The cannabis withdrawal syndrome: current insights

Introduction

Cannabis is a psychotropic substance with widespread recreational use worldwide, surpassed only by nicotine and alcohol.¹ Its use continues to be high in West and Central Africa, Western and Central Europe, Australasia, and North America, where recently an increase in the prevalence of past year cannabis use was recorded in the USA (12.6%).¹ In Europe, prevalence rates of annual cannabis use rise in Nordic countries (7%–18%) and France (22%). They decline in Spain, UK, and Germany (currently 12%), and there is an increase in the number of treatment demands for cannabis-related problems across Europe² and the USA.³ Although such prevalence rates are useful to indicate consumption trends, it is doubted whether these rates are relevant to reflect a health risk. Approximately 1% of European adolescents and young adults use cannabis daily or almost daily (defined as use on ≥20 days in the last month),² a consumption pattern which is more likely to produce cannabis-related disabling disorders.^4,5 The prevalence of cannabis dependence (Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition – Text Revision [DSM-IV-TR]) is highest in Australasia (0.68%), followed by North America (0.60%), Western Europe (0.34%), Asia Central (0.28%), and southern Latin America (0.26%).⁴ In Germany, ~0.5% of the adult population have a cannabis dependence diagnosis.⁶ Most of the other regions of the world providing data report a prevalence of cannabis dependence of <0.2%.⁴ There is a significant positive correlation between the region’s economic situation and the prevalence of cannabis dependence.⁴ A hallmark of cannabis dependence (Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition [DSM-IV] or International Classification of Diseases [ICD]-10) as well as cannabis use disorder (CUD) (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition [DSM-5]) is the cannabis withdrawal syndrome (CWS) that characteristically occurs after quitting a regular cannabis use abruptly.

Although there was early evidence from animal experiments⁷ and despite observations in humans in every decade,^8,9 CWS entity was doubted before the 1990s, when a new cannabis wave started to roll in worldwide, particularly in affluent regions.⁴ This was related with a mounting number of patients seeking treatment due to various cannabis-related disorders, including cognitive deficits, psychosis, and dependence.^4,5 Considering these populations and also nontreatment-seeking cannabis-dependent individuals, larger retrospective clinical trials^10,11 demonstrated that discontinuation of regular cannabis use is frequently followed by waxing and waning behavioral, mood and physical symptoms such weakness, sweating, restlessness, dysphoria, sleeping problems, anxiety, and craving, which are subsequently positively associated with relapse to cannabis use.^11–19 However, other studies did not find this association.²⁰ CWS was further validated by epidemiological,^21,22 retrospective,^11,19,23 and prospective outpatient^{12,13,20,24–26} and inpatient laboratory studies^27–30 (Table 1). Based on this research, diagnostic criteria of CWS were newly included in DSM-5 (Table 2).³¹ In ICD-10, CWS is still vaguely defined³² and awaits due definition in ICD-11.³³ More recent clinical inpatient detoxification studies arranging controlled abstinence conditions confirmed the entity of CWS.^34–36 The CWS was also verified in youths and adolescents (aged 13–19 years), who sought treatment for their disabilitating cannabis dependence.^18,37–40

Table 1 Clinical and laboratory studies on human CWS in the past 20 years Abbreviations: NA, not applicable; CWS, cannabis withdrawal syndrome; ICD, International Classification of Diseases; CUD, cannabis use disorder; THC, delta-9-tetrahydrocannabinol; ADHD, attention-deficit hyperactivity disorder; DSM, Diagnostic and Statistical Manual of Mental Disorders; LSD, lysergic acid diethylamide.

Table 2 Marijuana Withdrawal Checklist (MWC) Notes: A total MWC score is obtained by summing the severity ratings, mild = 1, moderate = 2, severe = 3 points; *symptoms listed in DSM-5. There is no valid definition available for assigning a cannabis withdrawal syndrome to be mild, moderate, or severe. An MWC score of 10 points was found to be comparable with 5 points on the Clinical Global Impression – Severity scale (CGI-S), which is a 7-point scale. Four or more withdrawal symptoms were shown to predict the severity of cannabis-related problems at 1-year follow-up among treated adolescents (N=214, 92% retention). Data from previous studies.18,24,26,31,36,37,80 Abbreviation: DSM-5, Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition.

There is a consistent evidence that CWS occurs in ~90% of the patients being diagnosed with cannabis dependence according to ICD-10 or DSM-IV^{12,13,38,41,42} (Table 1). Among them, most often, male adolescents and young adults demonstrated a significant loss of quality of life during their cannabis dependence as measured by disability-adjusted life years in the Global Burden of Disease 2010 Study (cf Figures 2 and 3 in http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0076635, accessed November 25, 2016).⁴

Recent studies revealed that 35%–75% patients seeking outpatient cannabis detoxification developed a CWS post-cessation, which usually seemed to be mild to moderate in severity.^{11–13,15,16,19} However, most of the cannabis dependents developed a CWS of greater severity.³⁶ Adult cannabis dependents were shown to develop a severe CWS likelier than adolescent frequent users.^24,37 A prolonged and heavier cannabis use predicts a stronger CWS.^12,13,19 It was confirmed again more recently that the occurrence of CWS is a highly specific indicator of a cannabis dependence, particularly in adolescents and young adults.⁴²

This review intends to provide a synthesis of current evidence on the biology and clinical characteristics of the human CWS and its treatment. In addition, it includes information on the role of CWS in the course of CUD³¹ or cannabis dependence.^22,43

Materials and methods

This study is a review of the current literature on human CWS. The search for articles was performed on the PubMed⁴⁴ (Medline) and Scopus,⁴⁵ using the a combination of the search terms “cannabis withdrawal,” “humans,” “epidemiology,” “disability,” “clinical studies,” “clinical trials,” “case reports,” “cannabis use disorder,” “cannabis dependence,” “treatment,” “psychotherapy,” “psychosocial,” “exercise,” “occupational therapy,” “pharmacotherapy,” and “potency”. In addition, an active search for related literature was carried out in the reference lists of the selected publications. In total, 2,440 documents were screened, and mainly those studies providing information on human CWS and those published in English or German (N=101) were considered. Articles published up to November 25, 2016, were included.

Human biological background

The cannabis plant contains >420 chemical compounds of which 61 being cannabinoids themselves being defined to bind to cannabinoid 1 and 2 (CB1, CB2) receptors.⁴⁶ Regular cannabis use is associated with neuroanatomic abnormalities within brain regions with a high density of CB1 receptors, particularly the hippocampus and prefrontal cortex.^47,48 It is assumed that, the main psychoactive ingredient of cannabis, the partial CB1 receptor agonist delta-9-tetrahydrocannabinol (THC) is involved in the etiology of this damage,⁴⁷ which certainly awaits further study. For instance, a contribution of receptor-independent mechanisms of cannabinoids^49,50 as well as distress due to psychiatric CUD or CWS cannot as yet be excluded. A crucial role of THC in the genesis of CWS in humans is demonstrated by 1) pharmacokinetic studies showing a hysteresis effect between the decrease in plasma THC and onset of CWS,^51,52 2) an abstinence syndrome following oral THC^12,13 and THC analogs,⁵³ 3) alleviation of CWS by oral THC and THC analogs,^29,54,55 and 4) the occurrence of CWS-like symptoms after quitting recreational intake of synthetic cannabinoid (SC) receptor agonists, often being full CB1 receptor agonists, differing from THC being a partial agonist.^56,57 The withdrawal syndrome of SCs binding closer to CB1 receptors than THC seemed to be stronger than CWS and obviously showed characteristics unknown to CWS, such as seizures.⁵⁸ Otherwise, single cases of patients with diagnosed epilepsy who quit regular cannabis use are reported to exacerbate,⁵⁹ which is attributed to an anticonvulsive effect of cannabis.⁴⁶ The psychoactive potency of bred cannabis products sold for recreational use has been increasing in many markets over the past decade,^1,2 which could lead to a stronger withdrawal syndrome than usually known for cannabis. Intriguingly, there is one case report regarding improvement of CWS following the administration of cannabidiol,⁶⁰ another constituent of cannabis, shown to reverse some adverse effects of THC in the laboratory.⁶¹ The cardiovascular functioning seemed to be scarcely altered during CWS.⁶² Although the endocannabinoid system is involved in the regulation of most of the other peripheral organ systems, the immune system and the gut, too, we are unaware of any such study on the contribution of these organs to human CWS. Notably, applying a CB1 receptor antagonist (rimonabant) to cannabis-dependent patients substituted with THC analogs did not precipitate a relevant CWS.⁶³ This may be due to the low doses of rimonabant applied (20 and 40 mg) or the CWS-generating mechanisms that are at least partly independent upon CB1 receptors.^49,50 Cannabis users with opioid dependence are less likely to experience CWS,⁶⁴ which may indicate the contribution of the endogenous opioid system. In a laboratory study, the µ-opioid receptor antagonist naltrexone was recently shown to reduce self-administration of active cannabis and its related subjective positive effects on heavy cannabis users.⁶⁵ The authors are unaware of any study having directly examined the effect of naltrexone on the CWS under naturalistic conditions.

Abstinence-induced craving is associated with reduced amygdala volumes in frequent adolescent cannabis users, which was also found in adult alcohol and cocaine users.⁶⁶ Thus, the specificity of this finding for CWS is doubted and may represent a more general precursor of substance abuse itself;⁶⁶ that is, early stress in life.^67,68 With respect to the three “a”s of CWS (anger, aggression, and anxiety) (Table 1), the threat-related amygdala reactivity was shown to be inversely related to the level of cannabis use in adolescents with comorbid cannabis dependence and major depression.⁶⁹ This finding may reflect the neurobiological basis of these transient, mostly short-lasting CWS symptoms, thus possibly being even rebound “amygdala-related” symptoms after quitting regular cannabis use. Nevertheless, the CWS symptoms could persist even longer in genetically or epigenetically more susceptible individuals upon withdrawal.

Regular cannabis intake is related to a desensitization and downregulation of human cortical and subcortical CB1 receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning after ~4 weeks of abstinence,⁷⁰ which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for craving. In support, cannabis dependents were recently shown to have a robust negative correlation between CB1 receptor availability in almost all brain regions and their withdrawal symptoms after 2 days of cannabis abstinence which in turn resolved in the next 28 days of abstinence.⁷¹

If compared with nonusers, long-term cannabis users were demonstrated to have greater brain activity during cannabis cues relative to natural reward cues (ie, fruit itself being superior to neutral cues) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area.⁷² The users had positive correlations between neural response to cannabis cues in the fronto-striatal-temporal regions and subjective craving, cannabis-related problems, serum levels of THC metabolites, and the intensity of CWS. All of which were not found in non-cannabis users,⁷² suggesting a sensitization and specificity of the brain response to cannabis cues in long-term cannabis users.⁷²

In the San Francisco Family Study, some symptoms of CWS, craving and cannabis-related paranoia were found to be heritable,⁷³ which could have been confounded by the heritability of age at first-ever use, for instance. It was suggested that genetic factors determine whether an individual may try or use cannabis; however, environmental factors are more crucial in determining whether a person develops dependence or not.⁷³ Recent findings provide evidence that the use of nicotine, alcohol, or cannabis shares genetic and environmental pathways on the way to develop a substance use disorder.⁷⁴ Regular intake of alcohol, nicotine, cannabis, or other drugs of abuse alters the stress response sustainably⁷⁵ and, thereby, may precipitate a substance use disorder.

Characteristics of CWS

Considering the cannabis research of the last 20 years,^{12,13,16,18–20},³¹ there was no doubt that cessation of heavy or prolonged cannabis use is most likely followed by typical symptoms, such as

1. irritability

2. nervousness/anxiety

3. sleep difficulty

4. decreased appetite or weight loss

5. depressed mood

6. one of the following physical symptoms such as abdominal pain, shakiness/tremors, sweating, fever, chills, or headache.

According to DSM-5,³¹ CWS (292.0) is diagnosed if three or more of these symptoms (1–6) develop within ~1 week after quitting cannabis use abruptly.³¹ Withdrawal severity and duration can vary widely between individuals and fluctuate depending on the amount of prior cannabis use, context of cessation (eg, outpatient vs inpatient, voluntary vs involuntary), personality traits, psychiatric and somatic comorbidity, current life stressors, previous experiences, expectations, support, and severity of dependence.^12,13 Women seeking treatment for CUD were shown to generate more frequent and more severe withdrawal symptoms than men after quitting their frequent cannabis use.^36,76,77 However, older studies did not reveal this gender effect (Table 1).

Additional heavy tobacco use was reported to be associated with stronger irritability during the CWS of adolescents.⁴⁰ Black adolescents were shown to have lower withdrawal complaints and experience less severe depressed mood, sleep difficulty, and nervousness/anxiety than non-Black adolescents.⁴⁰ In youths with conduct disorder, this disorder antedated cannabis use.³⁸

Currently, psychometrically validated cannabis withdrawal scales are unavailable. Several versions to measure CWS^{11–13,16,18,24,78} were developed, some of which compared with each user by Gorelick et al.¹⁹ All these versions were based on the Marijuana Withdrawal Checklist (MWC) of Budney et al.²⁴ The MWC was originally designed with 22 items that assessed mood, behavioral, and physical symptoms and was revised to a 15-item version comprising these items that had been most frequently endorsed during cannabis withdrawal^12,13,26,37 (Table 2). Later, this version builds the construct of the DSM-5 definition of CWS³¹ (Table 2), which, however, does not consider cannabis craving and nausea.³¹

Regarding the course of the overall CWS, there were two different types described in the available literature (Figure 1 and Table 1). One peaked between the second and sixth abstinence day (type A)^{11,15,16,19,20,23,26,27,35,36,56,79} and the other decreased continuously following cannabis cessation (type B).^28,34,39 It is assumed that type-A CWS includes more intoxication symptoms which vanished during the first few days post-cessation, thereby unmasking the “pure” CWS.³⁶ A negative correlation with serum levels of THC at admission, which would support this assumption, was found in type A.^35,36 Type-B CWS was not investigated to this subject. Alternative explanations are that the contribution of single items (cf Figures 2 and 3) differed between types A and B or more patients without a measurable CWS were included in the group of patients producing a type-B course.

Figure 1 Courses of overall CWS post-cessation. The CWS usually lasts up to 3 weeks and its average peak severity (burden) is comparable to that of a moderate depression or alcohol withdrawal syndrome or in outpatient settings, similar to that of a tobacco withdrawal syndrome. Data from previous studies.14,36,79 Abbreviation: CWS, cannabis withdrawal syndrome.

Figure 2 Mean and standard deviation of the (A) CWS checklist (MWC score according to previous studies24,26,37) and (B) the Clinical Global Impression Scale (CGI-S Score80) during the course of the study. Reduced sample sizes on day 12 (n=35) and day 16 (n=28) due to regular dismissals and missed assessments are indicated by dashed lines. The effect size according to Cohen (Cohen’s d) was 1.1 for the CWS (day 1 to day 16), Cohen’s d ≥0.8 is defined to reflect a strong effect.130 Vertical imaginary Y-axis: severity scores. Horizontal imaginary X-axis: time course. Note: Reproduced from Drug Alcohol Depend, 143, Bonnet U, Specka M, Stratmann U, Ochwadt R, Scherbaum N, 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, 189–197. Copyright (2014), with permission from Elsevier.36 Abbreviations: CWS, cannabis withdrawal syndrome; MWC, Marijuana Withdrawal Checklist.

Figure 3 Mean rating of single symptoms of the MWC (MWC score according to previous studies24,26,37); 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = heavy). Note the delayed occurrence of strange dreams.25 Vertical imaginary Y-axis: severity scores. Horizontal imaginary X-axis: time course. Note: Reproduced from Drug Alcohol Depend, 143, Bonnet U, Specka M, Stratmann U, Ochwadt R, Scherbaum N, 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, 189–197. Copyright (2014), with permission from Elsevier.36

In the following, the course of a CWS (Figures 2 and 3) is presented, which was recorded during a controlled inpatient detoxification treatment of a sample consisting of long-term cannabis users (N=39, 38 Caucasians, 8 females, median age: 27 years, median daily cannabis use: 2.5 g, median duration of daily cannabis use: 36 months).³⁶ Their cannabis consumption was in the upper range if compared with other clinical studies on CWS.^{11,12,16,20,34} All patients of this sample developed a considerable CWS.³⁶ Although this study was conducted in a large detoxification ward of a university hospital residing in a metropolitan area (Ruhr Area, Germany), it lasted 5 years (2006–2011) to find 39 appropriate patients seeking treatment due to a current sole cannabis dependence without a competing additional substance use (except for tobacco) or active comorbidity to measure a CWS as pure as possible.³⁶ This study aimed to apply both MWC²⁴ and the Clinical Global Impression Scale (CGI-S)⁸⁰ to this sample to make the severity of CWS comparable to the severity of other psychiatric disorders.³⁶ The course of the single items is shown in Figure 3. Cronbach’s α coefficients were 0.67, 0.78, and 0.73 on days 4, 8, and 12, respectively.³⁶ The MWC applied to this sample achieved α coefficients comparable to that of the CWS criteria proposed for DSM-5 (0.75)¹⁹ and to that of the original MWC of Budney et al (0.77).^12,24

CWS severity in comparison with other psychiatric conditions

As outlined earlier, the severity of CWS is positively related to the cumulative amount and potency of cannabis used before cessation,^12,13,19 gender,^36,76,77 and several environmental^12,13,73 as well as heritable⁷³ factors. Therefore, its naturalistic severity varies a lot. There are some evidences that the discomfort due to CWS is similar to that found during tobacco withdrawal^14,79 or a moderate alcohol withdrawal syndrome.³⁶ Inpatients detoxifying from heavy cannabis use were rated to be “moderately ill” at the peak of CWS according to CGI-S.³⁶ For a first orientation, inpatients suffering from acute schizophrenic episodes and patients with acute depressive episodes in outpatient settings have been rated in the majority to be “severely ill” and “moderately ill,” respectively.³⁶ Strong CWS can mimic eating disorders associated with gastrointestinal symptoms, food avoidance, and weight loss of adolescents.⁸¹

The role of nausea in CWS

There is one case report of severe nausea being associated with CWS.⁸² In the last years, increasing cases with a cannabis-hyperemesis syndrome were noticed, which characteristically occurred in frequent and long-term cannabis users and vanished in their next 5–20 abstinent days.^83-–85 In order to differentiate this condition from CWS, we studied the course of the item “nausea” in the “cannabis burdened” sample mentioned earlier and found no correlation (r=–0.14 to 0.19) with the other items of MWC, whose internal consistency did not change, if “nausea” was excluded from the scale.³⁶ Thus, we found no evidence of nausea being a characteristic element in the orchestra of the CWS, which confirms the previous results of others.^11,12,19

Nevertheless, nausea seems to be a less common cannabis withdrawal symptom than chills, shaking, sweating, depressed mood, and stomach pain.¹³ This is supported by the observation that nausea can occur more pronounced in the female CWS than in the male CWS.^76,77

A retrospective chart review found preliminary evidence that “nausea and vomiting” might emerge more frequently in the withdrawal syndrome of SC agonists (Table 1)⁵⁶ often being full agonists at the CB1 receptor, other than the partial agonist THC.⁵⁷ Is this a clue that nausea breaks through when very potent agonists are removed from CB1 receptors? On the other hand, “severe nausea and vomiting” were key symptoms of the intoxication syndrome following the intravenous application of crude marijuana extracts⁸⁶ and are typical signs for the overdosing of smoking or swallowing cannabis preparations,^46,86 including the first-ever intake experience. However, low to moderate amounts of cannabis preparations or THC analogs have well-known antiemetic properties.⁴⁶

Treatment of CWS

Cannabis detoxification treatment is usually performed in outpatient settings. However, in the case of a moderate or severe dependence syndrome, low psychosocial functioning or moderate or severe psychiatric comorbidity, an inpatient treatment is required. In Germany, inpatient cannabis detoxification is ideally performed in specialized wards following a “qualified detoxification” protocol. This includes supportive psychosocial interventions, psychoeducation, non-pharmacological symptom management, occupational and exercise therapy, professional care, as well as medical and psychiatric diagnostics and therapy of comorbid conditions. The treatment duration is related to the severity of the comorbidity or the CUD. An inpatient detoxification treatment on grounds of the diagnosis of “cannabis dependence” alone is mostly not accepted by the German health care providers, and they prima vista doubted the existence of a treatment-relevant CWS. This point of view may have a historical background, because many physicians consider cannabis to be a “soft drug,” as probably 20 years ago it contained lower THC contents.^87–90 This view may change with a clear definition of CWS in current diagnostic classification systems, such as DSM-5.³¹ As a rule of thumb, an “acute” inpatient detoxification treatment lasts between a few days and up to 3 weeks. In case of a too high psychiatric comorbidity and too low psychosocial functioning for an outpatient treatment, the patients could be transferred into specialized inpatient rehabilitation wards. Because this post-acute treatment approach is paid by the German Person Fund (DRV), a substantial formal request is required. The rehabilitation treatment normally lasts for several weeks and is a special feature of the German health care system. In Germany, most of the cannabis patients entering outpatient (28,000 individuals in 2014) and inpatient (3,367 individuals in 2014) rehab programs show additional problems with the co-use of alcohol (7%–14%), opioids (30%–55%), cocaine (45%–60%), stimulants (45%–70%), and pathological gambling (6%–18%).⁹¹ This pattern of comorbidity is common in other high-income countries.¹

The effects of behavioral approaches on the mitigation of CWS were not intentionally studied , even though a beneficial action of aerobic exercise therapy can be assumed.⁹²

Currently, there are no approved medications for the treatment of CUD. Nevertheless, various pharmaceuticals have been studied in small (N<80) controlled, mostly outpatient or laboratory pilot trials: lithium, antidepressants (bupropion, nefazodone, venlafaxine, fluoxetine, escitalopram, and mirtazapine), anticonvulsants (divalproex and gabapentin), norepinephrine reuptake inhibitor (atomoxetine), glutamate modulator and mucolytic agent (N-acetylcysteine), muscle relaxants (baclofen), anxiolytic (buspirone), antipsychotics (quetiapine), and CB receptor agonists (dronabinol and nabiximols).^55,93 The antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect on the CWS or had worsened it.^55,93 For instance, venlafaxine was shown to aggravate CWS and, thus, was accused to uphold cannabis smoking.⁹⁴ Quetiapine (200 mg/day) improved appetite and sleep quality during the CWS but worsened marijuana craving and drove self-administration of marijuana.⁹⁵ A more recent open pilot study reported a decrease of cannabis use within 8 weeks of quetiapine treatment (25–600 mg).⁹⁶

Putatively beneficial agents

There is evidence for an improvement of CWS with gabapentin (1200 mg/day).⁹⁷ The efficacy of the THC analogs dronabinol and nabiximols (plus cannabidiol) in reducing CWS is demonstrated in three small but well-controlled outpatient studies.^98–101 An improvement of the dependence syndrome or craving was not found.^98–101 Although innovative compounds, high costs of dronabinol or nabiximols may limit not only the use but also the abuse of these drugs. A significant effect of the THC substitution on the severity of cannabis dependence, craving, or cannabis-related problems was not found yet.^98–101 Nabiximols is a drug containing two of the main active cannabinoids, namely, THC and cannabidiol, and has been approved in some countries for the treatment of spasticity of multiple sclerosis (MS).^99–101 It is an oral spray formulation, and each puff of 100 μL contains 2.7 mg of THC and 2.5 mg of cannabidiol. A treatment with six puffs over the day revealed >10 times smaller blood THC concentrations than the blood concentrations known to produce psychotropic effects.¹⁰² For the nabiximols regimes in the treatment of CWS, cannabis users had been instructed to take eight sprays qid^99,100 or a maximum of four sprays every hour (up to 40 sprays/day).¹⁰¹ Oral dronabinol had been administered in 20 mg doses three times a day.⁹⁸ The effectiveness of N-acetylcysteine (1200 mg/day) on CWS was not assessed directly, but this agent was shown to reduce relapse markers in the urine alongside a large (N=116) well-controlled study.¹⁰³ A recent laboratory study demonstrated the efficacy of the THC analog nabilon.¹⁰⁴

Because sleep difficulty is the withdrawal symptom that is assumed to be most associated with relapse to cannabis use,¹⁰⁵ a few sleeping medications were tested in the CWS treatment with first promising results for mirtazapine³⁰ and zolpidem^106,107 during the first days of abstinence, necessarily taking care for zolpidem’s potential misuse. Nevertheless, both the drugs had no effects on CWS in general or relapse prevention.^30,107

The withdrawal syndrome of SC receptor agonists⁵⁶ awaits further characterization and may respond to benzodiazepines and quetiapine.¹⁰⁸

Impact on CUD or dependence

The CWS is part of a CUD (DSM-5)³¹ and dependence-syndrome (ID-10, DSM-IV-R)^32,43 being characterized by frequent, heavy, or prolonged cannabis use. The importance of the treatment of CWS on the maintenance of cannabis use or substance use trajectories over time is unclear and awaits further study. From previous literature, there is small evidence for both 1) CWS treatment initiated abstinence or dose reduction^12,13 and 2) CWS treatment does not influence cannabis use in the following.^18,20,42,109 Frequent cannabis users had reported that withdrawal symptoms negatively influence their desire and ability to quit.^12,13,18,105 Two actual studies on adolescents and young adults found no association of CWS with abstinence rates being monitored up to 3 months²⁰ and 1 year posttreatment,¹⁰⁹ which confirmed the previous finding of Arendt et al.²⁰ Furthermore, patients with CWS relapsed sooner than those without CWS.²⁰ Patients recognizing a problem with CWS were associated with better abstinence rates than patients not recognizing a problem with CWS⁴² pointing to a potential value of psychoeducation, an approach to be further studied in the management of CUD.

Abstaining from cannabis was reported to be followed by an increase of alcohol and tobacco use, which decreased again after continuation of cannabis use.¹¹⁰ CWS in people with schizophrenia is associated with behavioral change, including relapse with cannabis and increased tobacco use.¹¹¹ “Religious support” and “prayer” were self-identified by cannabis users to be the most helpful quitting strategies and both were associated with higher 1-month and 1-year abstinence rates in these population.¹¹¹ Furthermore, the symptom severity of patients with posttraumatic stress disorder was positively associated with the use of cannabis (probably taken as a “self-medication”), cannabis use problems, and severity of CWS.¹¹²

Studies that compared the effectiveness of outpatient versus inpatient treatments with respect to the severity and prognosis of CUD, especially their differential efficacy on long-term relapse prevention, dose reduction, or psychosocial functioning, are missing. At the end of a 16-day lasting inpatient detoxification treatment (qualified detox) of heavy cannabis users, the following effect sizes were found (Cohen’s d): 1.1 (CWS), 1.4 (cognition), psychiatric symptoms (0.8–0.9).¹¹³ The bothersome global distress of this sample had improved significantly during the qualified detox (Figure 4).

Figure 4 Significant improvement (p<0.001) of the subjective global distress of adult heavy cannabis users during inpatient qualified detoxification as measured by the Symptom Checklist 90, revised version (SCL-90-R).129 Y-axis: percent of the sample (N=35); X-axis: global distress according to T-values: T<60: normal global distress; T>70: severe global distress;129 T1 = admission day and T16 = last day (day 16) of the controlled inpatient qualified detoxification treatment.113 Note: Reproduced from Dtsch Med Wochenschr, 141(2), Bonnet U, Specka M, Scherbaum N, Häufiger Konsum von nichtmedizinischem Cannabis, 126–131. Copyright (2016), with permission from Georg Thieme Verlag.113

At present, the effectiveness of different cannabis detoxification treatments on the course of the CUD has not been studied in depth. Outpatient treatment programs improved the psychosocial functioning and dropped the cannabis use for a while.^12,13 Currently, only a few long-term follow-ups are available, so far showing no sustaining improvement of CUD subsequent to outpatient detoxification attempts.^18,20,42,109

Discussion

With the definition of the DSM-5 criteria,³¹ the CWS comes of age. Genetic influences on cannabis withdrawal were described to be the same as those affecting cannabis abuse and dependence.¹¹⁴ Beyond that, the existence of the CWS has solid neurobiological underpinnings since it was found that the availability of brain CB1 receptor in cannabis dependents was inversely associated with the occurrence of CWS .^70,71 After 4 weeks of abstinence, the anomalies of CB1 receptors binding had been normalized in cannabis dependents, thus giving a rough time frame of the duration of CWS,^70,71 which apt to the clinical observations that have been obtained in the past 20 years (Table 1). Two different courses of CWS might result from the different contribution of cannabis residual symptoms assumed to be initially more prominent in the type A than in type B CWS.³⁶ Looking at a key symptom of cannabis use, such as “increase in appetite,”^5,7 this was indeed reported more often in the first days of the type A CWS (Table 1).^19,20,35

Mood and behavioral symptoms, namely, insomnia, dysphoria, and anxiety, are the key symptoms of the CWS (Tables 1 and 2). Similar symptoms occurred in the obesity treatment with the CB-1 receptor antagonist rimonabant (also known as SR14171) and were the reason why rimonabant was withdrawn from the market in 2008.¹¹⁵ Possibly, a “sustained CWS” had been precipitated when the effects of the physiological tone of endogenous endocannabinoids on brain and peripheral CB1 receptors were impeded by receptor antagonists, even in non-addicted but susceptible individuals. In support, the neurocircuitries involved in the regulation of stress, anxiety, and mood (such as the serotonergic, noradrenergic, and dopaminergic systems) were demonstrated to be sensitive to CB-1 receptor antagonists.¹¹⁵

Influence of alcohol and tobacco

Regular alcohol drinking might influence the clinical expression of the CWS, and this is not through the overlapping alcohol withdrawal symptoms. Continuous exposure to ethanol, in either cell culture or rodent models, led to an increase in endocannabinoid levels that resulted in downregulation of the CB1 receptor and uncoupling of this receptor from downstream G protein signaling pathways.¹¹⁶ A similar downregulation of CB1 receptors was found in multiple brain regions of chronic drinkers.¹¹⁶ Alcoholic drinks were reported to be co-used by 33%–46% of regular cannabis users. The rates of co-use for cocaine, stimulants, and hallucinogens were 37%–43%, 30%–52%, and 36%–42%, respectively^1,2,116 – all putatively being able to influence the course and intensity of the CWS. Approximately 90% of cannabis users are also tobacco smokers, possibly reflecting the common route of administration, and even synergistic and compensatory actions of cannabis and tobacco as well as genetic and epigenetic factors assumed to mediate addiction vulnerability.^117,118 More specifically, smoking tobacco use was shown to increase the number of cannabis dependence symptoms¹¹⁹ and precipitated cannabis relapse.¹²⁰ Vice versa, cannabis use decreased the likelihood of abstaining from tobacco.^117,118 There is a preliminary evidence that simultaneous tobacco and cannabis abstinence predicts better psychosocial treatment outcomes.^117,118 There is still a paucity of clinical studies on this important subject, although alcohol, tobacco, and cannabis were consistently identified to be the substances with earliest onset of use, the highest prevalence of lifetime use, and the highest prevalence of lifetime disorder.^1–6,74

Choice of treatment setting

In comparison with outpatient programs, inpatient detoxifications can provide strict abstinence conditions and, thus, can be used to better differentiate CWS from comorbidity, but are much more expensive and usually not the first choice of patients seeking treatment due to CUD. However, 1) the inability to initiate cannabis abstinence due to bothersome CWS, 2) the continuous co-use of other harmful drugs of dependence, or 3) the coexistence of other disabling psychiatric or somatic complaints give reasons for the medical necessity of an inpatient detoxification program, the duration of which depends on the intensity of the withdrawal symptoms and concomitant complaints.^5,113 At this juncture, the duration of an inpatient detoxification program of heavy cannabis users is recommended to be not less than 14 days, ideally 21 days, taken into account that their pure CWS itself usually lasted up to 14–21 days (Table 1),^12,13,36,113 and the diagnosing of potentially underlying comorbidity is more sensitive from then on. It remains a challenge of future in-depth studies to compare the impact of outpatient and inpatient treatment programs on the long-term course and disability of substance use disorders, which applies to CUD, too.

Influence of high potency cannabis preparations, gender, and so on

Similar to the cannabis addiction syndrome itself,¹²¹ one of its hallmark, the CWS, is based upon complex interactions between drug-induced neurobiological changes, environmental factors, genetic and epigenetic factors, comorbidity, personality traits, gender influences, and stress responsivity, all of which contributing to the high inter- and intrapersonal variations in the composition, annoyance, and duration of the CWS (Table 1).^{12,13,114,121}

In addition to an increasing awareness of the existence of the CWS, its increasing emergence in the last 20 years might result from the increasing psychotropic potency of the used marijuana originating from the breeding of strains with high THC (10%–18.5%) and low cannabidiol concentrations (<0.15%) being found especially in high-income countries.^{1,88–90,122} In the Netherlands, the recent cannabidiol content of imported resin was ~7%.⁹⁰ According to animal experiments, cannabidiol can counterbalance some adverse effects of cannabis,⁶¹ and in patient populations, there is mounting evidence of anticonvulsive and antipsychotic properties of cannabidiol.¹²³ Since the early 1950s, it is known that the chemical composition of the resin itself varies with cannabidiol activities between 0% and 50% depending on the provenance of the drug.⁸⁷ Whether the users of more potent cannabis strains adjust their intake according to the potency is still unclear.⁸⁸ However, there is first evidence that the occurrence of first-episode psychosis as well as the intensity of the CUD increased alongside the use of high potency cannabis preparations.^124,125 This throws an extremely critical light on emerging modern cannabis ingestion methods (“dabbing” or “cannavaping” of cannabis concentrates with 20%–80% THC) used by individuals seeking a more rapid and even bigger than being possible with smoking flowers that THC contents are usually in the range of 2% and 6%.^126,127 Marijuana users who had turned to “dabbing” reported higher tolerance and withdrawal experiences.¹²⁶

The CWS could have an measurement bias regarding a recent finding that it was endorsed more likely by the US than by Dutch cannabis users, which applies to other CUD criteria, such as tolerance, and gender effects on CWS, too.⁷⁷ In this context, recent studies revealed a consistent gender impact on CWS, because women experienced a stronger CWS (Table 1)^36,76 and were shown to have a greater susceptibility to developing CUD than men.^121,128 Women were also found to be more sensitive to the cannabis than men.^121,128 Remarkably, women reported physical CWS complaints more likely, such as nausea and stomach pain (Table 1).^19,76

CWS in the ICD-11 Beta Draft

In 2018, the 11th revision of the ICD-11 is planned to be published. The so-called Beta-Draft of the chapter about “Mental and Behavioral Disorders” is already available online at http://apps.who.int/classifications/icd11/browse/f/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f637576511 (accessed November 25, 2016).³³ The current version of this ICD-11 Beta Draft³³ lists the usual mood and behavioral CWS symptoms according to DSM-5"> (accessed November 25, 2016).³³ The current version of this ICD-11 Beta Draft³³ lists the usual mood and behavioral CWS symptoms according to DSM-5xs³¹ but does not consider physical CWS symptoms.³³ We recommend to include at least “nausea” and “stomach pain” into the final version because these symptoms were recently found to be more prominent in the female CWS,^{76,77,121,128} and yet, it seems likely that the increasing use of high potency cannabis preparations are associated with more physical CWS symptoms. It is also recommended to include a note on the high intra- and interpersonal variability of the CWS intensity and the observation that – if a CWS occurs – it is extra distressing between the first and the third week after quitting a frequent, heavy, or prolonged cannabis use (Table 1).^12,13,36 Heavy users were shown to experience a CWS whose average severity is comparable to the burden of a moderate depression or moderate alcohol withdrawal syndrome.³⁶ In outpatient settings, the average discomfort of CWS was similar to that of tobacco withdrawal.^14,79

Certainly, it awaits future study whether the inhalation of very potent cannabis concentrates^126,127 is indeed associated with a further decrease of psychosocial functioning, higher comorbidity, and a stronger CUD and CWS – eventually with more physical features (eg, hyperalgesia, nausea, sweating, tremor, flu-like symptoms)³¹ than occurring after the cessation of a heavy or prolonged use of traditional non-concentrated cannabis preparations.

Conclusion

The CWS is a criterion of CUDs (DSM-5) and cannabis dependence (DSM-IV-R, ICD-10). Several lines of evidence from human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. However, comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably a qualified detox) and post-acute rehabilitation or long-term outpatient care. There are promising results with gabapentin and THC analogs in the treatment of CWS. Mirtazapine could improve insomnia, and venlafaxine was found to worsen the CWS. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to psychopharmacological or behavioral approaches, such as aerobic exercise therapy or psychoeducation, in the CWS treatment. The preliminary up-to-date content for the ICD-11³³ (intended to be finally published in 2018) is recommended to be expanded by physical CWS-symptoms, the specification of CWS severity and duration as well as gender effects.

Disclosure

The authors report no conflicts of interest in this work.

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