LIVER DISEASE

Following the runaway success of "alcohol use disorder" attempts to set up a rival disorder - "cannabis use disorder" - met with little success:



Sticking to the script, Fakhoury et al (2025) found that alcoholics are less likely to die from alcoholic liver disease (ALD) by abusing cannabis:

"Using the TriNetX US Collaborative Network, we identified adult patients with AUD between 2010 and 2022. Three cohorts were constructed: cannabis use disorder (CUD), cannabis users without cannabis abuse or dependence (CU) and non-cannabis users (non-CU). Outcomes included ALD, hepatic decompensation and composite all-cause mortality over 3 years. Incidence and hazard ratios were calculated using Kaplan-Meier analysis and Cox regression.

"Results: After matching, 33 114 patients were included in each of the CUD and non-CU groups. Compared to non-CU, CUD was associated with a lower risk of ALD (HR 0.60, 95% CI 0.53-0.67; p < 0.001), hepatic decompensation (HR 0.83, 95% CI 0.73-0.95; p =0.005) and all-cause mortality (HR 0.86, 95% CI 0.80-0.94; p < 0.001) among individuals with AUD. Although CU was associated with lower risks of ALD, its risks of hepatic decompensation and all-cause mortality were similar to those of the non-CU cohort with AUD."

Notice how in these unpleasant results "similar" means the same as 40%, 17%, and 14% lower risks.
https://pubmed.ncbi.nlm.nih.gov/41117396/ [5505]

Not all liver disease is exclusively alcohol-related.

"Increased incidence of obesity and excess weight lead to an increased incidence of non-alcoholic fatty liver disease. FLI [Fatty Liver Index] scores than non-users (F = 13.874; p < .001). Moreover, cannabis users less frequently met the criteria for liver steatosis than non-users (X2 = 7.97, p = .019). Longitudinally, patients maintaining cannabis consumption after 3 years presented the smallest increment in FLI over time, which was significantly smaller than the increment in FLI presented by discontinuers (p = .022) and never-users (p = .016). No differences were seen in fibrosis scores associated with cannabis."
https://www.sciencedirect.com/science/article/abs/pii/S0278584619301393 [541]

Castro and Abdel Bermdez-del Sol (2025) present an alternative name for NAFLD:

"Potential associations have been investigated between metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, and cannabis use. This study aimed to determine the association between cannabis use frequency and MASLD. Up to January 2025, the evidence from PubMed, Scopus, and Web of Science was synthesized in this systematic review and meta-analysis, which was registered in PROSPERO (CRD42025025065) and followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Of the 711 initial records, 11 observational studies involving 5,968,702 individuals met the inclusion criteria. A pooled analysis revealed that cannabis use was associated with a reduced risk of hepatic steatosis (OR = 0.58; 95% CI: 0.42-0.81; p = 0.002; I = 97%). The subgroup analysis revealed a protective association for past users (OR = 0.84; 95% CI: 0.77-0.93) and occasional users (OR = 0.35; 95% CI: 0.20-0.64), with no significant association observed for frequent users. The study revealed that cannabis users exhibited a decline in both the fatty liver index (mean difference (MD) = -11.02) and the BMI (MD = -1.89 kg/m). However, the findings did not show any statistically significant changes in liver fat (%), transaminases (aspartate aminotransferase and alanine aminotransferase), and triglycerides. A risk-of-bias assessment identified notable methodological limitations. Overall, the findings suggest a strong association between cannabis use and MASLD, though causality cannot be established."
https://www.researchgate.net/profile/Nestor-Quinapanta-Castro/publication/395836766_A_Systematic_Review_and_Meta-Analysis_of_Cannabis_Use_Frequency_and_Metabolic_Dysfunction-Associated_Steatotic_Liver_Disease_Scapegoat_or_Healer/links/68d5556cf3032e2b4be32fd8/A-Systematic-Review-and-Meta-Analysis-of-Cannabis-Use-Frequency-and-Metabolic-Dysfunction-Associated-Steatotic-Liver-Disease-Scapegoat-or-Healer.pdf?_tp=eyJjb250ZXh0Ijp7ImZpcnN0UGFnZSI6InB1YmxpY2F0aW9uIiwicGFnZSI6InB1YmxpY2F0aW9uIn19 [5537]

According to the BMJ:

"Nonalcoholic hepatic steatosis, or nonalcoholic fatty liver disease (NAFLD), is one of the most common causes of chronic liver disease in the developed world.

"It is a spectrum of disease, ranging from hepatic fat accumulation without inflammation to steatohepatitis, fibrosis, cirrhosis, and end-stage liver disease.

"NAFLD is considered the hepatic manifestation of metabolic syndrome and is associated with obesity, dyslipidemia, and type 2 diabetes mellitus.

"The diagnosis of nonalcoholic fatty liver disease is based on exclusion of other etiologies of hepatic steatosis, such as alcohol use, and supportive laboratory tests and imaging. Liver biopsy and histology is the gold standard for diagnosis, and is performed for patients at higher risk of fibrosis or steatohepatitis."

and

"Hepatic steatosis occurs when intrahepatic fat is ≥5% of liver weight.

"Nonalcoholic fatty liver disease (NAFLD) is evidence of hepatic steatosis (imaging or histologic) in the absence of secondary causes of hepatic fat accumulation, such as significant alcohol consumption.

"NAFLD can be categorized as nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH), depending on histologic features. NAFL is the presence of hepatic steatosis without evidence of hepatocellular injury in the form of hepatocyte ballooning. NASH is the presence of hepatic steatosis and inflammation with hepatocyte injury (e.g., ballooning), with or without fibrosis. This distinction is important for prognosis because NASH may progress to cirrhosis and liver failure. The risk of NAFL progressing to cirrhosis or liver failure is minimal.

"To more accurately reflect the pathogenesis of fatty liver, a new nomenclature of metabolic associated fatty liver disease (MAFLD) has been suggested."
https://bestpractice.bmj.com/topics/en-us/796 [1968]

After five years of ZPPPD-inspired liver damage, the benefits of cannabis could be inferred from studies of endocannabinoid action. In a groundbreaking step, Osei-Hyiaman et al first demonstrated that CB1R deficiency in mice conveys a protective effect against diet-induced hepatic steatosis, independent of caloric intake, in "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity" (2005):

"Endogenous cannabinoids acting at CB(1) receptors stimulate appetite, and CB(1) antagonists show promise in the treatment of obesity. CB(1) (-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB(1) in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB(1) agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB(1). High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, and the latter is reduced by CB(1) blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB(1) ligands. We conclude that anandamide acting at hepatic CB(1) contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation."
http://www.jci.org/articles/view/23057/files/pdf [3962]

Even without alcoholism, liver disease will knock nearly three years off your life:

"In this nationwide population-based cohort, all patients with NAFLD diagnosis and without baseline CVD (ascertaining from the Swedish National Patient Register from 1987 to 2016, n = 10,023) were matched 10:1 on age, sex, and municipality to individuals from the general population (controls, n = 96,313). CVD diagnosis and mortality were derived from national registers. Multistate models and flexible parametric survival models were used to estimate adjusted hazard ratios (aHRs) for CVD risk and loss in life expectancy due to NAFLD. We identified 1037 (10.3%) CVD events in patients with NAFLD and 4041 (4.2%) in controls. CVD risk was 2.6-fold higher in NAFLD compared with controls (aHR = 2.61, 95% CI = 2.362.88) and was strongest for nonfatal CVD (aHR = 3.71, 95% CI = 3.294.17). After a nonfatal CVD event, the risk for all-cause mortality was similar between patients with NAFLD and controls (aHR = 0.89, 95% CI = 0.641.25). Life expectancy in patients with NAFLD was, on average, 2.8 years lower than controls, with the highest loss of life-years when NAFLD was diagnosed in middle age (4060 years).

"Conclusions
NAFLD was associated with a higher risk of nonfatal CVD but did not affect post-CVD mortality risk. Patients diagnosed with NAFLD have a lower life expectancy than the general population."

As for cardiovascular events in those with a liver diagnosis:

"Patients with NAFLD and cirrhosis at baseline had higher rates of all CVD events in the first model (HR 7.92, 95% CI = 4.7113.3), although this estimate was lower after adjustments for CVD risk factors (aHR 2.56, 95% CI = 1.315.01)."

and

"Several observations can be made from this large nationwide cohort study set in a secondary or tertiary setting. First, we found an elevated risk of nonfatal CVD events in patients with NAFLD compared with matched controls. Second, patients with cirrhosis had a higher CVD risk than controls, but not compared to patients with noncirrhotic NAFLD. Third, while NAFLD was associated with increased overall mortality, no increased mortality was observed in patients with NAFLD with incident CVD compared to matched controls who had also experienced a nonfatal CVD event. Finally, the overall loss of life expectancy in patients with NAFLD was about 3 years, which was affected by age and clinical setting at diagnosis. LEL [loss of expectancy in life] was highest in hospitalized patients and when the diagnosis of NAFLD was made at middle age, whereas no apparent loss in life expectancy was observed for those aged ≥80."
https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32519 [1967]

In 2017's "Cannabis use is associated with reduced prevalence of non-alcoholic fatty liver disease: A cross-sectional study", Adejumo et al... "...conducted a population-based case-control study of 5,950,391 patients using the 2014 Healthcare Cost and Utilization Project (HCUP), Nationwide Inpatient Survey (NIS) discharge records of patients 18 years and older. After identifying patients with NAFLD (1% of all patients), we next identified three exposure groups: non-cannabis users (98.04%), non-dependent cannabis users (1.74%), and dependent cannabis users (0.22%). We adjusted for potential demographics and patient related confounders and used multivariate logistic regression (SAS 9.4) to determine the odds of developing NAFLD with respects to cannabis use. Our findings revealed that cannabis users (dependent and nondependent) showed significantly lower NAFLD prevalence compared to non-users (AOR: 0.82[0.760.88]; p<0.0001). The prevalence of NAFLD was 15% lower in non-dependent users (AOR: 0.85[0.790.92]; p<0.0001) and 52% lower in dependent users (AOR: 0.49 [0.360.65]; p<0.0001). Among cannabis users, dependent patients had 43% significantly lower prevalence of NAFLD compared to non-dependent patients (AOR: 0.57[0.420.77]; p<0.0001). Our observations suggest that cannabis use is associated with lower prevalence of NAFLD in patients. These novel findings suggest additional molecular mechanistic studies to explore the potential role of cannabis use in NAFLD development."
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0176416&type=printable [2772]

In 2020 Collaborators of the ANRS CO13 HEPAVIH Study Group report:

"Mortality among individuals co-infected with HIV and hepatitis C virus (HCV) is relatively high. We evaluated the association between psychoactive substance use and both HCV and non-HCV mortality in HIV/HCV co-infected patients in France, using Fine and Gray's competing-risk model adjusted for socio-demographic, clinical predictors and confounding factors, while accounting for competing causes of death. Over a 5-year median follow-up period, 77 deaths occurred among 1028 patients. Regular/daily cannabis use, elevated coffee intake, and not currently smoking were independently associated with reduced HCV-mortality (adjusted sub-hazard ratio [95% CI] 0.28 [0.10-0.83], 0.38 [0.15-0.95], and 0.28 [0.10-0.79], respectively). Obesity and severe thinness were associated with increased HCV-mortality (2.44 [1.00-5.93] and 7.25 [2.22-23.6] versus normal weight, respectively). Regular binge drinking was associated with increased non-HCV-mortality (2.19 [1.10-4.37]). Further research is needed to understand the causal mechanisms involved. People living with HIV/HCV co-infection should be referred for tobacco, alcohol and weight control interventions and potential benefits of cannabis-based therapies investigated."
https://pubmed.ncbi.nlm.nih.gov/31286317/ [3385]

From the perspective of organ damage from alcohol, Yan et al set out to settle the vexed question of whether it is a good idea to add cannabis to alcohol. Reporting in the Journal of Biochemical and Molecular Toxicology:

"Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALTalanine transferase, ASTaspartate aminotransferase, ALPalanine peroxidase, MDAmalondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA [enzyme-linked immunosorbent assay] revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jbt.23260 [1859]

El Moneim Hussein et al of Alexandria University in Egypt used a different experimental model of liver damage in "Protective and therapeutic effects of cannabis plant extract on liver cancer induced by dimethylnitrosamine in mice" (2019), finding that the Group III mice, who received a cannabis extract with a ratio of ~2:1 THC:CBD pre-treatment in advance of the DMNA did better than those who received cannabis with or after the treatment, concluding:

"...exposure to DMNA plays a role in pathogenesis of liver disease leading to carcinogenicity and causes disturbances in the activities of mice liver enzymes while cannabis causes a partial improvement in these enzymes. The protective effect of cannabis extract is more pronounced than other groups and this is demonstrated in group III. Cannabinoids might exert their anti-tumor effects by direct induction of apoptosis and can decrease telomerase activity by inhibiting the expression of hTERT [telomerase reverse transcriptase] gene. Coordination between inhibition of telomerase activity and induction of apoptosis might be a potential therapeutic agent for cancer treatment."
https://www.tandfonline.com/doi/full/10.1016/j.ajme.2014.02.003 [4073]

Glutathione exists in reduced (GSH) and oxidized (GSSG) states. The ratio of reduced glutathione to oxidized glutathione within cells is a measure of cellular oxidative stress where increased GSSG-to-GSH ratio is indicative of greater oxidative stress. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH), with the remainder in the disulfide form (GSSG).

In the reduced state, the thiol group of cysteinyl residue is a source of one reducing equivalent. Glutathione disulfide (GSSG) is thereby generated. The oxidized state is converted to the reduced state by NADPH. This conversion is catalyzed by glutathione reductase:

NADPH + GSSG + H2O → 2 GSH + NADP+ + OH−
https://en.wikipedia.org/wiki/Glutathione [1922]

In 2011 Vara et al reported the "Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy":

"Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids--a novel family of potential anticancer agents--on the growth of HCC. We found that Δ(9)-tetrahydrocannabinol (Δ(9)-THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB(2)) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB(2) receptor. We also found that Δ(9)-THC- and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase β was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that Δ(9)-THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC."
https://www.nature.com/articles/cdd201132.pdf [3691]

Adejumo et al have performed several studies on the incidence of hepatic disorders and cannabis:

In 2018's "Cannabis use is associated with reduced prevalence of progressive stages of alcoholic liver disease" the aim was to

"...determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol.

"Methods: We analysed the 2014 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS) discharge records of patients 18 years and older, who had a past or current history of abusive alcohol use (n = 319 514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabis exposure groups: non-cannabis users (90.39%), non-dependent cannabis users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4).

"Results: Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC [alcoholic steatosis, steatohepatitis, fibrosis-cirrhosis, hepatocellular carcinoma] (AOR: 0.55 [0.48-0.64], 0.57 [0.53-0.61], 0.45 [0.43-0.48] and 0.62 [0.51-0.76]). Furthermore, dependent users had significantly lower odds than non-dependent users for developing liver disease.

"Conclusions: Our findings suggest that cannabis use is associated with a reduced incidence of liver disease in alcoholics."
https://pubmed.ncbi.nlm.nih.gov/29341392/ [2771]

In another 2018 paper Adejumo et al, starting with 188,333 records, also looked at the effect of cannabis use on chronic liver disease (CLD) from Hepatitis C Virus (HCV) infection, the most common cause of CLD, and...

"...revealed that cannabis users (CUs) had decreased prevalence of liver cirrhosis (aPRR: 0.81[0.72-0.91]), unfavorable discharge disposition (0.87[0.78-0.96]), and lower total health care cost ($39,642[36,220-43,387] versus $45,566[$42,244-$49,150]), compared to noncannabis users (NCUs). However, there was no difference among CUs and NCUs on the incidence of liver carcinoma (0.79[0.55-1.13]), in-hospital mortality (0.84[0.60-1.17]), and LOS [length of stay] (5.58[5.10-6.09] versus 5.66[5.25-6.01]). Among CUs, dependent cannabis use was associated with lower prevalence of liver cirrhosis, compared to nondependent use (0.62[0.41-0.93])."
https://downloads.hindawi.com/journals/cjgh/2018/9430953.pdf [2773]

In 2019 Adejumo was back again with "Reduced Risk of Alcohol-Induced Pancreatitis With Cannabis Use"...

"We analyzed data from 2012 to 2014 of the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample discharge records of patients 18 years and older. We used the International Classification of Disease, Ninth Edition codes, to identify 3 populations: those with gallstones (379,125); abusive alcohol drinkers (762,356); and non-alcohol-non-gallstones users (15,255,464). Each study population was matched for cannabis use record by age, race, and gender, to records without cannabis use. The estimation of the adjusted odds ratio (aOR) of having acute and chronic pancreatitis (AP and CP) made use of conditional logistic models.

and

"Concomitant cannabis and abusive alcohol use were associated with reduced incidence of AP and CP (aOR: 0.50 [0.48 to 0.53] and 0.77 [0.71 to 0.84]). Strikingly, for individuals with gallstones, additional cannabis use did not impact the incidence of AP or CP [acute and chronic pancreatitis]. Among non‐alcohol‐non‐gallstones users, cannabis use was associated with increased incidence of CP, but not AP (1.28 [1.14 to 1.44] and 0.93 [0.86 to 1.01]).

"Conclusions Our findings suggest a reduced incidence of only alcohol-associated pancreatitis with cannabis use."
https://taliabardash.commons.gc.cuny.edu/files/2022/01/PAncreatitis-article.pdf [2776]

Spaccavento et al (2025) present "Medical cannabis for the management of pain in chronic pancreatitis with recurrent exacerbations: a case report". It worked.
https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00303-w [5266]

In "Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation" McIntosh et al (2018) considered how

"Phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC), bind and activate cannabinoid (CB) receptors, thereby piggy-backing on the same pathway's endogenous endocannabinoids (ECs). The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic chaperone protein with high affinity for both Δ9-THC and ECs suggests that Δ9-THC may alter hepatic EC levels."

They went on to show:

"First, the phytocannabinoid CB1 agonist, Δ9-THC, significantly increased AEA and 2-AG levels in WT hepatocytes. Consistent with this finding, phytocannabinoids (i.e., Δ9-THC, cannabidiol) increase levels of AEA and 2-AG in the blood and brains of humans and rodents. Because CB1 has a similar affinity for AEA as for Δ9-THC, this suggests that Δ9-THC may, at least in part, exert its activating effect on CB1 by increasing the hepatocytes' endogenous level of AEA. Δ9-THC even more dramatically increased the WT hepatocyte level of 2-AG by 2-fold more than AEA. Despite CB1's weaker affinity for 2-AG than for either AEA or Δ9-THC, 2-AG is about 3-fold more potent than AEA at CB1. While the 2-AG-induced increase in WT hepatocyte level of 2-AG may be attributable, at least in part, to increased 2-AG available for uptake, 2-AG had no effect on the non-ARA-containing 2-MGs, i.e., 2-OG and 2-PG, in WT hepatocytes. Taken together, these novel observations showed that exogenously added Δ9-THC, as well as 2-AG, increased the WT hepatocyte level of AEA and, even more so, 2-AG. Although the hepatocytes were incubated with about 20-fold higher concentration levels than typically observed in mouse serum after either intravenous injection of 3 mg/kg or inhalation of 20 mg of Δ9-THC, uptake did not appear saturated with respect to concentration.

"Second, loss of FABP1 (i.e., Fabp1 gene ablation) alone increased AEA and 2-AG levels in cultured primary mouse hepatocytes by more than 2-fold. This finding is physiologically significant because LKO also significantly increased AEA and 2-AG in mouse liver, albeit to a smaller extent, near 30%. In addition, LKO concomitantly increased WT hepatocyte levels of EPEA and 2-OG by >2- and 4-fold, respectively. A similar effect, albeit also of smaller magnitude, was also observed in livers of LKO mice. The significance of LKO's impact on the non-ARA-containing NAE (i.e., EPEA) and 2-MG (i.e., 2-OG) lies in their ability to indirectly alter the effectiveness of CB1 agonists. While non-ARA-containing NAEs (OEA, PEA) and 2-MGs (2-OG, 2-PG) do not directly bind/activate CB receptors, they represent entourage molecules that may enhance the effects of AEA by competing with either the transporters or the enzymes mediating the inactivation of ECs or by enhancing binding/action of ECs, such as AEA. In contrast, the EPA-derived EPEA displaces AEA and 2-AG from cell membranes to reduce AEA and 2-AG release by synthetic enzymes. In fact, EPA supplementation in humans and animals decreases 2-AG and AEA in brain and plasma. Because LKO elicits a several-fold larger increase in hepatocyte 2-OG than EPEA, this would suggest potential net potentiation of CB1 agonists.

"Third, LKO blocked/diminished the ability of Δ9-THC to increase both AEA and 2-AG, but, in contrast, potentiated the ability of 2-AG to increase the hepatocyte level of AEA and 2-AG. The reasons for the opposite effects of LKO on the ability of Δ9-THC and 2-AG to impact hepatocyte AEA and 2-AG are not completely clear. One possibility is based on differences in CB1's and FABP1's affinities for these ligands. For example, CB1 binds Δ9-THC with nearly 10-fold higher affinity than for 2-AG. On the other hand FABP1 binds 2-AG with 10-fold higher affinity than for Δ9-THC. An alternate possibility may relate to a mechanistic difference in uptake of Δ9-THC and 2-AG. Nearly 90% of oral CB undergoes first-pass removal by the liver by an as yet poorly understood mechanism. Although the mechanism of EC (AEA, 2-AG) uptake across the plasma membrane is also not completely clear, AEA uptake appears to be driven by intracellular degradative enzymes. Much less is known about 2-AG uptake, except that it is saturable and blocking 2-AG hydrolysis does not alter the rate of 2-AG uptake."
https://www.jlr.org/article/S0022-2275(20)33916-X/fulltext [5605]

This increased anandamide is the same anandamide pronounced by other researchers to be lacking in psychosis, e.g. Morgan et al's "first study to examine CSF eicosanoid levels in cannabis users" - in 2013 - in which 33 subjects subjected themselves to a lumbar puncture for fifty quid.
https://www.cambridge.org/core/services/aop-cambridge-core/content/view/6C4E16919C53C3444C90AA53C76DC85D/S0007125000274485a.pdf/div-class-title-cerebrospinal-fluid-anandamide-levels-cannabis-use-andpsychotic-like-symptoms-div.pdf [5606]

Alcohol reduces circulating anandamide and AEA levels are repressed in AUD. In a 2023 study by Sloan et al:

Several lines of evidence suggest that endocannabinoid signaling may influence alcohol consumption. Preclinical studies have found that pharmacological blockade of cannabinoid receptor 1 leads to reductions in alcohol intake. Furthermore, variations in endocannabinoid metabolism between individuals may be associated with the presence and severity of alcohol use disorder. However, little is known about the acute effects of alcohol on the endocannabinoid system in humans. In this study, we evaluated the effect of acute alcohol administration on circulating endocannabinoid levels by analyzing data from two highly-controlled alcohol administration experiments. In the first within-subjects experiment, 47 healthy participants were randomized to receive alcohol and placebo in a counterbalanced order. Alcohol was administered using an intravenous clamping procedure such that each participant attained a nearly identical breath alcohol concentration of 0.05%, maintained over 3 hours. In the second experiment, 23 healthy participants self-administered alcohol intravenously; participants had control over their exposure throughout the paradigm. In both experiments, circulating concentrations of two endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were measured at baseline and following alcohol exposure. During the intravenous clamping procedure, acute alcohol administration reduced circulating AEA but not 2-AG levels when compared to placebo. This finding was confirmed in the self-administration paradigm, where alcohol reduced AEA levels in an exposure-dependent manner. Future studies should seek to determine whether alcohol administration has similar effects on brain endocannabinoid signaling. An improved understanding of the bidirectional relationship between endocannabinoid signaling and alcohol intake may deepen our understanding of the etiology and repercussions of alcohol use disorder.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9413364/ [5608]

The Defence believes the depressed AEA levels of chronic alcoholism shoot back up in long-term alcohol withdrawal but may never return to baseline. According to a review by Serrano and Natividad (2022)

"...the effects produced by chronic cannabis use returned to normal function after a protracted abstinence period, whereas the disruptions in patients with AUD persisted after 4 weeks of withdrawal from alcohol use. These findings suggest that CB1 receptor downregulation is a common neuroadaptation to chronic substance use, although seemingly more extensive under alcohol exposure than with substances that directly interact with CB1 receptors. This may suggest that alcohol has potent effects on the mechanisms of CB1 receptor expression and function (e.g., signaling transduction, epigenetic changes). Alcohol is also a notable activator of neuroinflammation, which over the course of repeated use may temper the anti-inflammatory responses of exogenous/endogenous cannabinoid signaling. Moreover, it is possible that alcohol may play a role in altering endogenous mediators of cannabinoid signaling (e.g., eCBs), from which lapses in the recovery of these signaling ligands influence the long-lasting deficits in CB1 receptor signaling."

Table 1 summarises selected research on alcohol and AEA and 2-AG up to then.

"Findings from the Parsons laboratory demonstrated that acute alcohol self-administration elicits increases in eCB release that are tempered over repeated exposure; however, readers are referred to the Alcohol-Induced Alterations in Brain eCB Levels section of this review for noteworthy distinctions. In addition, the method of alcohol exposure plays a marked role in the subsequent analysis of abstinence-related effects. That stated, chronic alcohol exposure is generally associated with the disruption of eCB clearance mechanisms, impaired eCB mediated forms of synaptic plasticity, and the downregulation of cannabinoid receptor function. The dysregulation of eCB signaling may be relevant given that eCBs play a prominent role in the maintenance of affective states and the constraint of stress responses, both of which serve as provocateurs of continued use and relapse."
https://www.researchgate.net/journal/International-Journal-of-Molecular-Sciences-IJMS-1422-0067/publication/367536935_Cannabinoids_in_the_Modulation_of_Oxidative_Signaling/links/68043d63ded43315572db3c1/Cannabinoids-in-the-Modulation-of-Oxidative-Signaling.pdf?_tp=eyJjb250ZXh0Ijp7ImZpcnN0UGFnZSI6InB1YmxpY2F0aW9uIiwicGFnZSI6InB1YmxpY2F0aW9uIn19 [5607]

In the opinion of Dibba et al (2018) both CB1 and CB2 receptors have roles in anticirrhotic mechanisms:

"Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects. The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis."

We learn:

"Those with clinically significant disease are at risk of complications including ascites, encephalopathy, varices, variceal hemorrhage, postsurgical decompensation and hepatocellular carcinoma. Serum albumin, presence of gastroesophageal varices, and Model for End-Stage Liver Disease [MELD] are predictors of decompensation in these patients. Decompensated cirrhosis refers to those who possess one of these complications in the setting of cirrhosis."

And in our fundamental appraisal of the dangers of NECUD in cirrhosis:

"Median survival rate for compensated cirrhotic patients ranges between 9 and 12 years. Decompensated cirrhotic patients have poor survival with a 1-year survival rate less than 50% in patients with ascites and variceal hemorrhage."
https://www.mdpi.com/2305-6320/5/2/52 [4963]

In a 2021 paper by Sobotka et al "Cannabis use may reduce healthcare utilization and improve hospital outcomes in patients with cirrhosis"

"Cannabis use was detected in 370 (2.1%) of 17,520 cirrhotics admitted in 2011 and in 1162 (5.3%) of 21,917 cirrhotics in 2015 (p-value <0.001). On multivariable analysis, cirrhotics utilizing cannabis after its legalization experienced a decreased rate of admissions related to hepatorenal syndrome (Odds Ratio (OR): 0.51; 95% Confidence Interval (CI): 0.34−0.78) and ascites (OR: 0.73; 95% CI: 0.63−0.84). Cirrhotics with an etiology of disease other than alcohol and hepatitis C had a higher risk of admission for hepatic encephalopathy if they utilized cannabis [OR: 1.57; 95% CI: 1.162.13]. Decreased length of stay (-1.15 days; 95% CI: -1.62, -0.68), total charges (-$15,852; 95% CI: -$21,009, -$10,694), and inpatient mortality (OR: 0.68; 95% CI: 0.51−0.91) were also observed in cirrhotics utilizing cannabis after legalization compared to cirrhotics not utilizing cannabis or utilizing cannabis prior to legalization."
https://www.sciencedirect.com/science/article/pii/S1665268120302052?via%3Dihub [3886]

By 2023 we had "Marijuana use is inversely associated with liver steatosis detected by transient elastography in the general United States population in NHANES 2017-2018: A cross-sectional study" and according to Du et al at the General Hospital of Central Theater Command, Wuchangqu, Wuhan:

"A total of 2622 participants were included in this study. The proportions of never marijuana users, past users, and current users were 45.9%, 35.0%, and 19.1%, respectively. Compared to never marijuana users, past and current users had a lower prevalence of liver steatosis (P = 0.184 and P = 0.048, respectively). In the alcohol intake-adjusted model, current marijuana use was an independent predictor of a low prevalence of liver steatosis in people with non-heavy alcohol intake. The association between marijuana use and liver fibrosis was not significant in univariate and multivariate regression.

"Conclusion: In this nationally representative sample, current marijuana use is inversely associated with steatosis. The pathophysiology is unclear and needs further study. No significant association was established between marijuana use and liver fibrosis, irrespective of past or current use."
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0284859&type=printable [2775]

Paladiya et al (2024) used the National Inpatient Sample (NIS) 20162020:

"Of the 3,379,484 patients, CU was identified in 52,315 (1.54%) patients. The majority of the CU patients were aged 18-44 years (46.4%), male (59.7%) and White race (59.75). Table shows the prevalence of CU among various comorbidities. Patients with CU had a lower prevalence of cirrhosis (21.8% vs 36.8%, P< 0.001), decompensated cirrhosis (DC) (11.9% vs 21.2%, P< 0.001), hepatocellular cancer (HCC) (0.8% vs 1.7%, P< 0.001), chronic kidney disease (CKD) (13% vs 24.3%, P< 0.001), heart failure (HF) (14.7% vs 22.5%,P< 0.001), and in-hospital mortality (IHM) (2.2% vs 4.5%, P< 0.001). (Figure 1) After adjusting for confounding factors, patients with CU had lower odds of IHM (aOR- 0.70, 95% CI-0.61-0.80, P< 0.001), cirrhosis (aOR- 0.72, 95% CI-0.68-0.76, P< 0.001), DC (aOR-0.73, 95% CI-0.68-0.78, P< 0.001), CKD (aOR-0.81, 95% CI-0.76-0.86, P< 0.001) and HCC (aOR-0.71, 95% CI 0.57-0.89, P=0.003), however had higher odds of myocardial infarction (MI) (aOR-1.42, 95% CI-1.27-1.83, P< 0.001) and stroke (aOR-1.53, 95% CI-1.27-1.83, P< 0.001)."
https://journals.lww.com/ajg/fulltext/2024/10001/s2046_cannabis_use_in_metabolic.2047.aspx [5776]

Now what is it that makes people keep going back to the pub? Conditioned Place Preference (CPP) is one of the most popular models to study the motivational effects of alcohol in animals. According to Amaral et al "Susceptibility to extinction and reinstatement of ethanol-induced conditioned place preference is related to differences in astrocyte cystine-glutamate antiporter content":

"One important regulator of glutamate homeostasis, maintaining extrasynaptic glutamatergic tone, is the astrocyte cystine-glutamate antiporter (xCT). It acts by transporting one glutamate molecule at the same time as transporting one cystine molecule. This non-vesicular transport direction is dependent on extra and intracellular concentrations of the substrates, transporting the substrate both to the intracellular and the extracellular space. Since the intracellular concentration of glutamate is much higher than that of cystine in astrocytes, xCT essentially transports one cystine molecule to the intracellular space while transporting one glutamate molecule to the extracellular space (Bridges et al., 2012). It is expressed throughout the adult mouse brain, including the NAcc, the medial prefrontal cortex (mPFC) and the amygdala (Amy) (Van Liefferinge et al., 2016).

"Recent data have shown that chronic drug intake or withdrawal alter xCT expression in animal models of addiction. Nicotine self-administration or inhalation through electronic cigarettes decreases xCT expression in the striatum, ventral tegmental area (VTA), and hippocampus (Alasmari et al., 2017; Knackstedt et al., 2009). Withdrawal from chronic ethanol consumption decreases xCT content in the NAcc, while chronic ethanol consumption has the opposite effect (Peana et al., 2014). In alcohol-preferring rats, chronic ethanol consumption decreases xCT in the Amy (Aal-Aaboda et al., 2015)."
https://www.sciencedirect.com/science/article/abs/pii/S0168010220304028 [976]

...while Ryu et al at the Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea, add that:

"Chronic alcohol drinking results in oxidative stress-mediated shortage of cysteine and thereby induces the depletion of glutathione (GSH), which leads to the upregulation of Slc7a11 expression (encoding xCT in system xc--cystine/glutamate antiporter) to compensate for the cysteine shortage. Consequently, xCT-mediated glutamate excretion stimulates metabotropic glutamate receptor 5 (mGluR5) in neighboring HSCs to produce 2-AG in a diacylglycerol lipase-β-dependent manner. In addition, this study demonstrated that the inhibition of the xCT and mGluR5 substantially reversed alcohol-mediated hepatic steatosis by reducing 2-AG production in HSCs."

and writing in May 2022 they say:

"Recent studies have begun to dissect the interaction of neurotransmitters such as endocannabinoid, glutamate and neuroendocrine factors, and hepatic non-parenchymal cells. Signaling pathways involved in different neurotransmitters indicate their contributions to ALD pathogenesis."

Regarding the endocannabinoid part of this (while avoiding cannabis completely) they announce that:

"Recent studies have suggested that endocannabinoids and their receptors might be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatic fibrosis. Extending these findings, our studies demonstrated the pathogenic effects of endocannabinoid 2-AG and CB1 receptor in alcohol-related hepatic steatosis. In mice, chronic alcohol consumption induces 2-AG production in HSCs [hepatic stellate cells], which then stimulates CB1 receptor to upregulate the expression of SREBP1c [Sterol regulatory element-binding protein 1] and FAS (CD95) [aka Fas receptor, FasR, apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6)*] and inhibit the activation of AMPK, enhancing fat accumulation in hepatocytes. Conversely, treatment of rimonabant, a selective antagonist of CB1 receptor, and genetic inhibition of CB1 receptor ameliorated alcohol-related hepatic steatosis in mice. A recent study further supported this finding by delineating the underlying mechanism of 2-AG production in HSCs. Chronic alcohol drinking results in oxidative stress-mediated shortage of cysteine and thereby induces the depletion of glutathione (GSH), which leads to the upregulation of Slc7a11 expression (encoding xCT in system xc--cystine/glutamate antiporter) to compensate for the cysteine shortage. Consequently, xCT-mediated glutamate excretion stimulates metabotropic glutamate receptor 5 (mGluR5) in neighboring HSCs to produce 2-AG in a diacylglycerol lipase-β-dependent manner. In addition, this study demonstrated that the inhibition of the xCT and mGluR5 substantially reversed alcohol-mediated hepatic steatosis by reducing 2-AG production in HSCs. This study also emphasized the bidirectional loop pathway where hepatocytes and HSCs interact with each other by secreting neurotransmitters (e.g. glutamate and 2-AG) and expressing their receptors (e.g. mGluR5 and CB1), and proposed a new concept of metabolic synapse between hepatocytes and HSCs. In contrast to CB1 receptors, CB2 receptors in KCs are known to have protective effects against ASH. CB2 receptor activation attenuates alcohol-induced steatohepatitis and the main mechanism is explained by paracrine interaction of endocannabinoid between hepatocyte and Kupffer cell. The more precise mechanism has suggested that the CB2 receptor protects the liver from steatosis by CB2-mediated autophagy in KCs through a heme-oxygenase-1 dependent pathway, ameliorating inflammatory responses in ALD. to produce 2-AG in a diacylglycerol lipase-β-dependent manner."

The study

"...emphasized the bidirectional loop pathway where hepatocytes and HSCs interact with each other by secreting neurotransmitters (e.g. glutamate and 2-AG) and expressing their receptors (e.g. mGluR5 and CB1), and proposed a new concept of metabolic synapse between hepatocytes and HSCs. In contrast to CB1 receptors, CB2 receptors in KCs are known to have protective effects against ASH. CB2 receptor activation attenuates alcohol-induced steatohepatitis and the main mechanism is explained by paracrine interaction of endocannabinoid between hepatocyte and Kupffer cell [resident macrophages in the liver]. The more precise mechanism has suggested that the CB2 receptor protects the liver from steatosis by CB2-mediated autophagy in KCs through a heme-oxygenase-1 dependent pathway, ameliorating inflammatory responses in ALD."
https://www.sciencedirect.com/science/article/pii/S2542568422000599 [1955]

In "Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty Liver" (2008) Jeong et al

"...report that the steatosis induced in mice by a low-fat, liquid ethanol diet is attenuated by concurrent blockade of cannabinoid CB1 receptors. Global or hepatocyte-specific CB1 knockout mice are resistant to ethanol-induced steatosis and increases in lipogenic gene expression and have increased carnitine palmitoyltransferase 1 activity, which, unlike in controls, is not reduced by ethanol treatment. Ethanol feeding increases the hepatic expression of CB1 receptors and upregulates the endocannabinoid 2-arachidonoylglycerol (2-AG) and its biosynthetic enzyme diacylglycerol lipase b selectively in hepatic stellate cells. In control but not CB1 receptor-deficient hepatocytes, coculture with stellate cells from ethanol-fed mice results in upregulation of CB1 receptors and lipogenic gene expression. We conclude that paracrine activation of hepatic CB1 receptors by stellate cell-derived 2-AG mediates ethanol-induced steatosis through increasing lipogenesis and decreasing fatty acid oxidation."

and

"Although alcoholic fatty liver is reversible in its early stages by cessation of drinking, this is often not feasible. The present findings suggest that treatment with a CB1 antagonist may slow the development of steatosis and thus prevent or delay its progression to more severe and irreversible forms of liver disease. Importantly, our finding that the steatogenic effect of ethanol specifically involves CB1 receptors expressed in hepatocytes suggests that selective targeting of peripheral CB1 receptors may be effective in this pathology, thereby reducing the potential for centrally mediated adverse effects of CB1 blockade, such as anxiety and depression (Pacher et al., 2006). The additional antifibrogenic effect of CB1 blockade could add to the benefit of such treatment."
https://www.sciencedirect.com/science/article/pii/S1550413107003804/pdfft?md5=ac54de6d739e3cab493ff27893441f7a&pid=1-s2.0-S1550413107003804-main.pdf [1957]

*The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis) if it binds its ligand, Fas ligand (FasL). It is one of two apoptosis pathways, the other being the mitochondrial pathway.
https://en.wikipedia.org/wiki/Fas_receptor [1956]

To these antisteatogenic Benedictions we may add the deduction, from alcohol spending, of cannabis expenditure.

In support of their findings they cite Yeong et al:

"In view of the observed upregulation of CB1 receptors and their endogenous ligand 2-AG in ethanol-fed mice, we tested whether activation of CB1 receptors contributes to the development of ethanol-induced steatosis. Male mice were treated every other day with intraperitoneal injections of vehicle or 10 mg/kg of the CB1 antagonist SR141716 (rimonabant) throughout their 3 week exposure to the ethanol-containing diet. Body weight gain and ethanol intake were slightly lower in the rimonabanttreated mice than in their controls, but the intake of ethanol per g of body weight was similar in the two groups, and blood ethanol concentrations were also similar (see Figure S1 available online). Despite this, rimonabant-treated mice were resistant to the steatogenic effect of ethanol: their hepatic lipid content, as verified histologically and by measuring hepatic triglyceride concentrations, was not different from that of mice on the control liquid diet (Figures 1F and 1G), although rimonabant did not prevent the rise in plasma ALT levels."

and

"Ethanol-induced steatosis can be prevented or reversed by in vivo treatment with AMPK activators such as metformin (Yamauchi et al., 2002), adiponectin (Bergheim et al., 2006), or 5-aminoimidazole-4-carboxamide-1-b-D-furosamide (AICAR) (Tomita et al., 2005), and the phytocannabinoid D9 -tetrahydrocannabinol has been shown to inhibit hepatic AMPK activity (Kola et al., 2005)."
https://www.sciencedirect.com/science/article/pii/S1550413107003804/pdfft?md5=ac54de6d739e3cab493ff27893441f7a&pid=1-s2.0-S1550413107003804-main.pdf [1957]

Kola et al indeed aver that THC outperforms 2-AG in antisteatotic activity

"While leptin, which is associated with appetite suppression, inhibits AMPK activity in the arcuate and paraventricular nucleus of the hypothalamus, ghrelin has been shown to stimulate whole hypothalamic AMPK activity after peripheral administration. In the current study using a functional AMPK assay we observed that in whole hypothalamus total AMPK activity increased to 153 8% of control after central 2-AG injection and to 156 26% after i.c.v. ghrelin injection (Fig. 1A). Similar responses were also seen after peripheral injection of THC (174 31% of control) and ghrelin (177 12%, Fig. 1B). This increase in AMPK activity was, as expected, associated with an increase in Thr-172 phosphorylation of AMPK (Fig. 1, C and D), while total AMPK levels did not change in either of the tissues studied. One of the best established downstream targets of AMPK (and therefore a good marker for AMPK activation) is ACC. Phosphorylation by AMPK at the equivalent sites on the two isoforms ACC1 [acetyl coenzyme A carboxylase 1] and ACC2 causes inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, respectively. Using an antibody that detects phosphorylation of both isoforms, we detected an increase in phosphorylation of ACC after central cannabinoid and ghrelin treatment in the hypothalamus (Fig. 1E). We and others have described important peripheral effects of desacyl ghrelin (see Ref. 8 and references therein), although this form cannot activate the full-length, functionally active GHS-R1a [growth hormone secretagogue receptor 1a]. In this study no change was observed in hypothalamic AMPK activity (Fig. 1F) or AMPK phosphorylation (Fig. 1G) after i.c.v. administration of desacyl ghrelin."

The effects of AMPK in the liver and the cardiovascular system must be distinguished.

"AMPK is activated by ischemia in the heart, leading to increased glucose uptake and phosphorylation of the heart-specific 6-phosphofructo-2-kinase, which activates production of ATP by glycolysis under anaerobic conditions. Activation of AMPK during ischemia also lowers malonyl-CoA and thus increases ATP generation via fatty acid oxidation during reperfusion. Recent results using mice expressing a dominant negative AMPK mutant in the heart suggest that the presence of AMPK protects cardiac ATP levels and reduces infarct size and damage to myocytes during ischemia. The lack of fat tissue cytokine adiponectin (known to stimulate AMPK activity) results in pressure overload and cardiac hypertrophy in knock-out animals, and this could be reversed by the reintroduction of adiponectin. Recent data suggest that long term cannabinoid treatment improves atherosclerosis via a CB2-mediated effect on immune cells. Our present data suggest that the beneficial effects of cannabinoids could be mediated via activation of AMPK, although excessive activation of AMPK may be deleterious to the heart. We also found a large increase in the phosphorylation and activity of AMPK activity in response to ghrelin. There have been several previous studies describing the beneficial effects of ghrelin and its synthetic analogues on cardiovascular function. These seem to be direct effects that are independent of growth hormone release, as positive results were obtained both in hypophysectomized rats and in in vitro studies on embryonic (H9c2) and adult (HL-1) heart muscle cell lines. Ghrelin and GHS-R mRNA are present in human myocardium, and protein expression has also been detected both in primary tissue and in the HL-1 cell line, where ghrelin has anti-apoptotic effects. Diastolic dysfunction associated with myocardial stunning is improved with ghrelin analogue treatment. Human studies have shown that ghrelin increases stroke volume both in healthy volunteers and in chronic heart failure, while chronic administration of ghrelin improves left ventricular dysfunction and attenuates the development of cardiac cachexia in rats with heart failure. As elevated ghrelin levels have been reported in patients with cardiac cachexia, this could be part of a compensatory mechanism in response to catabolic-anabolic imbalance. In patients with obesity (or other insulin-resistant states that are associated with low ghrelin levels, such as type 2 diabetes and polycystic ovarian syndrome) the low levels of ghrelin could contribute to heart failure, where cardiomyocyte apoptosis is known to play a role. In contrast, the beneficial effects of weight loss on cardiac function may, at least in part, be the result of the beneficial effects of increased ghrelin levels."

and in sum

"We have shown that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart and inhibit AMPK activity in the liver and adipose tissue, while we found no effect on skeletal muscle. Given the proposed role of AMPK in energy sensing and metabolism, the present findings provide important evidence of interactions between this enzyme and the orexigenic actions of cannabinoids and ghrelin. Either class of agent could potentially increase appetite by central AMPK stimulation or by facilitating the restorative actions of AMPK as the hypothalamus senses fuel deprivation. By contrast, peripheral inhibition of AMPK by cannabinoids and ghrelin may lead to fuel, particularly fat, storage. The combined effect of both central and peripheral signals would therefore be increased food intake and lipid storage, leading to lipid deposition. The cardiac and metabolic effects of cannabinoids we report may have important implications for the anticipated widespread clinical use of rimonabant and other CB1 antagonists in the treatment of obesity."
https://www.jbc.org/article/S0021-9258(20)65672-1/pdf [1958]

In 2006 Pi-Sunyer et al similarly reported positive results with this frankencannabinoid:

"At year 1, the completion rate was 309 (51%) patients in the placebo group, 620 (51%) patients in the 5 mg of rimonabant group, and 673 (55%) patients in the 20 mg of rimonabant group. Compared with the placebo group, the 20 mg of rimonabant group produced greater mean (SEM) reductions in weight (-6.3 [0.2] kg vs -1.6 [0.2] kg; P<.001), waist circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001). Patients who were switched from the 20 mg of rimonabant group to the placebo group during year 2 experienced weight regain while those who continued to receive 20 mg of rimonabant maintained their weight loss and favorable changes in cardiometabolic risk factors. Use of different imputation methods to account for the high rate of dropouts in all 3 groups yielded similar results. Rimonabant was generally well tolerated; the most common drug-related adverse event was nausea (11.2% for the 20 mg of rimonabant group vs 5.8% for the placebo group)."
https://jamanetwork.com/journals/jama/fullarticle/202374 [3970]

In 2008 Kola et al reported that "The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System":

"Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons."
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001797 [4200]

Shimizu et al (2009) brought the news that in mice...

"Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner."
https://academic.oup.com/endo/article-abstract/150/2/662/2455552 [4958]

"Current Understanding of the Role of Nesfatin-1" from Schalla and Stengel (2018) in the Journal of Endocrinology:
https://academic.oup.com/jes/article/2/10/1188/5092030 [4959]

Despite Rimonabant's long-concluded life as a safe and effective drug for obesity with the unfortunate side-effect of suicidal ideation (RIP 2006-2009), Folgueira et al were still unravelling its anorexigenic mechanism in 2017, with "Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway" contributing to a leptin-independent understanding of satiety:

"Despite being secreted by the same cells, Nucb2 and ghrelin have opposing biological functions and regulation. Central and peripheral administration of Nucb2 suppresses feeding behavior, while ghrelin stimulates appetite. Interestingly, the fact that Nucb2 and ghrelin are produced in the same gastric cells but in different vesicles suggests that both proteins might experience differential regulation at the gastric level to maintain energy balance. Supporting this theory, Nucb2/nesfatin-1 production and regulation by nutritional status decreases during fasting, while ghrelin levels are up-regulated. Lastly, this decrease in Nucb2 production during fasting conditions is concomitant with inhibition of the mTOR/pS6k1 pathway, a sensor of the metabolic status of organism. Ghrelin secretion, meanwhile, is negatively associated with mTOR/pS6k1 pathway activity under fasting conditions.

"The cannabinoid system plays an important role as an endogenous regulator of energy balance, acting at multiple levels. One of those mechanisms includes its interaction with gastric ghrelin production to regulate appetite and body weight. More specifically, the blockade of the cannabinoid receptor CB1 decreases ghrelin expression in the stomach, and this effect was mediated by activation of the mTOR/pS6k1 pathway. Taking into account the opposing functions and regulation of ghrelin and Nucb2/nesfatin at the gastric level, as well as their opposite relationship with the mTOR/S6K1 pathway, we sought to investigate whether the cannabinoid system might also regulate Nucb2/nesfatin-1 production in the stomach and whether the mTOR/pS6k1 intracellular pathway mediates this effect."

And you can see from the title that it did.
https://www.wjgnet.com/1007-9327/full/v23/i35/6403.htm [4957]

So am I correct Slovenia is in a battle with alcohol?

And yet as drinkers and drink drivers, are many Slovenians not also in a psychological battle against any IDEA disputing the idea that excess alcohol is mandatory?

And isn't their IDEA of excess "more than I drink"?

Isn't the IDEA that cannabis is bad supportive of alcohol profits?

Isn't the IDEA that cannabis is protective of alcohol damage unwelcome because it not only introduces the notion of alcohol damage, but that it must be really serious, since we already have an IDEA of how terrible cannabis is.

For alcohol must be really bad, if we are compelled by reason to take such a drastic leap in favour of what we have been told is dangerous, in order to combat the alcohol folk beliefs tell us is normal, but which is objectively 114 times worse [852].

In the area of hepatology, motivated ignorance is fortunate: people might notice that smoking cannabis helps them cope with a hangover, but the histology of their liver is subclinical and on a day-by-day basis this damage is invisible to them.

According to ElTebany et al in "Lower Rates of Hepatocellular Carcinoma Observed Among Cannabis Users: A Population-Based Study" (2022), to more than halve your chance of hepatocellular carcinoma, you should "abuse cannabis".

For the variables tested, only being female gave a lower odds ratio than cannabis (0.39 versus 0.45). (Table 3).

"Using data from the National Inpatient Sample (NIS) database between 2002 and 2014, we identified the patients with HCC and cannabis use diagnosis using the International Classification of Disease 9th version codes (ICD-9). Then, we identified patients without cannabis use as the control group. We adjusted for multiple potential confounders and performed multivariable logistic regression analysis to determine the association between cannabis abuse and HCC.

"Results: A total of 101,231,036 patients were included in the study. Out of the total, 996,290 patients (1%) had the diagnosis of cannabis abuse versus 100,234,746 patients (99%) in the control group without cannabis abuse. We noticed that patients with cannabis abuse were younger (34 vs 48 years), had more males (61.7% vs 41.4%) and more African Americans (29.9% vs 14.2%) compared with the control group (P<0.001 for all). Besides, patients with cannabis use had more hepatitis B, hepatitis C, liver cirrhosis, and smoking, but had less obesity and gallstones, (P<0.001 for all). Using multivariable logistic regression, and after adjusting for potential confounders, patients with cannabis abuse were 55% less likely to have HCC (adjusted Odds Ratio {aOR}, 0.45, 95% Confidence Interval {CI}, 0.42-0.49, P<0.001) compared with patients without cannabis abuse.

"Conclusion: Based on our large database analysis, we found that cannabis use patients were 55% less likely to have HCC compared to patients without cannabis use."

Gallstones (ICD-9-CM cod 574) were 40% lower in the cannabis group (Table 1)
https://pmc.ncbi.nlm.nih.gov/articles/PMC9138632/ [1735]

In Slovenia, there were 231 new cases of cancer of the liver and intrahepatic bile duct in 2018, of which 126 (54.5%) were microscopically confirmed.
https://www.onko-i.si/fileadmin/onko/datoteke/rrs/lp/Letno_porocilo_2018.pdf [1854]

And so applying the findings of ElTebany, of 55% less HCC in the 101,231,036 patients versus a 100% NECUD condition, a 0% incidence of NECUD would have predicted 0.55 x 231 = 127 fewer cases in 2018, about one case every three days.

Tajik et al found "Extracellular vesicles of cannabis with high CBD content induce anticancer signaling in human hepatocellular carcinoma" (2022):

"The discovery of extracellular vesicles in the 1950s opened new insights into the understanding of intercellular, inter-species, and inter-kingdom communications. EVs, nano-sized bilayer lipid vesicles, are being released from different cell types and can be classified into subgroups, namely apoptotic bodies, microvesicles, and exosomes, according to their origin and size. Apoptotic bodies (10005000 nm) are being generated from the cells that undergo apoptosis, to be phagocytosed. Microvesicles are being originated from phospholipid membrane with a size range of 1501000 nm. Exosomes with 30150 nm in size are being derived from multi-vesicular bodies (MVBs. Naturally, EVs transfer endogenous molecules as cargo to recipient cells. In EV-based therapeutics, molecules such as siRNA, microRNA, as well chemicals, and biological drugs have been encapsulated within these vehicles to be delivered to the targets of interest. Exosomes have been considered as the promising biomarkers in the early diagnosis of diseases such as infectious diseases, autoimmune disorders, diabetes, and several types of cancers. Recently, large-scale production of EVs from edible and herbal plants (range in size, 30500 nm) has been noticed as an excellent source of nanovesicles with phenomenal intrinsic properties and known minimal side-effects."

and in their test comparing EVs from high and low CBD strains, both with THC:

"Cytotoxicity assay showed that H.C-EVs strongly decreased the viability of two hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh-7, in a dose and time-dependent manner compared with L.C-EVs. H.C-EVs had no significant effect on HUVECs normal cell growth. The finding showed that the H.C-EVs arrested the G0/G1 phase in the cell cycle and significantly induced cell death by activating mitochondrial-dependent apoptosis signaling pathways in both HCC cell lines."
https://www.sciencedirect.com/science/article/pii/S0753332222005984?via%3Dihub [2961]

Esmaeli and Dehabadi at Gerash University of Medical Sciences, Iran (2025) reviewed 16 mixed studies on CBD and hepatocellular cancer:

"A systematic search (PubMed, Scopus, Web of Science, Google Scholar) up to March 2025 identified 16 relevant studies (in vitro, in vivo, clinical). CBD exerts antitumor effects via multiple pathways, including apoptosis, autophagy regulation, metastasis suppression, and tumor microenvironment modulation. CBD interacts with the endocannabinoid system (ECS), inhibits oncogenic signaling (PI3K/AKT/mTOR), and enhances chemotherapeutic efficacy (sorafenib, cabozantinib). Studies show CBD induces pyroptosis via caspase-3/GSDME, and modulates autophagy by inhibiting the PI3K/Akt/mTOR pathway. It also sensitizes HCC cells to sorafenib and cabozantinib. Preclinical results are promising, but clinical studies are limited."
https://link.springer.com/content/pdf/10.1186/s12935-025-03870-3.pdf [5090]

The Court may recall CBN was found to be beneficial to mitochondrial biogenesis [876,877]. Akbari and Taghizadeh-Hesary (2023) looked at "COVID-19 induced liver injury from a new perspective: Mitochondria", pointing out that:

"Patients with COVID-19 are at high risk of liver damage.

"The underlying mechanism is still undefined.

"SARS-CoV-2 can damage mitochondria directly or through systemic inflammation.

"COVID-induced liver injury is more in patients with weaker mitochondria.

"Boosting mitochondria can protect liver from COVID-induced injury."

Moreover:

"Upon entering the hepatocytes, the RNA and RNA transcripts of SARS-CoV-2 engages the mitochondria. This interaction can disrupt the mitochondrial electron transport chain. In other words, SARS-CoV-2 hijacks the hepatocytes mitochondria to support its replication. In addition, this process can lead to an improper immune response against SARS-CoV-2. Besides, this review outlines how mitochondrial dysfunction can serve as a prelude to the COVID-associated cytokine storm. Thereafter, we indicate how the nexus between COVID-19 and mitochondria can fill the gap linking CiLI and its risk factors, including old age, male sex, and comorbidities. In conclusion, this concept stresses the importance of mitochondrial metabolism in hepatocyte damage in the context of COVID-19. It notes that boosting mitochondria biogenesis can possibly serve as a prophylactic and therapeutic approach for CiLI."
https://www.sciencedirect.com/science/article/pii/S1567724923000338 [4986]

Huang et al (2025) examined "The protective role of cannabidiol in stress-induced liver injury: modulating oxidative stress and mitochondrial damage":

"CBD exhibited significant protective effects against stress-induced liver injury in mice. Decreases in liver function indicators (including Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)) and inflammatory cytokines (such as IL-1β and Tumor Necrosis Factor-alpha (TNF-α)) were observed. CBD enhanced CB2R expression and reduced α-SMA levels, mitigating liver fibrosis. It also decreased ACSL4 levels, increased SOD and GSH-Px activities, and upregulated SLC7A11 protein expression. Furthermore, CBD improved mitochondrial morphology, indicating a reduction in oxidative cell death.

"Conclusion: CBD activates the CB2R/α-SMA pathway to modulate liver inflammation and fibrosis. Through the SLC7A11/ACSL4 signaling pathway, CBD alleviates oxidative stress in stress-induced liver injury, enhances mitochondrial morphology, and reduces liver damage. These findings provide a theoretical basis for the potential application of CBD in the prevention and treatment of stress-induced liver injury."
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1567210/full [5184]

Zhan et al (2025) reveal how "Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2":

"In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.

"Results: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD's protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.

"Conclusion: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2."
https://pubmed.ncbi.nlm.nih.gov/41419044/ [5754]

Degrave et al (2025) examined the "Effects of five cannabis oils with different CBD: THC ratios and terpenes on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor in an experimental model":

"Male Wistar rats were fed either a: (1) reference diet (RD; standard commercial laboratory diet) or a: (2) sucrose-rich diet (SRD) for 3 weeks. 3 to 7 SRD + CO as following: (3) SRD + THC; (4) SRD + CBD; (5) SRD + CBD:THC 1:1; (6) SRD + CBD:THC 2:1; and (7) SRD + CBD:THC 3:1. The COs were administered orally at a dose of 1.5 mg total cannabinoids/kg body weight daily. The cannabinoid and terpenes content of all COs used in the study was determined. The terpenes found in COs were beta-myrcene, d-limonene, terpinolene, linalool, beta-caryophyllene, alpha-humulene, (-)-guaiol, (-)-alpha-bisabolol. During the experimental period, body weight, food intake and blood pressure were measured. Serum glucose, triglyceride, total cholesterol, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) levels were evaluated. Liver tissue histology, NAFLD activity score (NAS), triglyceride and cholesterol content, lipogenic enzyme activities, enzyme related to mitochondrial fatty acid oxidation, reactive oxygen species (ROS), thiobarbituric acid reactive substance (TBARS), and antioxidant enzyme activities were also evaluated. The CB1 receptor expression was also determined.

"Results
The results showed that SRD-fed rats developed hypertension, dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation, and oxidative stress. This was accompanied by upregulation of liver CB1 receptor expression. CBD-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO and CBD:THC 3:1 ratio CO showed antihypertensive properties. THC-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO showed the greatest beneficial effects against hepatic steatosis and liver damage. All COs exhibited antioxidant effects in liver tissue. This was associated with normal liver CB1 receptor expression."

...

"Figure 5A and B shows that liver ROS and TBARS were significantly increased (P < 0.05) in the SRD group compared to the RD group. When CBD-rich CO, THC-rich CO, CBD:THC ratio 1:1 CO, CBD:THC ratio 2:1 CO and CBD:THC ratio 3:1 CO were administered in the SRD, these parameters decreased significantly (P < 0.05) reaching similar values to those of the RD group. In addition, the decrease in the GSH content in the liver of the SRD group was increased (P < 0.05) in the SRD + CBD, SRD + THC, SRD + CBD:THC 1:1, SRD + CBD:THC 2:1 and SRD + CBD:THC 3:1 groups, reaching values similar to those of the RD group (Fig. 5C). Moreover, a significant decrease in CAT, GPx and GR activities was observed in the SRD group (P < 0.05). CBD-rich CO and THC-rich CO increased the CAT activity, although the values were still lower than in the RD group. CBD:THC ratio 1:1 CO, CBD:THC 2:1 ratio CO and CBD:THC ratio 3:1 CO increased the CAT activity, reaching values similar to those of the RD group (Fig. 5D). GR activity was increased (P < 0.05) in SRD + CBD, SRD + THC and SRD + CBD:THC 1:1 groups, although the values were still lower than in the RD group. In contrast, the SRD + CBD:THC 2:1 and SRD + CBD:THC 3:1 groups showed a further increase in GR activity, reaching levels similar to the RD group (Fig. 5E). In Fig. 5F was observed an increased GPx activity in SRD + CBD, SRD + THC and CBD:THC 1:1 groups, reaching values similar to those of the RD group. In SRD + CBD:THC 2:1, SRD + CBD:THC 3:1 groups, the GPx enzyme activity increased significantly, although the values were still lower than those in the RD group."
https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00286-8 [5286]

Bader Eddin et al (2025) concentrated their attention on how "β-Caryophyllene Ameliorates Thioacetamide-Induced Liver Fibrosis in Rats: A Preventative Approach", describing prophylactic effects:

"The BCP treatment (50 mg/kg) protected against cell injury and potentiated antioxidant defense by replenishing hepatic GSH, improving catalase activity, and inhibiting the formation of MDA. The co-administration of BCP mitigated the TAA-induced inflammatory response by decreasing the release of proinflammatory cytokines. Histological examination showed preserved cellular integrity, decreased collagen deposits with other extracellular matrix proteins, and low levels of myofibroblast activation. In addition, the BCP-treated rats demonstrated upregulated sirtuin 1 (SIRT1) expression, which had a direct inhibitory effect on hypoxia inducible factor (HIF-1α). AM630 pre-treatment inhibited all the aforementioned protective mechanisms of BCP. Based on our findings, BCP exerts protective effects in liver fibrosis, which can be attributed to its agonist action on CB2 receptors. This study provides preclinical evidence of the potential preventative benefits of BCP in liver fibrosis."
https://www.mdpi.com/1422-0067/26/17/8493 [5413]

To avoid liver disease, you may quit alcohol. To quit alcohol or opioids you may, on condition of your already successful cessation, be prescribed the opioid receptor blocker Naltrexone - which also has hepatotoxic risks. Common side effects of Naltrexone, which may be administered orally or via long-term injection, include:

nausea
sleepiness
headache
dizziness
vomiting
decreased appetite
painful joints
muscle cramps
cold symptoms
trouble sleeping
toothache

Serious side effects of Naltrexone:

Severe reactions at the site of injection, including: intense pain; tissue death for which surgery may be required; swelling, lumps, or hardness; scabs, blisters, or open wounds

Liver damage or hepatitis, including; stomach area pain lasting more than a few days; dark urine; yellowing of the whites of your eyes; tiredness

Serious allergic reactions, including: skin rash; swelling of face, eyes, mouth, or tongue; trouble breathing or wheezing; chest pain; feeling dizzy or faint

Pneumonia

Depressed mood
https://www.samhsa.gov/medications-substance-use-disorders/medications-counseling-related-conditions/naltrexone [3811]

CaPs of course are not commonly associated with these experiences.

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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