Full length articleAbstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification: Cannabis withdrawal syndrome and its correlation with delta-9-tetrahydrocannabinol and -metabolites in serum
Introduction
Cannabis is a psychotropic substance with widespread use worldwide, surpassed only by nicotine and alcohol (UNDOC, 2013). In Germany, for example, the12-month prevalence for cannabis use amounts to 4.5% for adults in general, with highest rates in the age groups of 18–20 years (16.2%) and 21–24 years (13.7%; Pabst et al., 2013). 12-month prevalence for cannabis dependence (DSM-IV) was recently estimated as 0.5% in all German adults (Pabst et al., 2013).
Retrospective studies on larger clinical (Wiesbeck et al., 1996, Levin et al., 2010) and epidemiological (Agrawal et al., 2008, Hasin et al., 2008) populations have shown that discontinuation of regular cannabis use is frequently followed by one or more symptoms like anxiety, irritability, craving for cannabis, or sleeping problems, which are associated with distress and impairment of daily activities and with relapse to cannabis use (Budney et al., 2004, Allsop et al., 2011). Starting from various definitions the existence of a clinical cannabis withdrawal syndrome (CWS) was validated in prospective studies with outpatients or untreated subjects supervised after cessation of cannabis use (Budney et al., 1999, Kouri and Pope, 2000, Budney et al., 2004, Arendt et al., 2007, Allsop et al., 2011) and by inpatient laboratory studies (Haney et al., 2008, Haney et al., 2010). On this basis diagnostic criteria for CWS have been recently operationalized and newly included in DSM-5 (American Psychiatric Association, 2013). In ICD-10, the CWS is still vaguely defined (Dilling et al., 2004). The CWS emerges most pronounced after stopping a lengthy and heavy cannabis intake and in treated samples its intensity is associated with a patient's motivation for detoxification and with characteristics of the treatment setting (Budney et al., 2004). In most cases, the syndrome reaches its peak between the 2nd and 6nd day after cessation of cannabis inhalation and usually lasts for about 14 days (Kielholz and Ladewig, 1970, Wiesbeck et al., 1996, Budney et al., 2004). Some symptoms such as ‘sleeplessness’, ‘irritability’, or ‘strange dreams’, however, may last for longer (Budney et al., 2004, Vandrey et al., 2011, Lee et al., 2014). It is interesting to note in this context that down-regulated cannabinoid CB1 receptors return to normal functioning after about 4 weeks of abstinence (Hirvonen et al., 2012), which would constitute a physiological time frame for the occurrence of abstinence symptoms.
Studies on the CWS carried out within clinical inpatient settings provide further evidence for the validity of this syndrome, but are still rare (Preuss et al., 2010, Lee et al., 2014). In a controlled inpatient environment, the CWS is expected to be less influenced by relapse-associated cues than in an everyday environment (Budney et al., 2004). Moreover, inpatient conditions provide improved relapse prevention and easier detection of relapses (Dasgupta, 2007). In the inpatient study of Preuss et al. (2010) with treatment-seeking white adolescents and young adults (n = 73) who were observed for 10 days, the intensity of most self-reported symptoms peaked on the first day in treatment and then decreased nearly linearly. Intensity of most symptoms ranged between low and moderate (Preuss et al., 2010). The symptom rated as ‘strong’ or ‘very strong’ most frequently (37.9%) was craving (Preuss et al., 2010).
Since the CWS in animal experiments and human studies can be alleviated by the administration of Δ-9-tetrahydrocannabinol (THC; Budney et al., 2007, Haney et al., 2008, Vandrey et al., 2013), which is mainly responsible for the euphoric and reinforcing effects of cannabis (Cone and Huestis, 1993, Mechoulam, 1999), it is likely that a decrease in THC levels in the extracellular brain fluid is crucially involved in the formation of the syndrome. In 2006, to the time when our study started, there was only one small study available, which had investigated the course of plasma cannabinoids after initiation of abstinence in chronic cannabis users (8 men were followed for 10–15 days; Johansson et al., 1989). Because that study revealed high inter-individual variability in the elimination half-lives of THC (Johansson et al., 1989), the question arises whether THC-levels in the peripheral blood-compartment are associated with severity of cannabis withdrawal symptoms. The first study that addressed this question was published most recently; in non-treatment seeking, African–American chronic cannabis dependent patients, an overarching correlation between CWS and serum THC had not been found (Lee et al., 2014). In addition to THC, which is highly lipophilic with a long terminal elimination half-life of up to 12.6 days in blood from chronic cannabis users (Johansson et al., 1989), two major metabolites are of interest in the present context: the hydrophilic and also psychoactive metabolite 11-hydroxy-Δ-9-tetrahydrocannabinol (THC-OH) and the lipophilic, but no longer psychoactive metabolite 11-nor-Δ-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) (Mechoulam, 1999, Grotenhermen, 2003, Musshoff and Madea, 2006).
The present study had therefore two objectives. First, to describe – under controlled inpatient conditions – the course of the CWS from shortly after cessation of chronic cannabis inhalation to up to 16 days, and second, to relate the CWS-severity to serum levels of THC and its metabolites.
Section snippets
Sample
The study was conducted in 2006–2011 in an inpatient ward for detoxification from alcohol, medical drugs, and cannabis at the Psychiatric University-Hospital in Essen, Germany. Patients could be included into the study if they (a) were diagnosed as cannabis dependent according to ICD-10 (Dilling et al., 2004), (b) had consumed cannabis by inhalation daily or almost daily during the 6 months before admission, (c) had consumed cannabis within 24 h before admission, (d) had used no other
Sample description
Forty-three patients were eligible for the study and gave their informed consent. Four of them terminated treatment within the first 36 h after admission. No patient showed comorbid symptoms requiring additional treatment during the study. We did not find any evidence that a patient had used cannabis, alcohol or other psychotropic drugs during our supervised inpatient treatment. Five patients had reduced their usual daily tobacco use at the end of the study, but none of them by more than a
What is new about this study?
The study presents data on CWS from a white and treatment-seeking population of chronic cannabis dependent patients during inpatient detoxification about 16 days. It revealed a gender effect on CWS-severity and related CWS-severity to CGI-S, thus making the intensity of CWS comparable to other disorders. Negative correlations between CWS-severity and serum levels of THC and, more robustly, of THC-OH and THC-COOH were found at baseline, which extended recently published results that described a
Conclusion
CWS of an adult population of chronic cannabis-dependent patients was studied under controlled inpatient abstinent conditions. It declined within 16 days and peaked on abstinent day 4. At this time the patients were markedly sick. The CWS was dominated by psychological withdrawal symptoms in the order craving > restlessness > nervousness > sleeplessness. The first three of these symptoms scored higher than the rest already at baseline. MWC scores for women were significantly higher than for men from
Role of funding source
Nothing declared.
Contributors
Conception and design: U.B.; collection, analysis and interpretation of data: M.S., U.B., R.O., U.S.; drafting the article: U.B.; revising it critically for important intellectual content: N.S, M.S. All authors have read and approved the final version of the manuscript.
Conflict of interest statement
U.B. received fees for lectures and the organization of training courses by the following pharmaceutical companies: Actelion, Boehringer-Ingelheim, Bristol-Myers Squibb, esparma, GlaxoSmithKline, Janssen-Cilag, Lilly, Lundbeck, Merz, and Servier. N.S. received fees for lectures, development of educational presentations and board memberships from Lundbeck, Jassen-Cilag, Reckitt-Benckiser and a grant from Roche. M.S., R.O. and U.S. had no conflict of interest.
Acknowledgements
The authors thank Ms. Raga Qasem and Mr. Markus Kudla as well as the staff of the detoxification ward ‘Station S1’ (LVR-Klinikum Essen, Germany) for their help with conducting the study. We are grateful to all participants for study support.
References (58)
- et al.
The cannabis withdrawal scale development: patterns and predictors of cannabis withdrawal and distress
Drug Alcohol Depend.
(2011) - et al.
Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms
Drug Alcohol Depend.
(2007) - et al.
Diagnostic criteria for cannabis withdrawal syndrome
Drug Alcohol Depend.
(2012) - et al.
Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers
Drug Alcohol Depend.
(2010) - et al.
Extended urinary Δ9-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure
Drug Alcohol Depend.
(2009) - et al.
Prospective assessment of cannabis withdrawal in adolescents with cannabis dependence: a pilot study
J. Am. Acad. Child Adolesc. Psychiatry
(2008) - et al.
A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances
Drug Alcohol Depend.
(2008) - et al.
Sleep disturbance and the effects of extend-release zolpidem during cannabis withdrawal
Drug Alcohol Depend.
(2011) - et al.
The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users
Drug Alcohol Depend.
(2013) - et al.
Is there evidence for symptoms of cannabis withdrawal in the national epidemiologic survey of alcohol and related conditions?
Am. J. Addict.
(2008)
Diagnostic and Statistical Manual of Mental Disorders
Withdrawal Symptoms do not predict relapse among subjects treated for cannabis dependence
Am. J. Addict.
Pharmacotherapy and psychotherapy in cannabis withdrawal and dependence
Expert Rev. Neurother.
Impact of prolonged cannabis smokers‘blood on per se drugged driving laws
Clin. Chem.
Dose-related neurocognitive effects of marijuana use
Neurology
Cannabis use disorders. Part II: Psychiatric and somatic sequelae and comorbidities
Fortschr. Neurol. Psychiat.
Comparison of two oral symptom-triggered pharmacological inpatient treatments of acute alcohol withdrawal: clomethiazole vs. clonazepam
Alcohol Alcohol.
Psychomotor function in chronic daily cannabis smokers during sustained abstinence
PLoS One
Marijuana withdrawal among adults seeking treatment for marijuana dependence
Addiction
Review of the validity and significance of cannabis withdrawal syndrome
Am. J. Psychiatry
The clinical global impression scale: applying a research tool in clinical practice
Psychiatry (Edgemont)
An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions
J. Addict. Med.
Relating blood concentrations of terahydrocannabinol and metabolites to pharmacologic effects and time of marijuana usage
Ther. Drug Monit.
The effects of adulterants and selected ingested compounds on drugs-of-abuse testing in urine
Am. J. Clin. Pathol.
Internationale Klassifikation psychischer Störungen. ICD-10 Kapitel V (F). Diagnostische Kriterien für Forschung und Praxis
The timeline followback reports of psychoactive substance use by drug-abusing patients: psychometric properties
J. Consult. Clin. Psychol.
Considering gender in cannabinoid research: a step towards personalized treatment of marijuana addicts
Drug Test. Anal.
Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man
Clin. Pharmacol. Ther.
A double-blind, multicenter study to assess the tolerability and efficacy of paroxetine compared with amitriptyline in the treatment of depressed patients in Australian general practice
Aust. N. Z. J. Psychiatry
Cited by (21)
Dose-dependent effects of cannabis on the neural correlates of error monitoring in frequent cannabis users
2015, European NeuropsychopharmacologyCitation Excerpt :In addition, including a test for alcohol intoxication would have been another improvement in securing the compliance of subjects with the study requirements. Moreover, it is possible that the observed results were affected by the fact that some subjects could had been experiencing cannabis withdrawal symptoms on the day of testing, due to the requirement to be abstinent from cannabis for 2 days prior the study (Bonnet et al., 2014). The results of this ERP study show that even a low dose of cannabis may have an effect on the neural correlates of error monitoring of frequent cannabis users.
Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification (Part II): Psychiatric complaints and their relation to delta-9-tetrahydrocannabinol and its metabolites in serum
2015, Drug and Alcohol DependenceCitation Excerpt :This prospective cohort study was conducted in 2006–2011 in an inpatient ward for detoxification from alcohol, medical drugs, and cannabis. Details on inclusion criteria, treatment of patients, and measurements of cannabinoid levels have been described elsewhere (Bonnet et al., 2014). In short, chronic cannabis dependents (ICD-10) with no acute psychiatric comorbidity underwent inpatient detoxification treatment with a scheduled duration of at least 16 days.
Synthetic cannabinoids: Epidemiology, patterns of use and clinical outcomes
2015, Toxicologie Analytique et CliniqueA narrative review of outcome measures used in drug and alcohol inpatient withdrawal treatment research
2023, Drug and Alcohol ReviewLong-Term Frequent Cannabis Use and Related Serum Cannabinoid Levels Are Not Associated with Kidney Dysfunction
2022, Cannabis and Cannabinoid Research