Cannabis Withdrawal Symptoms Research Articles

Validation of the Reasons for Quitting Smoking Cannabis Scale Among People with Cannabis Use Disorder

Background The prevalence of cannabis use disorder (CUD) has increased in the last ten years with medicinal and recreational legalization across the United States and increasing accessibility worldwide. Estimates suggest that 8-18% of individuals who use cannabis meet diagnostic criteria for CUD, leading to significant impairments across functioning. However, there are currently no measures that assess the reasons for quitting smoking cannabis to use in treatments with validation evidence in those with CUD. Method We validated the Reasons for Quitting Smoking Cannabis Scale (RQSCS) in adults (n = 133) who meet the diagnostic criteria for CUD as part of a laboratory-based clinical trial on transdermal nicotine patches for cannabis withdrawal symptoms (R01DA031006). We conducted standard psychometric testing, including exploratory factor analyses, estimating internal consistencies, exploring demographic variation, and testing construct validity. Results The RQSCS demonstrated a four-factor structure, including: (1) cognitive health, (2) social functioning, (3) health problems, (4) reputation, and a single item that assesses experimental incentive; λs > .410), with acceptable to high internal consistencies for each subscale (αs > .725). The scale demonstrated strong construct validity and minor demographic variation. Finally, all subscales were sensitive to detecting reasons for quitting cannabis and differentially predicted cannabis use 31 days after the study. Conclusion The RQSCS is a psychometrically robust, timely instrument for assessing the reasons for quitting smoking cannabis in individuals with CUD. The scale has the potential to provide useful information for clinicians attempting to help those with CUD reduce or cease their cannabis use, informing individualized treatment plans and enhancing motivation for change.

A preliminary investigation of sex differences in cognitive and fMRI changes following 28 days of cannabis abstinence

BackgroundPrevious studies have investigated the influence of cannabis on cognition among people with MS (pwMS), yet the influence of sex in the context of cannabis use remains unexplored. We aim to fill this gap by investigating cannabis-sex related differences in verbal learning, memory and processing speed in association with fMRI (resting state, and task-based) metrics. MethodOur sample consisted of 19 long-term, frequent cannabis users (8 males, 11 females). Assessments were conducted at baseline and after 28 days of cannabis abstinence. The tests included measures of verbal memory (Selective Reminding Test (SRT)), working memory (n-back), information processing speed (Symbol Digit Modalities Test (SDMT)) and the resting state DMN. To evaluate the effects of cannabis abstinence, we performed a group x time interaction analysis using repeated measures ANCOVA. This analysis controlled for several covariates, including the level of disability (EDSS), baseline cannabis THC metabolite levels, and cannabis withdrawal symptoms. By controlling for these variables, we aimed to isolate the impact of cannabis abstinence on cognitive performance over time. Statistical significance was set at p < 0.05. ResultsThere were no baseline cognitive differences between the sexes. After 28 days of cannabis abstinence, females performed better on the Selective Reminding Test (SRT) (p = 0.04), with a large effect size (η² = 0.286). The mean correct response improved over time for females, but there was no statistically significant group x time interaction on the Symbol Digit Modalities Test (SDMT) and the n-back task. Resting state default mode network data showed overall increased activation in females relative to males at day 28, which meshed with lower brain activation during task-based fMRI paradigms. ConclusionCannabis negated sex-based cognitive differences. Functional MRI task-based paradigms revealed less cerebral activation in females compared to males, which was associated with comparable or better cognitive performance in females, particularly after cannabis abstinence.

Attenuation of cannabis withdrawal symptoms by Prosopis farcta extract, its luteolin and melatonin in mice: Involvement of brain-derived neurotrophic factor and dopamine.

The aim of this study was the identification of luteolin in Prosopis farcta extract (PFE) and melatonin to evaluate its effect on THC withdrawal syndrome in mice. Luteolin was identified by high-performance liquid chromatography (HPCL). Signs of toxicity of mice in PFE and luteolin were monitored for LD50 calculation. The behavioral symptoms of THC withdrawal (stereotypies, ambulation, and inactivity time) induced by the rimonabant challenge were illustrated in THC-dependent mice receiving PFE, luteolin, and melatonin. The expression of mature BDNF (mBDNF) was evaluated by Western blot analysis. The dopamine concentrations were measured using HPLC. PFE and luteolin LD50 were 650 and 220 mg/kg, respectively. PFE (300 mg/kg), all doses of luteolin, and melatonin increased significantly the mBDNF expression and decreased the dopamine concentration. The findings suggest that PFE, luteolin, and melatonin are mighty in reducing the signs of THC withdrawal. It seems these effects were due to a decrease in dopamine concentration level and an increase in mBDNF protein expression in mice brains.

Treatments for Cannabis Use Disorder across the Lifespan: A Systematic Review.

Cannabis use disorder (CUD) is a growing public health concern, with rising prevalence and significant impact on individuals across age groups. This systematic review examines 24 studies investigating pharmacological and non-pharmacological interventions for CUD among adolescents (up to 17), young adults (18-24), and older adults (25-65). Database searches were conducted for randomized controlled trials of CUD interventions reporting outcomes such as cannabis use, abstinence, withdrawal symptoms, and treatment retention. For adolescents, interventions such as contingent rewards and family engagement have shown promise, while young adults benefit from technology-based platforms and peer support. In older adults, pharmacological adjuncts combined with counseling have shown promise in enhancing treatment outcomes. However, optimal treatment combinations remain uncertain, highlighting the need for further research. Addressing CUD requires tailored interventions that acknowledge developmental stages and challenges across the lifespan. Although promising interventions exist, further comparative effectiveness research is needed to delineate the most efficacious approaches.

Cannabis-induced psychotic disorder with onset during withdrawal: a brief report of emerging evidence.

The link between cannabis use and psychotic symptoms or disorders is well known. However, the relation between cannabis withdrawal and psychotic symptoms is less studied. To our knowledge, this is the first publication of an observational systematic report of cannabis-induced psychotic disorder with onset during withdrawal. Here, we review patients presenting to a major emergency room in Montreal between January 2020 and September 2023 in a context of psychotic symptoms following cannabis cessation. In total, seven male and one female patients presented at the peak of cannabis withdrawal with acute psychotic symptoms, representing less than 1% of all emergency service admissions. We discuss current knowledge regarding the endocannabinoid system and dopamine homeostasis to formulate hypotheses regarding these observations.

Circulating Endocannabinoids and N-Acylethanolamines in Individuals with Cannabis Use Disorder-Preliminary Findings.

Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain. Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which may affect concentrations of AEA as well as other NAEs (OEA, DHEA). In overnight abstinent CUD, AEA, OEA and DHEA concentrations were significantly higher (31-40%; p < 0.05) and concentrations of the endocannabinoid 2-AG were marginally elevated (55%, p = 0.13) relative to HC. There were no significant correlations between endocannabinoids/NAE concentrations and cannabis analytes, self-reported cannabis use frequency or withdrawal symptoms. DHEA concentration was inversely related with marijuana craving (r = -0.86; p = 0.001). Genotype had no significant effect on plasma endocannabinoids/NAE concentrations. Our preliminary findings, requiring replication, might suggest that activity of the endocannabinoid system is elevated in chronic cannabis users. It is unclear whether this elevation is a compensatory response or a predating state. Studies examining endocannabinoids and NAEs during prolonged abstinence as well as the potential role of DHEA in craving are warranted.

Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence.

Cannabis use disorder (CUD) presents differently in men and women, particularly in symptoms of cannabis withdrawal. Novel pharmacotherapeutic interventions for CUD, such as those that target the endocannabinoid (eCB) system, must be developed in a manner consistent with these sex differences. The present pilot study sought to prospectively assess sex differences in cannabis withdrawal in a small sample of adults with moderate-to-severe CUD and to determine if withdrawal was associated with peripheral eCB and eCB congener tone. Men and women (n= 5/sex) completed 2 weeks of study participation separated by 1 month; in the latter week, participants abstained from cannabis use. Each week, participants attended in-person laboratory visits during which blood was drawn repeatedly to assess plasma eCB and eCB congener tone. Participants also completed multiple daily ambulatory assessments to assess cannabis use and withdrawal symptoms. As anticipated, women reported a greater increase in withdrawal symptoms during the abstinent week [Δ = 9.4 (SE = 1.1); p<0.001] than men [Δ = 1.2 (SE = 1.2); p=0.35]. Sex differences in levels of the eCB N-arachidonoylethanolamide (AEA), as well as the eCB congeners stearoylethanolamide (SEA) and linoleylethanolamide (LEA), were evident during abstinence at the morning time point only (p's <0.05). LEA was associated with withdrawal symptom expression in both sexes [β = 0.16 (SE = 0.09)] and palmitoylethanolamide (PEA) [β = 0.22 (SE = 0.13)] and 2-arachidonoylglycerol (2-AG) [β = 0.32 (SE = 0.15)] were associated with withdrawal symptoms in women only. Pharmacotherapeutic development for CUD should consider evident sex differences in eCB and eCB congener tone during abstinence and their associations with cannabis withdrawal, as eCB-based interventions may produce differential effects by sex.

Cannabis Use Patterns and Whole-Blood Cannabinoid Profiles of Emergency Department Patients With Suspected Cannabinoid Hyperemesis Syndrome.

The objectives of this study were to characterize the detailed cannabis use patterns (eg, frequency, mode, and product) and determine the differences in the whole-blood cannabinoid profiles during symptomatic versus asymptomatic periods of participants with suspected cannabinoid hyperemesis syndrome recruited from the emergency department (ED) during a symptomatic episode. This is a prospective observational cohort study of participants with symptomatic cyclic vomiting onset after chronic cannabis use. Standardized assessments were conducted to evaluate for lifetime and recent cannabis use, cannabis use disorder, and cannabis withdrawal symptoms. Quantitative whole-blood cannabinoid testing was performed at 2 times, first when symptomatic (ie, baseline) and at least 2 weeks after the ED visit when asymptomatic. The differences in cannabinoid concentrations were compared between symptomatic and asymptomatic testing. The study was conducted from September 2021 to August2022. There was a difference observed between delta-9-tetrahydrocannabinol metabolites, but not the parent compound during symptomatic episodes and asymptomatic periods. Most participants (84%) reported using cannabis > once per day (median 3 times per day on weekdays, 4 times per day on weekends). Hazardous cannabis use was universal among participants; the mean cannabis withdrawal discomfort score was 13, indicating clinically significant rates of cannabis withdrawal symptoms with cessation of use. Most participants (79%) previously tried to stop cannabis use, but a few (13%) of them had sought treatment. Patients presenting to the ED with cannabinoid hyperemesis syndrome have high cannabis use disorder scores. Further studies are needed to better understand the influence of THC metabolism and concentrations on symptomatic cyclic vomiting.

Modern methods of treating marijuana addiction (cannabis use disorders) and its influence on health

Introduction: Worldwide, cannabis is the most widely used illegal psychoactive substance and the third most common drug, after alcohol and tobacco. Cannabis use disorder (CUD) affects approximately 10% of the 193 million cannabis users worldwide. In recent years, cannabinoids have become more and more popular. The CUD is becoming a growing social and health problem. The search for effective forms of pharmacotherapy is still ongoing, and an effective combination of psychotherapy and pharmacotherapy may be crucial for the future of CUD treatment.&#x0D; &#x0D; Material and method: The article was based on a review and analysis of publications and discoveries in recent years, which were available in the PubMed and Google Scholar database.&#x0D; &#x0D; Results: 82 study participants attempted abstinence from cannabis use. In the final primary endpoint analysis, both 400 mg of CBD and 800 mg of CBD were more effective than placebo in reducing cannabis use. 50 people who were addicted to cannabis treated with gabapentin showed a significant reduction in cannabis use and cannabis withdrawal compared to placebo. Moreover, 70 men addicted to cannabis were randomized and those, who used FAAH inhibitors reported fewer cannabis withdrawal symptoms, less cannabis use and lower THC urine levels than placebo users.&#x0D; Conclusions: Gabapentin has been proven to show a reduction in CUD. The use of CBD, FAAH inhibitors and psychotherapy MET/CBT/CM also appear to be effective. In addition, the use of the principles of People-First Language, avoiding slang and idioms, using medical and curing vocabulary, respects the addicted person, and also positively influences the chances of abstinence.

Characterization of cannabis withdrawal symptoms and serum levels of neurotransmitters among cannabis-dependent smokers during sustained abstinence within a controlled residential environment

Introduction Cannabis (aka marijuana) is the most frequently consumed illicit substance worldwide, and a subset of frequent cannabis smokers (up to 30%) develop dependence. A less well-known consequence of cannabis dependence is withdrawal syndrome, characterized by a time-dependent constellation of symptoms (Lafaye et al. Dialogues Clin Neurosci 2017;19(3), 309-316). Objectives This study aims to prospectively assess the course of cannabis withdrawal symptoms within a controlled inpatient detoxification setting and to correlate the severity of withdrawal symptoms with the serum levels of neurotransmitters (NT). Methods N=45 treatment-seeking chronic cannabis dependents (assessed by ICD-10) were enrolled, and their withdrawal symptoms were assessed prospectively from admission (Day-0) to 28 days using Marijuana withdrawal checklist (MWC). Sociodemographic characteristics and self-reported drug use histories were reported. Serum levels of dopamine, serotonin, norepinephrine, epinephrine, and cortisol were measured. Cannabis abstinence symptoms were assessed daily using MWC for 4 weeks, and serum neurotransmitter levels were analyzed at admission (Day 0), 7, 14, 21, and 28. Comparison between groups was done using Friedman’s test. Correlation between NT level and MWC scores was performed using linear regression spearman correlation analysis Results The follow-up NT levels from Day 0 to 28 showed a significant (p&lt;0.05) decrease in serotonin and dopamine, whereas epinephrine levels showed a significant increase (Fig 1) with the course of withdrawal. Withdrawal symptoms like decreased appetite, sweating, and craving were significantly and positively correlated with serotonin, dopamine, and epinephrine NT levels (Fig 2). Image: Image 2: Conclusions Findings support the presence of clinically significant cannabis withdrawal symptoms with NT levels in subjects with cannabis dependence seeking substance abuse treatment. The data of this study determine the relationship between observed withdrawal symptoms and changes in brain chemistry and evaluate its possible utility as a predictor of relapse. Disclosure of Interest None Declared

Gender differences in cannabis use disorder symptoms: A network analysis

BackgroundWhile cannabis use in women is increasing worldwide, research into gender differences in cannabis use disorder (CUD) symptomology is lacking. In response to limited effectiveness of addiction treatment, research focus has been shifting from clinical diagnoses towards interactions between symptoms, as patterns of symptoms and their interactions could be crucial in understanding etiological mechanisms in addiction. The aim of this study was to evaluate the CUD symptom network and assess whether there are gender differences therein. MethodsA total of 1257 Dutch individuals reporting weekly cannabis use, including 745 men and 512 women, completed online questionnaires assessing DSM-5 CUD symptoms and additional items on plans to quit or reduce use, cigarette use, and the presence of psychological diagnoses. Gender differences were assessed for all variables and an Ising model estimation method was used to estimate CUD symptom networks in men and women using network comparison tests to assess differences. ResultsThere were gender differences in the prevalence of 6 of the 11 symptoms, but symptom networks did not differ between men and women. Cigarette use appeared to only be connected to the network through withdrawal, indicating a potential role of cigarette smoking in enhancing cannabis withdrawal symptoms. Furthermore, there were gender differences in the network associations of mood and anxiety disorders with CUD symptoms. ConclusionThe association between smoking and withdrawal as well as gender differences in the role of comorbidities in the CUD network highlight the value of using network models to understand CUD and how symptom interactions might affect treatment.

Abstinence phobia among adult African American/Black cannabis users

ObjectiveAfrican American/Black individuals experience significant health disparities, particularly as it relates to cannabis use. As such, there is a need to identify intrapersonal factors related to more severe patterns of use among this subpopulation. Worry about quitting or reducing cannabis as a result of the anticipated anxiety-related states during deprivation (i.e., abstinence phobia) is one factor that is theoretically important in the context of cannabis-related disparities. MethodThe current study sought to examine the cross-sectional association between abstinence phobia and cannabis use problems, perceived barriers for cannabis cessation, and cannabis withdrawal symptoms. Participants included 83 African American/Black cannabis users (31.3% female, Mage = 38.12, SD = 10.42). ResultsCannabis abstinence phobia was associated with greater severity of cannabis use problems, more perceived barriers for quitting cannabis use, and more severe cannabis withdrawal symptoms. ConclusionsAbstinence phobia may represent an underrecognized intervention target for addressing cannabis use problems and quit success.

A "Good" Smoke? The Off-Label Use of Cannabidiol to Reduce Cannabis Use.

BackgroundAlthough cannabis use is common in France, it is still criminalized. Cannabidiol (CBD) products, including CBD-rich cannabis, are legally available. Although previous results suggested that CBD may have benefits for people with cannabis use disorder, there is a lack of data on cannabis users who use CBD to reduce their cannabis consumption. We aimed to identify (i) correlates of this motive, and (ii) factors associated with successful attempts to reduce cannabis use.MethodsA cross-sectional online survey among French-speaking CBD and cannabis users was conducted. Logistic regressions were performed to identify correlates of using CBD to reduce cannabis consumption and correlates of reporting a large reduction.ResultsEleven percent (n = 105) of our study sample reported they primarily used CBD to reduce cannabis consumption. Associated factors included smoking tobacco cigarettes (adjusted odds ratio (aOR) [95% confidence interval (CI)] 2.17 [1.3–3.62], p = 0.003) and drinking alcohol (aOR [95%CI] 1.8 [1.02–3.18], p = 0.042). Of these 105, 83% used CBD-rich cannabis to smoke, and 58.7% reported a large reduction in cannabis consumption. This large reduction was associated with non-daily cannabis use (aOR [95%CI] 7.14 [2.4–20.0], p < 0.001) and daily CBD use (aOR [95%CI] 5.87 [2.09–16.47], p = 0.001). A reduction in cannabis withdrawal symptoms thanks to CBD use was the most-cited effect at play in self-observed cannabis reduction.ConclusionsCannabis use reduction is a reported motive for CBD use—especially CBD-rich cannabis to smoke—in France. More studies are needed to explore practices associated with this motive and to accurately assess CBD effectiveness.

Elevated striatal glutamate + glutamine in recreational cannabis users during abstinence

Cannabis withdrawal symptoms contribute to relapse, but the underlying mechanism remains unclear. We hypothesize that cannabis withdrawal may be associated with a reset of regional γ-amino butyric acid (GABA) and glutamate concentrations secondary to changes in the endocannabinoid system during abstinence and conducted a study on this issue. We used magnetic resonance spectroscopy (MRS) to detect the associated changes of these neurochemicals in twenty-six frequent, recreational cannabis users and eleven age-matched non-using controls. Twenty users (8F/12M) and ten control (5F/5M) participants completed a verified 21-day abstinence period. Striatal GABA and glutamine concentrations were measured at baseline and on abstinence days 7 and 21 in conjunction with measures of cannabis withdrawal symptoms and mood state. Cannabis users reported increased self-reported ratings of cannabis-withdrawal-symptoms on abstinence day 7 relative to controls. Striatal glutamate + glutamine (Glx) group concentrations were elevated in cannabis users at baseline and abstinence days 7 and 21 (F = 7.16, p = 0.012), and changes in GABA concentration and withdrawal symptoms between baseline and abstinence day 7 were positively correlated (r = 0.550, p = 0.010). In addition, baseline striatal GABA concentrations were negatively correlated with withdrawal symptoms on abstinence day 7 (r = −0.680, p = 0.003). Our data demonstrate that striatal Glx was elevated in cannabis users and baseline striatal GABA correlated with withdrawal during the abstinence. In addition, striatal GABA may temporally correlate with self-reported withdrawal symptoms during the initial days of abrupt cannabis abstinence. These findings provide preliminary evidence that striatal GABA and Glx are associated with the severity of cannabis withdrawal.

Analyzing the Behavior of Cannabis Users during the COVID-19 Confinement in Spain.

The impact of the COVID-19 pandemic on our lives is unquestionable, including in the area of substance consumption. This study aimed to evaluate the changes in the pattern of cannabis use during the Spanish COVID-19 lockdown and confinement, and to analyze the variations in the reported motives for cannabis use and withdrawal symptoms. A cross-sectional retrospective study was conducted between April and May 2020, using an instrument that included two time points. Time 1 collected retrospective information on the participants’ habits (N = 89; 73% male; mean age = 29.01) prior to confinement and Time 2 collected the same information during the confinement. Sociodemographic data were collected, as well as the frequency of substance use, cannabis use patterns, sources of cannabis, perceived availability of drugs and cannabis price, and the Marijuana Motives Measure questionnaire and the Cannabis Withdrawal Scale were used. Results showed a decrease in both cannabis use and consumption due to enhancement and social motives. All reported sources of cannabis experienced a reduction except for the Internet, which experienced a significant increase. There was a positive correlation between withdrawal symptoms and coping motives before and during the lockdown. These findings will allow professionals to better develop both prevention and intervention strategies.

Assessment of Withdrawal, Mood, and Sleep Inventories After Monitored 3-Week Abstinence in Cannabis-Using Adolescents and Young Adults.

Introduction: Among adolescents and young adults, cannabis use is prevalent. Prior studies characterizing withdrawal effects in this age range have primarily included treatment seeking or comorbid psychiatric samples; these studies have identified several affected domains, especially sleep, mood, and anxiety. The present study compared a community (i.e., nontreatment seeking) sample of cannabis-using and control participants on mood, anxiety, sleep, and withdrawal inventories during the course of a monitored 3-week cannabis abstinence period. Materials and Methods: Seventy-nine adolescent and young adult participants (cannabis-using group=37 and control group=42) were recruited from the community to undergo 3 weeks of confirmed abstinence (i.e., urine and sweat patch toxicology) and completion of Cannabis Withdrawal Symptom Criteria, State-Trait Anxiety Inventory, Beck's Depression Inventory, and Pittsburgh Sleep Quality Index across the study period. Repeated measures and cross-sectional regressions were used to examine main effects of group and interactions with time (where appropriate), while accounting for recent alcohol use and cotinine levels. Results: Cannabis-using participants reported higher mood (p=0.006), overall withdrawal (p=0.009), and sleep-related withdrawal (p<0.001) symptoms across abstinence compared to controls. Overall withdrawal severity (p=0.04) and sleep-related withdrawal symptoms (p=0.02) demonstrated a quadratic trajectory across the monitored abstinence periods, with an increase from baseline and subsequent decreases in symptom severity. No differences of anxiety scores (p=0.07) or trajectories (p=0.18) were observed. By study completion, groups did not differ among sleep quality components (all p's>.05). Conclusions: These findings revealed that nontreatment-seeking cannabis-using adolescents and young adults reported heightened total withdrawal symptoms during a 3-week sustained abstinence period relative to controls. Cannabis-using participants demonstrated an increase in withdrawal symptom trajectory during the first week followed by decreased symptoms from weeks 2 to 3, which contrasts with prior linear decreases observed in cannabis-using adolescent and young adults. More mood symptoms were observed in the cannabis-using group even while excluding for comorbid psychopathologies-along with significantly more sleep problems during the abstinence period. Implications include the necessity to provide psychoeducation for recreational, nontreatment-seeking cannabis-using individuals about cannabis withdrawal, mood symptoms, and sleep quality difficulties when cannabis cessation is attempted, to improve likelihood of long-term sustained abstinence.

Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings.

Cannabis sativa is the most widely used illicit drug in the world. Its main psychoactive component is delta‐9‐tetrahydrocannabinol (THC), one of over 100 phytocannabinoid compounds produced by the cannabis plant. THC is the primary compound that drives cannabis abuse potential and is also used and prescribed medically for therapeutic qualities. Despite its therapeutic potential, a significant subpopulation of frequent cannabis or THC users will develop a drug use syndrome termed cannabis use disorder. Individuals suffering from cannabis use disorder exhibit many of the hallmarks of classical addictions including cravings, tolerance, and withdrawal symptoms. Currently, there are no efficacious treatments for cannabis use disorder or withdrawal symptoms. This makes both clinical and preclinical research on the neurobiological mechanisms of these syndromes ever more pertinent. Indeed, basic research using animal models has provided valuable evidence of the neural molecular and cellular actions of cannabis that mediate its behavioral effects. One of the main components being central action on the cannabinoid type‐one receptor and downstream intracellular signaling related to the endogenous cannabinoid system. Back‐translational studies have provided insight linking preclinical basic and behavioral biology research to better understand symptoms observed at the clinical level. This narrative review aims to summarize major research elucidating the molecular, cellular, and behavioral manifestations of cannabis/THC use that play a role in cannabis use disorder and withdrawal.

Prevalence of Cannabis Withdrawal Symptoms Among People With Regular or Dependent Use of Cannabinoids: A Systematic Review and Meta-Analysis

Cannabis withdrawal syndrome (CWS)—a diagnostic indicator of cannabis use disorder—commonly occurs on cessation of heavy and prolonged cannabis use. The aim of our study was to estimate the prevalence of CWS among individuals with regular or dependent use of cannabinoids and identify factors associated with CWS.

Progression of cannabis withdrawal symptoms in people using medical cannabis for chronic pain.

Research from cohorts of individuals with recreational cannabis use indicates that cannabis withdrawal symptoms are reported by more than 40% of those using regularly. Withdrawal symptoms are not well understood in those who use cannabis for medical purposes. Therefore, we prospectively examined the stability of withdrawal symptoms in individuals using cannabis to manage chronic pain. Using latent class analysis (LCA) we examined baseline cannabis withdrawal to derive symptom profiles. Then, using latent transition analysis (LTA) we examined the longitudinal course of withdrawal symptoms across the time points. Exploratory analyses examined demographic and clinical characteristics predictive of withdrawal class and transitioning to more or fewer withdrawal symptoms over time. A cohort of 527 adults with chronic pain seeking medical cannabis certification or re-certification was recruited between February 2014 and June 2015. Participants were recruited from medical cannabis clinic waiting rooms in Michigan, USA. Participants were predominantly white (82%) and 49% identified as male, with an average age of 45.6years (standard deviation=12.8). Baseline, 12-month and 24-month assessments of withdrawal symptoms using the Marijuana Withdrawal Checklist-revised. A three-class LCA model including a mild (41%), moderate (34%) and severe (25%) symptom class parsimoniously represented withdrawal symptoms experienced by people using medical cannabis. Stability of withdrawal symptoms using a three-class LTA at 12 and 24months ranged from 0.58 to 0.87, with the most stability in the mild withdrawal class. Younger age predicted greater severity and worsening of withdrawal over time. Adults with chronic pain seeking medical cannabis certification or re-certification appear to experience mild to severe withdrawal symptoms. Withdrawal symptoms tend to be stable over a 2-year period, but younger age is predictive of worse symptoms and of an escalating withdrawal trajectory.

Evidence for the Endocannabinoid System as a Therapeutic Target in the Treatment of Cannabis Use Disorder.

Cannabis use disorder (CUD) is highly prevalent. Psychotherapy alone is not adequately effective, with few individuals achieving abstinence. Pharmacotherapeutic supplementation may improve efficacy, and the endocannabinoid system presents a target specifically dysregulated by heavy cannabis use. This review compiles current literature evaluating endocannabinoid modulation as a treatment strategy for CUD, with implications for future research. Cannabinoid receptor agonists have been found to reduce cannabis withdrawal symptoms without a notable effect on relapse, and antagonists can produce severe psychiatric symptoms. Fatty acid amide hydrolase inhibitors and cannabidiol demonstrate the most promising efficacy in treating CUD thus far, but research with these compounds is still preliminary. Components of the endocannabinoid system may serve as unique treatment targets with differential efficacy for the treatment of cannabis use disorder as a whole. Further research is needed exploring novel methods for targeting endocannabinoid dysfunction in CUD.