/articles/PMC11831899/ [4911]

Drake et al of the University of Pittsburghs School of Public Health found "a significant reduction in pharmacy-based codeine distribution in states that have legalized recreational cannabis use. The finding is promising from a public health policy perspective because misuse of prescription opioids annually contributes to more than 10,000 overdose deaths."

and

"The study is believed to be among the first to separately examine the impact of recreational cannabis laws on shipments of opioids to hospitals, pharmacies and other endpoint distributors. Previous studies have focused on medical cannabis laws or use of opioids by subsets of consumers, such as Medicaid beneficiaries."

and

"Key findings from states that passed recreational cannabis laws:

"A 26% reduction in pharmacy-based distribution of codeine and as much as a 37% reduction after recreational cannabis laws have been in effect for four years.

"Minimal impact on distribution of other opioids such as oxycodone, hydrocodone and morphine in any setting.

"Minimal impact on codeine distribution by hospitals, which often have less permissive policies than pharmacies."

"'This finding is particularly meaningful,' said senior author Coleman Drake of the University of Pittsburghs School of Public Health. 'Where previous studies have focused on more potent opioids, codeine is a weaker drug with a higher potential for addiction. It indicates people may be obtaining codeine from pharmacies for misuse, and that recreational cannabis laws reduce this illicit demand.'"
https://news.cornell.edu/stories/2023/01/when-recreational-cannabis-legal-codeine-demand-drops [2037]

B. Karmakar is an Assistant Professor in the Department of Statistics, University of Florida, G. Mukherjee is an Associate Professor in the Department of Data Sciences & Operations, University of Southern California and W. Kar is an Assistant Professor of Purdue University. Karmakar, Mukherjee and Kar (2023) studied the "Effect of Marijuana Legalization on Direct Payments to Physicians by Opioid Manufacturers" and say:

"Our analysis finds a significant decrease in direct payments from opioid manufacturers to pain medicine physicians as an effect of MML passage. We provide evidence that this decrease is due to the availability of medical marijuana as a substitute. Additionally, physicians in states with an MML are prescribing fewer opioids. Finally, the substitution effect is comparatively higher for female physicians and in localities with higher white, less affluent, and more working-age populations."

As they explain:

"In the wake of this evolving pain management paradigm, physicians must remain updated on drugs for appropriate patient care. Without the latest information regarding the drugs, physicians may be unable to prescribe opioids appropriately for pain management (Guo et al., 2021). There is significant concern that a subsequent decrease in opioid prescription could lead to opioid being a niche product or, in the extreme, could potentially lead to severely diminished usage of opioids (Feinberg, 2019, Szalavitz, 2023). Further, as a cascading effect, it can negatively affect research and development on opioids as well as decrease in the number of opioid manufacturers. Therefore, opioid manufacturers use different forms of interactions to engage with physicians on a regular basis. One of the most common conduits to facilitate such interactions is through direct payments to physicians from opioid manufacturers (Jones and Ornstein, 2016, Schwartz and Woloshin, 2019). These direct payments may be in the form of consulting and speaker fees, conference travel reimbursements, or meal vouchers."

and

"...due to the 'Sunshine Act,' pharmaceutical manufacturers are now mandated by law to report such payments (Richardson et al., 2014). The act was a federal response to concerns of potential conflict of interest in physicians accepting these payments, the subsequent possibility of bias in treatment, and rising health-care costs (Carey et al., 2021, DeJong et al., 2016, Engelberg et al., 2014, Jones and Ornstein, 2016). In September 2014, the first batch of data was made public. This dataset contains the dollar value of the gift/payment that transpired between a named physician and a named pharmaceutical manufacturer, associated products for their interaction, and payment date."

Using a customised synthetic control method:

"Our primary analysis considers all pain medicine physicians from 13 states, of which three (PA, OH, LA) were treated states that passed an MML in the second quarter of 2016. The method, described in Section 3.4, produces synthetic controls for each physician in the treated states using physicians in the control states, and likewise produces synthetic counterparts for each physician in the control states using physicians in the treated states."

So

"The results reported in Table 4 show a significant negative correlation between an increase in marijuana patients in preceding period as well as presence of a marijuana dispensary with opioid-prescribing physician payment; however, there is no significant association between physician payment and change in marijuana patients in the following period. These results provide us with further support that the substitution effect of marijuana is indeed the dominating factor in reducing payments to pain medicine physicians post-passage of MML."

Some tears are necessary for the "opioids ecosystem":

"Our study finds a significant decrease in financial interactions between opioid manufacturers and physicians as an effect of MML passage. The finding that the opioid manufacturers in states that passed MML are stepping away from this particular form of interaction is concerning, for such activity can significantly affect the opioids ecosystem."

But back with the patients themselves:

"Analyzing the annual prescription data (mentioned in Section 2), we found that, in 2015, they prescribed 49% more opioids than non-opioids in 30 days fill and a similar 49% more days of prescription for opioid vs non-opioid. From 2015 to 2017, in the states not passing an MML, 30 days fill of opioid vs non-opioid remained flat at a 1.38:1 ratio. However, in the states passing an MML, from 2015 to 2017, 30 days fill of opioid vs non-opioid decreased from a 1.57:1 ratio to a 1.52:1 ratio. The ratios for the number of days of prescription in the MML states also decreased from a 1.57:1 ratio in 2015 to a 1.52:1 ratio in 2017. In particular, the pattern of opioid vs non-opioid prescriptions did not change in the control states, while there was a relative decrease in opioid prescriptions in the MML states from 2015 to 2017."
https://people.clas.ufl.edu/bkarmakar/files/2023/03/physicians_opioids.pdf  [2328]

In "'I got a bunch of weed to help me through the withdrawals': Naturalistic cannabis use reported in online opioid and opioid recovery community discussion forums" Meachem et al (2022)

"...extracted all posts mentioning cannabis-related keywords (e.g., 'weed', 'cannabis', marijuana) from December 2015 through August 2019 from an opioid use subreddit and an opioid recovery subreddit. The most frequent phrases from the recovery subreddit referred to time without using opioids and the possibility of using cannabis as a treatment. The most common motivations for using cannabis were to manage opioid withdrawal symptoms in the recovery subreddit, often in conjunction with anti-anxiety and GI-distress 'comfort meds.' Despite limitations in generalizability from pseudonymous online posts, this examination of reports of naturalistic cannabis use in relation to opioid use identified withdrawal symptom management as a common motivation.
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0263583&type=printable [1834]

In 2021's "The association between cannabis use and outcome in pharmacological treatment for opioid use disorder" Rosic et al in the Harm Reduction Journal

"Participants receiving pharmacological treatment for OUD (n = 2315) were recruited from community-based addiction treatment clinics in Ontario, Canada, and provided information on past-month cannabis use (self-report). Participants were followed for 3 months with routine urine drug screens in order to assess opioid use during treatment. We used logistic regression analysis to explore (1) the association between any cannabis use and opioid use during treatment, and (2) amongst cannabis-users, specific cannabis use characteristics associated with opioid use. We found that amongst cannabis users, those who use cannabis daily are less likely to have opioid use than people who use cannabis occasionally. This association was present for both men and women. Future studies should further examine specific characteristics and patterns of cannabis use that may be protective or problematic in MAT [medication-assisted treatment]."

Sex differences were observed:

"Interaction analysis revealed no significant moderating effect of sex on our cannabis use characteristics of interest (age of onset of cannabis use by sex: OR = 0.99, 95% CI 0.94, 1.05, p = 0.725; daily cannabis use by sex: OR = 0.92, 95% CI 0.53, 1.57, p 0.748; side effects from cannabis by sex: OR = 1.53, 95% CI 0.93, 2.50, p = 0.092; marijuana cravings score by sex: OR = 1.01, 95% CI 0.99, 1.03, p = 0.100). Using subgroup analysis by sex, we found the association between reporting cannabis-related side effects and lower odds of opioid use to hold for men (OR = 0.55, 95% CI 0.40, 0.75, p < 0.001), but not for women (OR = 0.86, 95% CI 0.59, 1.26, p = 0.442). Additionally, for women, but not men, higher marijuana cravings score was associated with increased odds of opioid use (scaled for each 10-point increase in score: OR = 1.14, 95% CI 1.01, 1.28, p = 0.034)."

Overall

"For cannabis users, daily cannabis use was associated with lower odds of opioid use, when compared with occasional use (OR = 0.61, 95% CI 0.470.79, p < 0.001) as was older age of onset of cannabis use (OR = 0.97, 95% CI 0.94, 0.99, p = 0.032), and reporting cannabis-related side effects (OR = 0.67, 95% CI 0.51, 0.85, p = 0.001)."

And adopting a rather melancholy angle, they go on:

"Altogether, 75% of cannabis users perceived no impact of cannabis on their OUD treatment."
https://harmreductionjournal.biomedcentral.com/articles/10.1186/s12954-021-00468-6 [1835]

For Johns Hopkins University School of Medicine, Bergeria et al (2020)

"Two hundred individuals recruited through Amazon Mechanical Turk with past month opioid and cannabis use and experience of opioid withdrawal completed the survey. Participants indicated which opioid withdrawal symptoms improved or worsened with cannabis use and indicated the severity of their opioid withdrawal on days with and without cannabis. 62.5% of 200 participants had used cannabis to treat withdrawal. Participants most frequently indicated that cannabis improved: anxiety, tremors, and trouble sleeping. These results show that cannabis may improve opioid withdrawal symptoms and that the size of the effect is clinically meaningful."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212528/ [1836]

Wiese and Wilson-Poe reviewed the evidence in 2018.

"The endocannabinoid and opioidergic systems are known to interact in many different ways, from the distribution of their receptors to cross-sensitization of their behavioral pharmacology. Cannabinoid-1 (CB1) receptors and mu opioid receptors (MORs) are distributed in many of the same areas in the brain, including but not limited to the periaqueductal gray, locus coeruleus, ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex (PFC), central amygdala (CeA), bed nucleus of stria terminalis (BNST), caudate putamen (CP), substantia nigra, dorsal hippocampus, raphe nuclei, and medial basal hypothalamus. The extent of this overlapping expression and frequent colocalization of the CB1 and MOR provide clear morphological underpinnings for interactions between the opioid and cannabinoid systems in reward and withdrawal."

Besides,

"Interestingly, microinjections of CB1 agonists into the medial PFC creates an aversion to doses of morphine that are normally rewarding (CPP), while CB1 antagonism in this brain region creates a rewarding effect of subthreshold morphine doses."

"The evidence summarized in this article demonstrates the potential cannabis has to ease opioid withdrawal symptoms, reduce opioid consumption, ameliorate opioid cravings, prevent opioid relapse, improve OUD treatment retention, and reduce overdose deaths. The compelling nature of these data and the relative safety profile of cannabis warrant further exploration of cannabis as an adjunct or alternative treatment for OUD."
https://www.liebertpub.com/doi/10.1089/can.2018.0022 [1837]

In a 2025 paper "Cannabidiol attenuates heroin seeking in male rats associated with normalization of discrete neurobiological signatures within the nucleus accumbens with subregional specificity" from Chisholm et al of the Icahn School of Medicine at Mount Sinai, Departments of Neuroscience, Psychiatry; Addiction Institute of Mount Sinai:

"Heroin-trained animals exhibited high levels of cue-induced heroin-seeking behavior. Importantly, CBD attenuated cue-induced heroin-seeking behaviors. Postmortem RNA-sequencing of the NAcC and NAcS revealed shared transcriptomic alterations the NAc subregions in response to heroin, with a more robust impact of heroin in the NAcS. Though CBD had minimal impact on the heroin-induced perturbations in the NAcC, it normalized components of the transcriptomic signature altered by heroin in both NAc subregions including transcripts that correlated with heroin-seeking behavior. In contrast, CBD normalized a particular subset of NAcS genes that correlated to heroin-seeking behavior. Those genes were specifically linked to the extracellular matrix, astrocyte function, and their upstream regulators related to immune function."
https://www.sciencedirect.com/science/article/abs/pii/S0006322325014623 [5449]

Raman et al examined codeine sales at pharmacies in US states which had passed recreational cannabis laws as of November 2022.

"We implement two-way fixed-effects regressions and leverage variation from eleven U.S. states that adopted a recreational cannabis law (RCL) between 2010 and 2019. We find that RCLs lead to a reduction in codeine dispensed at retail pharmacies. Among prescription opioids, codeine is particularly likely to be used non-medically. Thus, the finding that RCLs appear to reduce codeine dispensing is potentially promising from a public health perspective."

"We are the first study, to our knowledge, to leverage ARCOS data which details distribution by endpointpharmacies, hospitals, specialists, and narcotic treatment programsto study the effects of" recreational legalization, the authors wrote.

They further said that the effect of legalization on codeine prescribing became more pronounced over years, "increasing from -17.5 percent one year after RCL implementation to -37.3 percent four years after implementation."
https://onlinelibrary.wiley.com/doi/10.1002/hec.4652 [2057]

A commonplace reason for using marijuana in Ptuj is as an exit drug. Even without any LSD or mushrooms, a proportion of the alcoholically-inclined realise at some point that things are not getting better. When you go drinking, it starts out good and goes downhill from there. Perhaps if I have some more it will get even better. It doesn't. In the long run most fortunately realise that the alcohol sweet spot really only lasts a very short time, and the older you get the shorter that sweet spot is.

If you want to use marijuana as an exit drug that's not a medical issue. You didn't need a prescription to get the drug that caused the problem, but you can't get one for the cure, because it's illegal. Clearly this interferes with the desire of the self-aware person in trouble with alcohol who wants an easy path to harm reduction."

A 2021 paper from Scripps Research Institute and the University of California report, which only looked at CBD, reports:

"Cannabidiol reduces craving in animal models of alcohol and cocaine use."

because...

"CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD."
https://pubmed.ncbi.nlm.nih.gov/33909102/ [839]

"Cannabidiol (CBD) facilitates cocaine extinction and ameliorates cocaine-induced changes to the gut microbiome in male C57BL/6JArc mice" say Chesworth et al (2024).

"Cocaine use disorder (CUD) is a global health problem with no approved medications. One potential treatment target is the gut microbiome, but it is unknown if cocaine induces long-lasting effects on gut microbes. A novel therapeutic candidate for CUD, cannabidiol (CBD), can improve gut function in rodent models. It is possible that protective effects of CBD against cocaine use are mediated by improving gut health. We examined this question in this experiment. Cocaine conditioned place preference (CPP) was conducted in adult male C57BL/6JArc mice. Mice were treated with vehicle or 20 mg/kg CBD prior to all cocaine CPP sessions (N = 1113/group). Mice were tested drug free 1, 14 and 28 days after cessation of cocaine and CBD treatment. Fecal samples were collected prior to drug treatment and after each test session. Gut microbiome analyses were conducted using 16 s rRNA sequencing and correlated with behavioural parameters. We found a persistent preference for a cocaine-environment in mice, and long-lasting changes to gut microbe alpha diversity. Cocaine caused persistent changes to beta diversity which lasted for 4 weeks. CBD treatment reduced cocaine-environment preference during abstinence from cocaine and returned gut beta diversity measures to control levels. CBD treatment increased the relative abundance of Firmicutes phyla and Oscillospira genus, but decreased Bacteroidetes phyla and Bacteroides acidifaciens species. Preference score in cocaine-treated mice was positively correlated with abundance of Actinobacteria, whereas in mice treated with CBD and cocaine, the preference score was negatively correlated with Tenericutes abundance. Here we show that CBD facilitates cocaine extinction memory and reverses persistent cocaine-induced changes to gut microbe diversity. Furthermore, CBD increases the abundance of gut microbes which have anti-inflammatory properties. This suggests that CBD may act via the gut to reduce the memory of cocaine reward. Our data suggest that improving gut health and using CBD could limit cocaine abuse."

https://www.sciencedirect.com/science/article/pii/S0278584624000824?via%3Dihub [3360]

Prohibition, if observed, makes it harder for people giving up smoking and cocaine.

The Defence anticipates the Court will be interested in obsessive craving. As Bnsch et al reveal in Human Molecular Genetics in 2005,

"Various studies have linked alcohol dependence phenotypes to chromosome 4. One candidate gene is NACP (non-amyloid component of plaques), coding for alpha synuclein. Recently, it has been shown that alpha synuclein mRNA is increased in alcohol-dependent patients within withdrawal state. This increase is significantly associated with craving, especially obsessive craving. On the basis of these observations, the present study analysed two polymorphic repeats within the NACP gene. We found highly significant longer alleles of NACP-REP1 in alcohol-dependent patients compared with healthy controls (KruskalWallis test, χ2=99.5; df=3, P<0.001). In addition, these lengths significantly correlate with levels of expressed alpha synuclein mRNA (χ2=8.83; df=2, P=0.012). The present results point to a novel approach for a genetic determination of craving, a key factor in the genesis and maintenance not only of alcoholism but also of addiction in general."
https://academic.oup.com/hmg/article/14/7/967/626665?login=false [2978]

According to Hallbeck et al (2024) "Accumulation of alpha-synuclein pathology in the liver exhibits post-translational modifications associated with Parkinsons disease"

"In previous work, we showed that human hepatocytes can take up α-syn assemblies via the gap junction protein connexin-32 (Cx32). Furthermore, we found an age-dependent accumulation of human α-syn pathology within the liver in multiple animal models of PD (L61, (Thy-1)-h[A30P])), and MSA (MBP29). Importantly, the accumulation of α-syn within the liver was not due to hepatic mRNA expression, indicating that α-syn deposits are derived directly from the brain or indirectly from other peripheral tissues. Moreover, we corroborated that α-syn pathology in neuropathologically confirmed PD cases can be found to a higher degree than in controls with no α-syn pathology in the brain. In the current report, we investigated the presence of α-syn post-translational modifications (PTMs) in the liver from aged (Thy-1)-h[A30P] mice (A30P). We now report the presence of hallmark PTMs associated with PD, including tyrosine nitration (nY39), phosphorylation (pY39, pS87 and pS129, Y133) and C-terminal truncation events (X-122). Ex vivo, we demonstrate that human hepatocytes (HuH-7) degrade pre-formed fibrils (PFF) more efficiently than oligomeric assemblies. However, by increasing autophagy using the pharmacological inhibitor rapamycin, we could enhance oligomeric α-syn degradation in a concentration-dependent manner. Moreover, ex vivo we also observe several PTMs that have been demonstrated in vivo. Taken together, our results demonstrate the presence of key pathological modifications associated with PD, also present in the liver of a mouse model of PD. Our findings suggest that α-syn aggregates are transported from the brain to the liver in a modified state or upon arrival, they undergo specific PTMs to facilitate their clearance and detoxification, suggesting a new role for the liver in the clearance of PD-associated pathology."
https://www.cell.com/iscience/fulltext/S2589-0042(24)02675-0 [3903]

What are the effects of cannabis on synuclein?

In "The Neuroprotective Effects of Cannabis-Derived Phytocannabinoids and Resveratrol in Parkinsons Disease: A Systematic Literature Review of Pre-Clinical Studies" (2021) by Prakash and Carter:

"A total of 1034 publications were analyzed, of which 18 met the eligibility criteria for this review. Collectively, the majority of PD rodent studies demonstrated that treatment with CDCs or RSV produced a significant improvement in motor function and mitigated the loss of dopaminergic neurons. Biochemical analysis of rodent brain tissue suggested that neuroprotection was mediated by anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms. This review highlights the neuroprotective potential of CDCs and RSV for in vivo models of PD and therefore suggests their potential translation to human clinical trials to either ameliorate PD progression and/or be implemented as a prophylactic means to reduce the risk of development of PD."

and

"Seven studies investigated the effects of RSV and CDCs on neuroinflammation in rodent brain tissue of the striatum and SNpc, and included neurotoxin models, a genetic model, as well as specific induction of neuroinflammation via LPS treatment. The results of these studies are summarized in Table 6 and have been divided by their intervention group (BCP [β-caryophyllene], THCV [tetrahydrocannabivarin], and RSV [resveratrol]), and then ascending year of study. Five studies showed increased markers of microglia and astrocytes activation via quantification of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1) protein or mRNA levels, and these were significantly reduced via administration of THCV, BCP, or RSV. Inflammatory protein markers and their complementary mRNA levels were significantly increased in the PD model groups and this was significantly countered with BCP or RSV treatment. The suppressor of cytokine signaling protein 1 (SOCS-1) was detected in α-synuclein transgenic mice and was significantly upregulated by RSV treatment."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699487/ [2979]

In "Neuroprotective effects of cannabidiol on dopaminergic neurodegeneration and α-synuclein accumulation in C. elegans models of Parkinson's disease" (2022) Muhammad et al found that:

"CBD at 0.025 mM (24.66 %), 0.05 mM (52.41 %) and 0.1 mM (71.36 %) diminished DA neuron degenerations induced by 6-hydroxydopamine (6-OHDA), reduced (0.025, 27.1 %), (0.05, 38.9 %), (0.1, 51.3 %) food-sensing behavioural disabilities in BZ555, reduced 40.6 %, 56.3 %, 70.2 % the aggregative toxicity of α-Syn and expanded the nematodes' lifespan up to 11.5 %, 23.1 %, 28.8 %, dose-dependently....these findings supported CBD as an anti-parkinsonian drug and may exert its effects by raising lipid depositions to enhance proteasome activity and reduce oxidative stress via the antioxidative pathway."
https://pubmed.ncbi.nlm.nih.gov/36108815/ [2980]

In Sao Paulo, Erustes et al (2025) found "Cannabidiol induces autophagy via CB1 receptor and reduces α-synuclein cytosolic levels":

"To investigate the participation of each cannabinoid receptor in the induction of autophagy, cells were treated with selective cannabinoid agonists that interact specifically with receptors of the human endocannabinoid system. In this way, autophagic flux was evaluated in cells treated with agonists and antagonists of cannabinoid receptors: ACEA/AM251 (10 M/10 M, CB1R), GW405833/AM630 (1 M/3 M, CB2R) and capsaicin/capsazepine (10 M/10 M, TRPV1). Cells were treated with these compounds for 4 h both in the presence or absence of NH4Cl (10 mM added during the last hour of treatment), which is used as an inhibitor of lysosomal degradation. In the groups treated with the agonist and antagonist, the antagonists were added during the first 30 min, followed by the addition of the agonists.

"The evaluation of autophagic flux demonstrated that compared with control cells and cells treated with ACEA [Arachidonoyl 2-chloroethylamide] in the absence of an inhibitor, cells stimulated with ACEA in the presence of NH4Cl accumulated LC3-II (Fig. 3a). Autophagic flux was inhibited when cells were treated with ACEA in the presence of AM251 (a CB1R antagonist); in this way, the addition of an antagonist blocked the effect of the agonist on the induction of autophagy."
https://www.sciencedirect.com/science/article/pii/S0006899324006693?via%3Dihub [3831]

Wang et al (2022) also found that:

"Cannabidivarin alleviates α-synuclein aggregation via DAF-16 in Caenorhabditis elegans"
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.202200278RR [2981]

"DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans....The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism."
https://en.wikipedia.org/wiki/Daf-16 [2984]

These studies point to the conclusion that cannabinoids inhibit synuclein. Therefore they reduce cravings as well as inhibiting neuroinflammatory pathways:

"Glycine receptors are expressed mainly in Purkinje cells. In hyperammonemic rats, enhanced glycinergic neurotransmission leads to reduced membrane expression of ADAM17, resulting in increased surface expression and activation of TNFR1 and of the associated NF-kB pathway. This increases the expression in Purkinje neurons of TNFa, IL-1b, HMGB1, and glutaminase. Increased glutaminase activity leads to increased extracellular glutamate, which increases extracellular GABA. Increased extracellular glutamate and HMGB1 potentiate microglial activation. Blocking glycine receptors with strychnine or extracellular cGMP completely prevents the above pathway in hyperammonemic rats."

And rats in this condition were used to test this because:

"Rats with chronic hyperammonemia reproduce the cognitive impairment and motor in-coordination shown by cirrhotic patients with minimal hepatic encephalopathy and are a good model to identify the underlying mechanisms and to test treatments to improve them. Chronic hyperammonemia induces neuroinflammation which alters glutamatergic and GABAergic neurotransmission in cerebellum and hippocampus leading to cognitive and motor impairment.
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01941-y [3832]

Wang et al (2022) also found that:

"Cannabidivarin alleviates α-synuclein aggregation via DAF-16 in Caenorhabditis elegans"
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.202200278R [2981]

"DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans....The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism."
https://en.wikipedia.org/wiki/Daf-16 [2984]

These studies point to the conclusion that cannabinoids inhibit synuclein. Therefore they reduce cravings as well as inhibiting neuroinflammatory pathways. As Arenas et al (2020) of the Prncipe Felipe Research Center in Valencia explain:

"Glycine receptors are expressed mainly in Purkinje cells. In hyperammonemic rats, enhanced glycinergic neurotransmission leads to reduced membrane expression of ADAM17, resulting in increased surface expression and activation of TNFR1 and of the associated NF-kB pathway. This increases the expression in Purkinje neurons of TNFa, IL-1b, HMGB1, and glutaminase. Increased glutaminase activity leads to increased extracellular glutamate, which increases extracellular GABA. Increased extracellular glutamate and HMGB1 potentiate microglial activation. Blocking glycine receptors with strychnine or extracellular cGMP completely prevents the above pathway in hyperammonemic rats."

And rats in this condition were used to test this because:

"Rats with chronic hyperammonemia reproduce the cognitive impairment and motor in-coordination shown by cirrhotic patients with minimal hepatic encephalopathy and are a good model to identify the underlying mechanisms and to test treatments to improve them. Chronic hyperammonemia induces neuroinflammation which alters glutamatergic and GABAergic neurotransmission in cerebellum and hippocampus leading to cognitive and motor impairment.
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01941-y [3832]

In the main, however, study of alpha-synucleinopathies is focussed on PD. A summary of the findings around alpha-synuclein can be found in Table 1 (PD), and other alpha-synucleinopathies in "Peripheral Tissues as a Possible Marker for Neurological Diseases and Other Medical Conditions" by Jimnez-Jimnez et al (2023).
https://www.researchgate.net/publication/373232996_Alpha-Synuclein_in_Peripheral_Tissues_as_a_Possible_Marker_for_Neurological_Diseases_and_Other_Medical_Conditions/link/64e191cd14f8d173380c05fe/download[2982]



Here we can see the difference between PD and MSA [multiple system atrophy] filamentous structures which was found to be significant enough for a distinguishing diagnosis.

Says Prof. Nobutaka Hattori, at the Department of Neurology of Juntendo University and current head of the Neurodegenerative Disorders Collaboration Laboratory at RIKEN Centre for Brain Science,

"'Our team has also discovered, for the first time, that these α-synuclein seeds have structures and properties characteristic of each disease, suggesting that they shape the pathology of each synucleinopathy.'"
https://www.uni.lu/en/news/ground-breaking-discovery-for-diagnosing-neurodegenerative-diseases/ [2983]

How many person years have been lost to alpha-synucleinopathies due to cannabis prohibition? The Defence believes it is lots. More than zero.

In a study published in Drug Alcohol Dependency by Cano, Oh et al (2022)

"Peer-reviewed studies and doctoral dissertations published in English between 1990 and July 19, 2022 were identified from PubMed, Web of Science, ProQuest Dissertations & Theses, PsycINFO, CINAHL, and EconLit. Eligible studies examined at least one county-level predictor of drug overdose mortality in US counties."

and

"Of 56 studies included, 42.9% were subnational, and 53.6% were limited to opioid overdose. In multiple studies, measures related to opioid prescribing, illness/disability, economic distress, mining employment, incarceration, family distress, and single-parent families were positively associated with drug overdose mortality outcomes, while measures related to cannabis dispensaries, substance use treatment, social capital, and family households were negatively associated with drug overdose mortality outcomes."
https://www.sciencedirect.com/science/article/abs/pii/S0376871622004513?via%3Dihub [1823]

Patients undergoing primary THA (total hip arthroplasty) or TKA (total knee arthroplasty) with minimum 6-month follow-up who self-reported cannabis use were retrospectively reviewed. A total of 210 patients (128 TKAs and 82 THAs) were matched by age; gender; type of arthroplasty. Self-reported perioperative cannabis use appeared to significantly reduce the number of patients that persistently used opioids greater than 90 days after TJA from 9.5% to 1.4%. [P<.001]

With cannabis, three patients instead of 20 showed persistent opioid use.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9493281/ [1824]

In "Use of Cannabis for Harm Reduction Among People at High Risk for Overdose in Vancouver, Canada (20162018)" Mok et al (2021) report that it's a common strategy for people trying to recover:

"We drew data about recent cannabis use and intentions from 3 prospective cohort studies of marginalized people who use drugs based in Vancouver, Canada, from June 2016 to May 2018. The primary outcome was use of cannabis for harm reduction, defined as using cannabis for substitution for licit or illicit substances such as heroin or other opioids, cocaine, methamphetamine, or alcohol; treating withdrawal; or coming down off other drugs.

"Results. Approximately 1 in 4 participants reported using cannabis for harm reduction at least once during the study period. The most frequent reasons included substituting for stimulants (50%) and substituting for illicit opioids (31%)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033988/ [3149]

Another meth study "Cannabidiol mechanism of action on modulating extinction and reinstatement of methamphetamine-seeking behavior: Targeting D2-like dopamine receptors in the hippocampus" by Omidiani et al (2025):

"Multiple lines of evidence suggest that CBD exerts its effects by modulating the mesocorticolimbic dopamine system. D2-like receptors in the CA1 region of the hippocampus play a significant role in relaying memory and emotional signals related to the processing of drug-related cues. Therefore, this study aims to investigate the role of CA1 D2-like receptors in mediating the effects of CBD on METH-seeking behavior during extinction and reinstatement in the conditioned place preference (CPP) model. For this purpose, rats were administered various doses of Sulpiride (0.25,1, or 4 μg/0.5 μl) as a D2-like receptor antagonist before intracerebroventricular (ICV) injection of CBD (10 μg/5 μl) during a 10-day extinction period. Additionally, a separate group of rats received Sulpiride (0.25,1, or 4 μg/0.5 μl) before a single CBD injection (50 μg/5 μl) on the reinstatement day. The findings indicated that Sulpiride (1 and 4 μg) significantly attenuated CBD's acceleration of METH-CPP extinction (p < 0.01 and p < 0.05, respectively). Moreover, Sulpiride (1 and 4 μg) during the reinstatement phase notably reversed CBD's preventive effects on the reinstatement of reward-seeking behavior (p < 0.05 and p < 0.001, respectively). In summary, these results suggest that CBD's ability to shorten the extinction period and suppress METH reinstatement is partially mediated through interactions with D2-like dopamine receptors in the CA1 region of the hippocampus. These findings offering insight into more precise and effective interventions for METH use disorder."
https://www.sciencedirect.com/science/article/abs/pii/S0022395625004091 [5402]

Danesh et al (2025) conclude that "D1-like dopamine receptors in the dentate gyrus mediate cannabidiol's facilitation of extinction and prevention of reinstatement in methamphetamine-induced conditioned place preference":

"Methamphetamine (METH) is a highly addictive psychostimulant, and despite its widespread abuse, there are no FDA-approved treatments for METH use disorder (MUD). Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise in reducing behaviors linked to psychostimulant use, including METH. However, the underlying neurobiological mechanisms remain unclear. Emerging evidence suggests that CBD may act on the dopamine system to influence drug-seeking behavior. D1-like dopamine receptors (D1Rs) in the hippocampus (HPC) are involved in memory processes related to rewards, which may contribute to CBD's effects. This study examined whether D1Rs in the dentate gyrus (DG) region of the HPC play a role in CBD's modulation of METH-induced conditioned place preference (CPP) during extinction and reinstatement. Adult male Wistar rats received the D1Rs antagonist SCH23390 (0.25, 1, and 4 μg/0.5 μl saline) into the DG region before intracerebroventricular injection of CBD (10 and 50 μg/5 μl of 12 % DMSO). Results show that the highest dose of SCH23390 (4 μg) significantly blocked CBD's ability to enhance extinction of METH-CPP. Moreover, SCH23390 (1 and 4 μg) reversed CBD's prevention of reinstatement of METH-CPP. These findings suggest that D1Rs in the DG region are involved in mediating CBD's effects and offer insights into its therapeutic potential for MUD."
https://www.sciencedirect.com/science/article/abs/pii/S0091305725001418 [5403]

Balu et al (2021) report:

"Overall, the average change in prescribed opioid use was found to be -12.3 morphine milligram equivalent (MME) units when including all individuals (p < 0.00001)."

They break it down.

In this study, we examined individuals who were provided with legal; medical cannabis certifications in the state of Delaware between June 2018 and October 2019 and were concurrently being treated with opioid medications for chronic pain at a private pain management practice. For non-outlier individuals with positive baseline opioid use before receiving medical marijuana certification (n=63), the average percent change in opioid use was found to be -31.3 percent. Examining subgroups based upon pain location, individuals with low back pain (n=58) displayed a 29.4 percent decrease in MME [morphine milligram equivalent] units, while individuals with neck pain (n=27) were observed to have a 41.5 percent decrease in opioid use. Similarly, individuals with knee pain (n=14) reduced their opioid use by 32.6 percent. Since the underlying pathology and their source of pain in the individuals was unlikely to significantly change during the period examined, medical marijuana use could have played a large role in allowing the individuals to decrease their opioid use."
https://www.cureus.com/articles/77114-medical-cannabis-certification-is-associated-with-decreased-opiate-use-in-patients-with-chronic-pain-a-retrospective-cohort-study-in-delaware [1825]

More than a quarter of U.S. adults suffering from chronic pain have turned to using cannabis to manage their discomfort, according to a study published in JAMA Open Network.

Researchers at Michigan Medicine surveyed 1,661 adults last spring with chronic pain who lived in one of the 36 states with active medical cannabis programs and Washington, D.C.

About 26 percent of survey participants reported using cannabis within the past year to manage pain, Bicket et al found. Moreover:

"More than half of adults who used cannabis to manage their chronic pain reported that use of cannabis led them to decrease use of prescription opioid, prescription nonopioid, and over-thecounter pain medications, and less than 1% reported that use of cannabis increased their use of these medications (Figure 1). Fewer than half of respondents reported that cannabis use changed their use of nonpharmacologic pain treatments. Among adults with chronic pain in this study, 38.7% reported that their used of cannabis led to decreased use of physical therapy (5.9% reported it led to increased use), 19.1% reported it led to decreased use of meditation (23.7% reported it led to increased use), and 26.0% reported it led to decreased used of cognitive behavioral therapy (17.1% reported it led to increased use) (Figure 2)."
https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2800119/bicket_2023_ld_220293_1671719838.02096.pdf  [2011]

"Δ8-Tetrahydrocannabivarin has potent anti-nicotine effects in several rodent models of nicotine dependence" revealed Xi et al in 2019:

"Both types of cannabinoid receptorsCB1 and CB2 regulate brain functions relating to addictive drug-induced reward and relapse. CB1 receptor antagonists and CB2 receptor agonists have anti-addiction efficacy, in animal models, against a broad range of addictive drugs. Δ9-Tetrahydrocannabivarin (Δ9-THCV)a cannabis constituentacts as a CB1 antagonist and a CB2 agonist. Δ8-Tetrahydrocannabivarin (Δ8-THCV) is a Δ9-THCV analogue with similar combined CB1 antagonist/CB2 agonist properties.

"Experimental Approach: We tested Δ8-THCV in seven different rodent models relevant to nicotine dependencenicotine self-administration, cue-triggered nicotine-seeking behaviour following forced abstinence, nicotine-triggered reinstatement of nicotine-seeking behaviour, acquisition of nicotine-induced conditioned place preference, anxiety-like behaviour induced by nicotine withdrawal, somatic withdrawal signs induced by nicotine withdrawal, and hyperalgesia induced by nicotine withdrawal.

"Key Results: Δ8-THCV significantly attenuated intravenous nicotine self-administration and both cue‐induced and nicotine-induced relapse to nicotine-seeking behaviour in rats. Δ8-THCV also significantly attenuated nicotine-induced conditioned place preference and nicotine withdrawal in mice."

and

"In summary, most studies on animal models for substance use disorders reported some beneficial effects for the cannabinoids under investigation, except for CBDA (see Fig. 3). Δ8-THCV showed anti-nicotine-dependence properties, while CBN, Δ8-THC, and 11-OH-Δ8-THC appeared to reduce morphine-withdrawal symptoms. Δ8-THC also seemed to have some capacity to inhibit the reinstatement of METH-seeking behavior. CBDA was not effective in reducing METH-induced or cocaine-seeking behaviors."

https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bph.14844[3808]

Kitchen et al (2025) examined "Cannabis use and illicit opioid cessation among people who use drugs living with chronic pain":

"Between June 2014 and May 2022, 2340 PWUD were initially recruited and of those 1242 PWUD reported chronic pain, use of unregulated opioids and completed at least two follow-up visits. Of these 1242 participants, 764 experienced a cessation event over 1038.2 person-years resulting in a cessation rate of 28.5 per 100 person-years (95% confidence interval [CI] 25.431.9). Daily cannabis use was positively associated with opioid cessation (adjusted hazard ratio 1.40, 95% CI 1.081.81; p = 0.011). In the sex-stratified sub-analyses, daily cannabis use was significantly associated with increased rates of opioid cessation among males (adjusted hazard ratio 1.50, 95% CI 1.092.08; p = 0.014)."
https://onlinelibrary.wiley.com/doi/abs/10.1111/dar.14014 [4794]

"Efficacy of cannabidiol alone or in combination with Δ-9-tetrahydrocannabinol for the management of substance use disorders: An umbrella review of the evidence" from Bertrand Redonnet et al (2025)

"...searched PubMed, Web of Science and Epistemonikos databases for SRs, with or without a meta-analysis, of randomized controlled trials focusing on interventions dispensing CBD, alone or in combination with THC, to treat SUDs, published from 1 January 2000 to 15 October 2024.

The results supported combined THC and CBD:

"22 SRs were included, 5 of which performed a meta-analysis. We found mixed evidence regarding the efficacy of CBD to manage and treat SUDs. Findings were interpreted in light of the quality of the SRs. Nabiximols, which contains CBD and THC, demonstrated positive effects on cannabis withdrawal and craving symptoms. Evidence supporting the efficacy of CBD is limited and inconclusive for abstinence, reduction or cessation of use of cannabis, tobacco, alcohol, opiates and other psychoactive substances.

"Conclusion
Cannabidiol (CBD) monotherapy does not appear to be efficacious for treatment of substance use disorders. CBD primarily exhibits effects on cannabis withdrawal and craving when combined with Δ-9-tetrahydrocannabinol (THC). Existing data on the efficacy of CBD alone with regard to other outcomes related to substance use disorders are limited."
https://onlinelibrary.wiley.com/doi/10.1111/add.16745 [4755]

 
https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/download/239/169 [4767]

Several descriptive commentaries from opoid users fighting addiction are featured in Ganesh et al (2024) "'Smoking weed it gets you over the hump': Cannabis co-use as a facilitator of decreased opioid use among people who inject drugs in Los Angeles, California" including this one:

"Participants also described using cannabis to mitigate opioid cravings after they had stopped regular use and were no longer experiencing withdrawal symptoms. This person reported that it helped them to 'get over the hump' of craving opioids and continue not to use.

"'I was really trying to get off of opiates and using weed, really helps to not have the first urge to use opiates. When you're addicted and you have a habit, then you have to use opiates. But when you don't have a habit and you're not getting sick from it every day, when you're smoking weed it gets you over the hump and that urge to get high for the first time. And that's what's so special out [sic] weed.' (5115 26, Male, Housed)"
https://www.sciencedirect.com/science/article/pii/S2772724624000416 [5063]

Looking at "Recreational Cannabis Laws and Fills of Pain Prescriptions in the Privately Insured" Steuart et al (2025) found no good cheer for the manufacturers and distributors of opioids:

"Objective: Almost half of U.S. states have passed recreational cannabis laws as of May 2024. While considerable evidence to date indicates cannabis may be a substitute for prescription opioids in the treatment of pain, it remains unclear if patients are treating pain with cannabis alone or concomitantly with other medications.Method: Using data from a national sample of commercially insured adults, we examine the effect of recreational cannabis legalization (through two sequential policies) on prescribing of opioids, NSAIDS, and other pain medications by implementing synthetic control estimations and constructing case-study level counterfactuals for the years 2007-2020. Results: Overall, we find recreational cannabis legalization is associated with a decrease in opioid fills among commercially insured adults in the U.S., and we find evidence of a compositional change in prescriptions of pain medications more broadly. Specifically, we find marginally significant increases in prescribing of non-opioid pain medications after recreational cannabis becomes legal in some states. Once recreational cannabis dispensaries open, we find statistically significant decreases in the rate of opioid prescriptions (13% reduction from baseline, p<.05) and marginally significant decreases in the average daily supply of opioids (6.3% decrease, p<.10) and number of opioid prescriptions per patient (3.5% decrease, p<.10). Conclusions: These results suggest that substitution of cannabis for traditional pain medications increases as the availability of recreational cannabis increases. There appears to be a small shift once recreational cannabis becomes legal, but we see stronger results once users can purchase cannabis at recreational dispensaries.The decrease in opioids and marginal increase in non-opioid pain medication may reflect patients substituting opioids with cannabis and non-opioid pain medications, either separately or concomitantly. Reductions in opioid prescription fills stemming from recreational cannabis legalization may prevent exposure to opioids in patients with pain and lead to decreases in the number of new opioid users, rates of opioid use disorder, and related harms."
https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/view/268/181 [5073]

Carey et al (2025) created some junkie monkeys to test the "Effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC:CBD mixtures on behavioral and physiological signs of morphine withdrawal in rhesus monkeys":

"Monkeys received escalating doses of morphine up to 3.2 mg/kg twice daily. After at least 2 weeks of morphine treatment, saline was substituted for morphine for 2 days. Behavioral and physiological signs of opioid withdrawal, including blood pressure, heart rate, body temperature, and activity were measured before and after administration of THC (0.321.0 mg/kg), CBD (1017.8 mg/kg), mixtures of THC (0.32 mg/kg) and CBD (1017.8 mg/kg), lofexidine (0.0320.32 mg/kg), or vehicle. Discontinuing morphine treatment markedly increased unusual tongue movements, a characteristic behavioral sign of opioid withdrawal in monkeys, and all physiological signs. The largest THC dose (1.0 mg/kg) decreased unusual tongue movements and heart rate, and the largest lofexidine dose (0.32 mg/kg) decreased unusual tongue movements, blood pressure, heart rate, and activity. CBD alone or with THC had no significant effect. These data demonstrate that THC attenuates some signs of opioid withdrawal; however, THC was not more effective than the currently available medication lofexidine."
https://www.sciencedirect.com/science/article/abs/pii/S0022356525398848 [5326]

In "Cannabis Use, Problem-Gambling Severity, and Psychiatric Disorders: Data from the National Epidemiological Survey on Alcohol and Related Conditions" (2019) Hammond et al

"... examined data from the first wave (20012002) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large, national survey of non-institutionalized U.S. adults, to examine relationships between problem-gambling severity and psychopathology in individuals with and without cannabis use. At the time of data collection of the first wave of the NESARC, medical cannabis use had been legalized in eight states; however, its recreational or non-medical use had not been legalized in any state. In addition, prevalence estimates of past-year use during this time period has ranged from 4.1% (Hasin et al., 2015) to 11% (Azofeifa, Mattson, Schauer, McAfee, Grant, & Lyerla, 2016). "In all cases, associations between problem-gambling severity and psychopathologies were weaker among the lifetime-cannabis-using group as compared to the never-using group.. Cannabis use moderates the relationships between problem-gambling severity and psychiatric disorders, with cannabis use appearing to account for some of the variance in the associations between greater problem-gambling severity and specific forms of psychopathology."






"Associations between problem-gambling severity and psychopathology among lifetime-cannabis-using and never-using groups. Figures compare odds ratios for specific disorders in association with low-risk gambling (LRG), at-risk gambling (ARG), and problem/pathological gambling (PPG), using of non-gambling/low frequency gambling as a reference group. Specific disorders are those as follows: A. Interactions with cannabis use in the associations between major depression and problem-gambling severity. B. Interactions with cannabis use in the associations between panic disorder and problem-gambling severity. C. Interactions with cannabis use in the associations between alcohol abuse/dependence and problem-gambling severity. D. Interactions with cannabis use in the associations between nicotine dependence and problem-gambling severity. E. Interactions with cannabis use in the associations between cluster A personality disorder and gambling severity. F. Interactions with cannabis use in the associations between cluster B personality disorders and problem-gambling severity. * Indicates statistically significant odds ratios at p<0.05. ** Indicates statistically significant interactions at p<0.05."

and

"Furthermore, cannabis-use status moderated the relationships problem-gambling severity and specific psychiatric disorders including major depression, panic disorder, alcohol-use disorders, nicotine dependence, cluster A PDs (especially paranoid PD), and cluster B PDs (especially antisocial PD)."

However Dr Hammond, who has

"...received support from the American Psychiatric Association Child & Adolescent Fellowship, an unrestricted education grant supported by Shire Pharmaceuticals and the American Academy of Child & Adolescent Psychiatry Pilot Research Award for Junior Investigators supported by Lilly USA, LLC. Dr. Marc Potenza has received financial support or compensation for the following: Dr. Potenza has consulted for and advised Shire, INSYS, RiverMend Health, Opiant/Lakelight Therapeutics, and Jazz Pharmaceuticals; has received unrestricted research support from Mohegan Sun Casino and grant support from the National Center for Responsible Gaming"

...tries to highlight cannabis in problem gambling, his own Figure 1 tells the real story. Even under prohibition conditions, it was another blow for NECUD/SPUK sufferers, who were worse at gambling and at being crazy too.

I've used my incredible graphics skills to show how the anti-cannabis woowoo is favoured by the layout of the histograms in Figure 1.

Please compare



...which charts interactions with cannabis use in the associations between major depression and problem-gambling severity for low-risk gambling (LRG), at-risk gambling (ARG), and problem/pathological gambling (PPG groups), with



...a left to right mirror image of 1A. You can see cannabis looks much better now, and we have begun with the most serious problem gamblers and worked our way downwards. I have not done mirror images for charts B-F, I'm sure the Court can imagine that for itself.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933114 [2711]

Another survey, published in JAMA Psychiatry by Grubbs and Kraus in 2024, found a relationship between problem drinking and problem gambling:

"A total of 4363 respondents were included (51.4% men, 46.4% women, and 2.2% nonbinary or other; mean [SD] age, 49.6 [16.2] years) (Table 1). The national census-matched survey consisted of 2806 participants (mean [SD] age, 48.9 [17.2] years; 1365 [48.6%] men and 1441 [51.4%] women; response rate, 2806 of 3203 [87.6%]). The oversample of sports gamblers consisted of 1557 participants (mean [SD] age, 41.7 [15.3] years; 1043 [67.0%] men and 514 [33.0%] women; response rate, 1557 of 1978 [78.7%]), of whom 1474 reported past year sports betting. Additionally, in the national sample, 338 respondents (12.0%) indicated they had gambled on sports in the past 12 months, resulting in a total of 1812 sports gamblers (Table 1). Sports gamblers were disproportionally likely to be men and younger. In these combined samples, 3267 respondents (74.9%) reported past year alcohol use. Sports wagerers were disproportionately more likely to report binge drinking at monthly or greater frequency over the past 12 months and were also disproportionately less likely to report no binge drinking episodes in the past 12 months (Table 1). Multinomial logistic regressions adjusted for age and race and ethnicity showed that sports gamblers were substantially more likely to report higher levels of binge drinking (Table 2), suggesting that elevated risky drinking episodes among sports gamblers are not due to demographic differences."
https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2816784/grubbs_2024_ld_240031_1710953595.81812.pdf [3483]

In view of the foregoing, we should not be surprised if "Expectancy of impairment attenuates marijuana-induced risk taking" (2017):

"Participants (N=136) were regular marijuana users. A balanced placebo design (BPD) was used crossing marijuana administration (i.e., 0% Tetrahydrocannabinol (THC) vs. 2.8% THC) with stimulus expectancy (i.e., Told Placebo vs. Told THC). Marijuana outcome expectancies were measured by self-report and dependent measures including a number of behavioral impulsivity tasks and the balloon analogue risk task (BART). ResultsAmong participants who received THC, higher expectancies for cognitive-behavioral impairment (CBI) were related to lower risk-taking on the BART. Among those who received placebo, there was no association between CBI expectancies and BART performance. CBI expectancies did not moderate drug effect on the BART and drug or stimulus expectancy effects on impulsivity measures."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC5796549&blobtype=pdf [2712]

 
"Treating alcoholism by cannabis substitution creates a different doctor-patient relationship," says Mikuriya.

"Patients seek out the physician to confer legitimacy on what they are doing or are about to do. My most important service is to end their criminal status, Aeschalapian protection from the criminal justice system, which often brings an expression of relief. An alliance is created that promotes candor and trust. The physician is permitted to act as a coach or an enabler in a positive sense." [3822]

Summarising the criteria for any substitution "treatment"...

"1. It should reduce alcohol use and related harms.

"2. It should ideally be free of harms, or at least less harmful than alcohol.

"3. Misuse should be less than that of alcohol.

"4. It should be shown that it can substitute for alcohol and not be used along with alcohol.

"5. It should be safer in overdose than alcohol.

"6. It should ideally not potentiate the effects of alcohol especially if either drug is taken in overdose.

"7. It should offer significant health economic benefits."

...Chick and Nutt (2012) found six criteria wholly satisfied by cannabis, while one (number 6) was partially satisfied, due to disagreement on whether it potentiates alcohol. The answer to that is, only if you drink alcohol. For details see Subbaraman's Table 1.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3992908/ [3823]

Cannabis legalisation in Slovenia can be expected to reduce morbidity, mortality and costs related to tobacco use. According to a survey of 9003 subjects by Pravosud et al (2024)

"In this longitudinal study, a web-based survey was administered to a nationally representative, population-based panel of US adults in 2017, 2020, and 2021. We used weighted unadjusted binomial logistic GEE models to assess changes in prevalence of cannabis, tobacco/nicotine use and co-use and weighted, adjusted binary logistic GEE models to assess associations of cannabis legalization with cannabis, tobacco/nicotine use and co-use."

"Between 2017 and 2021 current cannabis use increased +3.3 % and was higher in states with medical and recreational cannabis.

"Recreational cannabis legalization increased the odds of current cannabis use by 1.13 times above the effect of medical legalization.

"Current tobacco use declined −1.9 %, but this change was not associated with legalization."
https://www.sciencedirect.com/science/article/pii/S0955395924003025?via%3Dihub [4810]

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The Englishman stands for the rights of everyone disadvantaged, discriminated against, persecuted, and prosecuted on the false or absent bases of prohibition, and also believes the victims of these officially-sanctioned prejudices have been appallingly treated and should be pardoned and compensated.

The Englishman requests the return of his CaPs and other rightful property, for whose distraint Slovenia has proffered no credible excuse or cause.

The Benedictions represent both empirical entities as well as beliefs. Beliefs which the Defence evidence shows may be reasonably and earnestly held about the positive benefits of CaPs at the population level, in which the good overwhelmingly outweighs the bad. Below, the latest version of this dynamic list.




THE BENEDICTIONS                            REFERENCES                        TIMELINE OF DRUG LAW v. SCIENCE