Elsevier

Drug and Alcohol Dependence

Volume 143, 1 October 2014, Pages 189-197
Drug and Alcohol Dependence

Full length article
Abstinence 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

https://doi.org/10.1016/j.drugalcdep.2014.07.027Get rights and content

Abstract

Objective

To investigate the course of cannabis withdrawal syndrome (CWS) within a controlled inpatient detoxification setting and to correlate severity of CWS with the serum-levels of delta-9-tetrahydrocannabinol (THC) and its main metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH).

Methods

Thirty-nine treatment-seeking chronic cannabis dependents (ICD-10) were studied on admission and on abstinent days 2, 4, 8 and 16, using a CWS-checklist (MWC) and the Clinical Global Impression-Severity scale (CGI-S). Simultaneously obtained serum was analysed to its concentration of THC, THC-OH and THC-COOH.

Results

MWC peaked on day 4 (10.4 ± 4.6 from 39 points) and declined to 2.9 ± 2.4 points on day 16. Women had a significantly stronger CWS than men. The CWS was dominated by craving > restlessness > nervousness > sleeplessness. CGI-S peaked with 5 out of 7 points. On admission, THC and its metabolites did negatively correlate with the severity of CWS. There was no significant correlation afterwards, no matter if CWS was medicated or not. THC-OH in serum declined most rapidly below detection limit, on median at day 4. At abstinence day 16, the THC-levels of 28.2% of the patients were still above 1 g/ml (range: 1.3 to 6.4 ng/ml).

Conclusions

CWS increased and then decreased without any correlation between its severity and the serum-levels of THC or its main metabolites after admission. According to the CGI-S, most patients achieved the condition of ‘markedly ill’. Serum THC-OH was most clearly associated with recent cannabis use. Residual THC was found in the serum of almost one-third of the patients at abstinence day 16.

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.

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