Category Archives: Addiction

Recreational Cannabis Laws and Fills of Pain Prescriptions in the Privately Insured

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“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://pubmed.ncbi.nlm.nih.gov/39968486/

https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/view/268

Efficacy of cannabidiol alone or in combination with Δ-9-tetrahydrocannabinol for the management of substance use disorders: An umbrella review of the evidence

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“Background and aims: Substance use disorders (SUD) lead to a high burden of disease, yet treatment options are limited. Cannabidiol (CBD) is being investigated as a potential therapeutic target due to its pharmacological properties and mode of action in the endocannabinoid system. Recent systematic reviews (SR) on CBD and SUDs have shown inconsistent results. The objective of this umbrella review was to determine whether CBD alone or in combination with Δ-9-tetrahydrocannabinol (THC) is effective for managing and treating SUDs.

Methods: Following a registered protocol, we 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. Screening, data extraction and quality assessment with the AMSTAR 2 tool were performed by two researchers in parallel and duplicated.

Results: 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://pubmed.ncbi.nlm.nih.gov/39947878/

“This umbrella review does not suggest any efficacy of CBD monotherapy as a therapeutic agent in SUDs. CBD primarily exhibits effects on cannabis withdrawal and craving symptoms when combined with THC in nabiximols. The CBD:THC 1:1 effects suggest that the potential benefits observed in cannabis withdrawal and craving may be because of THC, with CBD providing no additional benefit. We found no evidence for CBD alone, in the absence of THC, in managing cannabis and other SUDs. “

https://onlinelibrary.wiley.com/doi/10.1111/add.16745

Cannabidiol interactions with oxycodone analgesia in an operant orofacial cutaneous thermal pain assay following oral administration in rats

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“Previous studies have driven the notion that the cannabis constituent cannabidiol could be an effective adjunct to opioid administration for managing pain.

Most of these studies have used experimental rodents with routes of administration, such as subcutaneous and intraperitoneal, that do not correspond with the routes used in clinical practice. In response to this, we tested the ability of cannabidiol co-administration to augment opioid analgesia via the more clinically-relevant oral route of administration.

To this end, male and female rats were orally gavaged with cannabidiol (25 mg/kg), oxycodone (1.4 mg/kg), or a combination of both, after which they were tested in an operant thermal orofacial pain assay in which they voluntarily exposed their faces to cutaneous thermal pain to receive a palatable reward.

All three drug conditions produced analgesic effects of varying degrees, being most profound in the combination group where a statistically significant enhancement over oxycodone-induced analgesia alone was evident. Additionally, oxycodone administration decreased lick frequencies – a measure of motor coordination of rhythmic movements – which too was magnified by co-administration of cannabidiol.

Together these studies provide further support of an ability of cannabidiol to augment opioid effects, particularly analgesia, when administered by a route relevant to human pain management. As such, they encourage the notion that cannabidiol could find utility as an opioid-sparing approach to treating pain.”

https://pubmed.ncbi.nlm.nih.gov/39914591/

“Cannabidiol is an orally active constituent of the cannabis plant”

“Cannabidiol potentiates opioid analgesia in an operant orofacial pain assay in rats”

“Cannabidiol as an opioid-sparing approach to treating pain is worthy of more study”

https://www.sciencedirect.com/science/article/abs/pii/S0091305725000152?via%3Dihub

Cannabidiol alters psychophysiological, craving and anxiety responses in an alcohol cue reactivity task: A cross-over randomized controlled trial

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“Background: Preclinical studies have demonstrated that cannabidiol (CBD) reduces alcohol-seeking behaviors and may have potential for managing alcohol use disorder (AUD). In this study, we examined the effects of CBD versus placebo on (i) psychophysiological, craving and anxiety responses to alcohol and appetitive cues; (ii) tolerability measures including cognitive functioning.

Methods: Twenty-two non-treatment-seeking individuals with AUD (DSM-5) participated in a cross-over, double-blind, randomized trial, receiving either 800 mg of CBD or matched placebo over 3 days. A laboratory alcohol cue reactivity task with appetitive control (juice) and alcohol exposures, and subsequent recovery periods to examine regulation of cue-elicited responses after cue-offset (recovery) was completed, with psychophysiological indices of autonomic nervous system activity (skin conductance, high-frequency heart rate variability [HF-HRV]) and self-reported measures (alcohol craving and anxiety). Self-reported scales of sedation and neuropsychological executive function tasks were also completed.

Results: CBD sessions were significantly associated with elevated parasympathetic nervous system (PNS) activity across the task, as indicated by increased HF-HRV. Reductions in self-reported anxiety during cue exposure stages compared to placebo sessions were also evidenced. Reductions in self-reported alcohol craving after cue exposure were seen during CBD sessions only. There were no significant differences between CBD and placebo on executive functioning performance.

Conclusions: In a short-term regimen, CBD appears to modulate PNS activity, reduce cue-elicited anxiety during cue exposure and reduce alcohol craving after cue exposure while not significantly impairing cognition. Large, parallel clinical trials with longer term regimens are now needed to determine the therapeutic potential of CBD in the management of AUD.”

https://pubmed.ncbi.nlm.nih.gov/39891614/

https://onlinelibrary.wiley.com/doi/10.1111/acer.15514

Emerging trends in cannabis administration for women with chronic pain

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“Cannabis use among women who experience chronic pain is on the rise in the United States. However, little is known about women’s motives and preferences for cannabis administration. The purpose of this study was to characterize cannabis use among women with chronic pain.

This study examined self-reported forms of cannabis administration and preferred source of cannabis, frequency and quantity of use, and self-reported side effects, and type, level, and intensity of chronic pain among adult women in the United States. This study also compared women who use cannabis for chronic pain and those who do not across the level of chronic pain, length of chronic pain, and the number of types of chronic pain experienced.

Participants showed a significant preference (60%) for using recreational cannabis to treat chronic pain but reported that medical cannabis was more effective. For participants who preferred medical cannabis 24.3% reported daily use, as compared to only 7.8% of recreational cannabis users. Smoking was the most common form of administration (62.1%), followed by edibles (25.3%), vaporizing in any form (7.4%), tinctures and concentrates (3.2%), and topicals (2.1%). Participants reported using 1-6 different forms of cannabis administration. Those who preferred smoking were significantly likely to use all other forms of administration. However, those who preferred alternatives to smoking were significantly likely to use all forms of administration except for smoking. Medical cannabis users preferred to obtain cannabis from a dispensary, while recreational users preferred to obtain cannabis from unlicensed sources.

Additionally, participants who used cannabis for chronic pain reported a 74% reduction in past 30-day opioid use.

Future research is needed to investigate the health effects associated with single and combined forms of cannabis administration for women with chronic pain. Results can inform educational and intervention programs, treatment development, content regulation of products, policy formation, women’s health research, and public health guidelines.”

https://pubmed.ncbi.nlm.nih.gov/39816373/

https://onlinelibrary.wiley.com/doi/10.1002/mhs2.88

Cannabinoid-based Pharmacology for the Management of Substance Use Disorders

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“In the last two decades, the endocannabinoid system has emerged as a crucial modulator of motivation and emotional processing. Due to its widespread neuroanatomical distribution and characteristic retrograde signaling nature, cannabinoid type I receptors and their endogenous ligands finely orchestrate somatic and axon terminal activity of dopamine neurons.

Owing to these unique features, this signaling system is a promising pharmacological target to ameliorate dopamine-mediated drug-seeking behaviors while circumventing the adverse side effects of, for instance, dopaminergic antagonists.

Despite considerable preclinical efforts, an agreement on the efficacy of endocannabinoid-targeting compounds for treating drug substance use disorders in humans has not been reached. In the following chapter, we will summarize preclinical and clinical evidence addressing the therapeutic potential of cannabinoids and endocannabinoid-targeting compounds in substance use disorders.

To bridge the gap between animal and clinical research, we capitalize on studies evaluating the impact of endocannabinoid-targeting compounds in relevant settings, such as the management of drug relapse.

Finally, we discuss the therapeutic potential of novel cannabinoid compounds that hold promise for treating substance use disorders.”

https://pubmed.ncbi.nlm.nih.gov/39813001/

https://link.springer.com/chapter/10.1007/7854_2024_551

Determination of the Negative Allosteric Binding Site of Cannabidiol at the CB1 Receptor: A Combined Computational and Site-Directed Mutagenesis Study

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“Cannabinoid receptor 1 (CB1R) has been extensively studied as a potential therapeutic target for various conditions, including pain management, obesity, emesis, and metabolic syndrome. Unlike orthosteric agonists such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) has been identified as a negative allosteric modulator (NAM) of CB1R, among its other pharmacological targets. Previous computational and structural studies have proposed various binding sites for CB1R NAMs. An X-ray crystal structure revealed a binding site for the NAM, ORG27569, at an extrahelical location within the inner leaflet of the membrane. In contrast, multiple computational studies have previously proposed several potential allosteric binding sites for CBD within the CB1R structure. Given that a prior structural study suggested CBD might occupy the same site as ORG27569, we conducted a comprehensive investigation of potential CBD binding sites using molecular docking, molecular dynamics (MD) simulations, metadynamics (MTD) simulations, binding free-energy calculations, and in vitro mutagenesis experiments. Molecular docking, MD, and MTD simulations results, along with binding free-energy calculations, suggest that CBD may potentially bind to either the same extrahelical site as ORG27569 or a previously unidentified intracellular site located near TMHs 2, 6, and 7 and helix 8. This intracellular site is consistent with allosteric binding sites observed in other G protein-coupled receptors (GPCRs). To establish the most favorable allosteric site for CBD, we conducted site-directed mutagenesis of key residues at each site. Mutations at S4018.47ΔA and D4038.49ΔA augmented the binding of [3H]-SR141716A, suggesting these residues play critical roles in CBD binding. As a result, the combined computational and mutagenesis results identified a binding site for CBD between TMHs 2, 6, and 7 and helix 8, involving residues Y1532.40, I1562.43, M3376.29, L3416.33, S4018.47, and D4038.49. These findings provide valuable insights into how CBD binds to CB1R, thereby informing the rational design of new, selective, and potent NAMs. Moreover, the elucidation of this previously unexplored allosteric site might explain the polypharmacology of CBD due to structural conservation among Class A GPCRs.”

https://pubmed.ncbi.nlm.nih.gov/39812521/

https://pubs.acs.org/doi/10.1021/acschemneuro.4c00343

CBD and the 5-HT1A receptor: A medicinal and pharmacological review

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“Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms.

It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD’s pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated.

This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling.

A comprehensive survey of the literature underscores CBD’s multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR.

Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.”

https://pubmed.ncbi.nlm.nih.gov/39778776/

“Cannabis was one of the first inhaled drugs utilized by humans, with evidence of use for gout, rheumatism, and malaria dating to 2737 BCE”

“The concurrent literature revealed that CBD produces several therapeutic effects through its complex pharmacodynamic interactions with 5-HT1AR. Therapeutic applications of CBD, including its anxiolytic, antidepressant, antipsychotic, anti-degenerative, neuroprotective, anti-epileptic, and anti-addictive properties were mediated, at least in part, by its binding to 5-HT1AR.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225000048?via%3Dihub

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

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

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

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

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

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

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

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

Cannabinoid for alcohol use disorder

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

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

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

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

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

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

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