The cannabis withdrawal syndrome: current insights

Figures & data

Table 1 Clinical and laboratory studies on human CWS in the past 20 years

Authors	Study design	Sample	CWS-measurement and characteristics	CWS type	Subjects reporting CWS (%)	Gender effects	Comorbidity	Other clues
Wiesbeck et al (USA)^Citation10	Epidemiologic cross-sectional study comparing patients reporting a CWS with those not reporting a CWS Data were generated through the Collaborative Study on the Genetics of Alcoholism (COGA)	N=1,735 frequent cannabis users (using cannabis >21 times in a year) Female <60% Adults >70% Caucasian, >15% African–American	Face-to-face interview, CWS symptoms (as reviewed by the authors from literature) were retrospectively screened in the COGA population Typical symptoms: nervousness, tense, restlessness, sleep disturbance, appetite change Controlled abstinence period: NA	NA	16.5% (all having used the drug almost daily for an average of almost 70 months)	NA	In the CWS group, significantly more psychiatric disorders: alcohol dependence (16.7%), other substance use disorder (28.5%), antisocial personality disorder (36.3%). No psychiatric diagnosis (4%)	Subjects reporting CWS were more likely to have been treated for alcohol or other substance dependence, but were not more likely to have close relatives with substance use disorders or antisocial personality disorder
Crowley et al (USA)^Citation38	Cross-sectional study, 13- to 19- year olds referred for substance and conduct problems (usually from social service or criminal justice agencies)	N=180 subjects with cannabis dependence (DSM-III-R) Female 23.1% Youths Caucasian > Hispanic > African–American	Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM) Typical symptoms: tiredness (61.1% males/42.3% females), anxiety, restlessness, irritability (44.2%/38.5%); trouble concentrating (41.1%/46.2%), yawning (45.3%/26.9%), decreased appetite (37.9%/50.0%), depressed mood (40.0%/34.6%), disturbed sleep (30.5%/34.6%), hallucinations (16.8%/19.2%), tremble, twitch (12.6%/23.1%), running eyes, nose (12.6%/15.4%), sweating, fever (11.6%/11.5%) Controlled abstinence period: NA	NA	Over two-thirds had withdrawal symptoms	No	Substance dependence (100%), current conduct disorder (82.1%), major depression (17.5%), ADHD (14.8%)	Onset patterns suggest that cannabis was as reinforcing as tobacco or alcohol for the sample, conduct symptoms antedated cannabis use More than one-quarter of the patients reported using cannabis to relief withdrawal symptoms
Budney et al (USA)^Citation24	Cross-sectional study of cannabis dependents (DSM-III-R) seeking outpatient treatment	N=54, 82% daily cannabis users seeking treatment Female 15% Adults All Caucasian	22-item Marijuana Withdrawal Checklist (0–28 points), mean score was 14.4±7.8 Symptom Checklist–90 revised (SCL–90R) Typical symptoms: craving cannabis, irritability, nervousness, depressed mood, sleep difficulties, strange dreams, decreased appetite, headache Controlled abstinence period: NA	NA	57% experienced ≥6 symptoms of at least moderate severity and 47% experienced ≥4 symptoms rated as severe	No	Withdrawal severity was greater in those with psychiatric symptomatology and other drug use in the past	Withdrawal severity was greater in those with more frequent marijuana use Most had problems with alcohol or cocaine use or psychiatric symptoms in the past
Haney et al (USA)^Citation28	Prospective study in a residential laboratory with frequent cannabis users	N=12 nontreatment-seeking people smoking cannabis 5.8±0.4 days/week All males Adults 7 African–American, 3 Caucasian, 2 Hispanic	50-item visual analog scale Typical symptoms: anxiousness, irritable, stomach pain, decreased appetite Controlled abstinence period: 4 days	Type B	All	–	Most participants reported drinking alcohol (2 days/week, 2 drinks per occasion) One person reported occasional cocaine use
Kouri and Pope (USA)^Citation27	Prospective outpatient laboratory study	N=30 (current chronic users, all cannabis dependent according to DSM-IV, nontreatment-seeking, 4 women) vs N=16 (former users, 6 women) vs N=14 (non-users, 1 woman) >85% Caucasian Adults	14-item diary Typical symptoms: ability to concentrate, irritability, anxiety, depressed mood, physical tension, decreased appetite, physical symptoms Controlled abstinence period: 28 days. The duration of CWS: symptoms were most pronounced in the first 10 abstinent days, but some symptoms (irritability, physical tension) exist for the entire 28-day study period	Type A	All	NA	No current comorbidity according to DSM-IV Axis I disorder	Comparison with control groups, relatively long study period (28 days)
Swift et al (Australia)^Citation41	Representative epidemiologic study of Australian adults completing a structured diagnostic interview assessing the prevalence of mental and substance use disorders in the last year, National Survey of Mental Health and Wellbeing (NSMHWB)	N=10,641. The 12-month prevalence of DSM-IV (1.5%) and ICD-10 (1.7%) cannabis dependence was similar Abuse (N=572) vs dependence (N=150) Adults	Composite International Diagnostic Interview (CIDI) Controlled abstinence period: NA	NA	~90% of the cannabis dependents reported withdrawal symptoms	NA	NA	12-month prevalence of DSM-IV dependence symptoms of cannabis dependents (N=150): tolerance (72.6±4.8%), withdrawal/withdrawal relief (88.8±3.2%), cannabis used in larger amounts or for longer than intended (62.8±4.5%), persistent desire or unsuccessful efforts to control use (86.9±3.0%), great deal of time spent in obtaining, using and recovering (42.5±6.3%), important activities given up or reduced (9.9±6.1%), continued use despite knowledge of physical or psychological problem (37.0±7.1%)
Budney et al (USA)^Citation25	Prospective outpatient study	N=12 daily heavy cannabis smokers, 92% met the DSM-IV criteria for cannabis dependence or abuse Female 41.7% Adults 83.3% Caucasian	15-item Marijuana Withdrawal Checklist, 10-item Marijuana Craving Questionnaire Typical symptoms: cannabis craving, decreased appetite, weight loss, aggression, anger, irritability, restlessness, strange dreams Controlled abstinence period: 3 days	NA	NA	NA	No current comorbidity other than nicotine dependence	The symptoms were estimated to be similar in type and magnitude to those observed in studies of nicotine dependence
Budney et al (USA)^Citation26	Prospective outpatient study	N=18 frequent, heavy cannabis users seeking treatment (39% female) vs N=12 ex-cannabis users Female 25% Adults 94% Caucasian	15-item Marijuana Withdrawal Checklist, 10-item Marijuana Craving Questionnaire Typical symptoms: irritability, sleep difficulty, strange dreams, decreased appetite, restlessness, nervousness/anxiety, aggression, anger, sweating, chills, shakiness, stomach pain, cannabis craving, depressed mood Controlled abstinence period: 45 days	Type A	All	NA	No current comorbidity other than nicotine dependence, 10.9±8.6 days of alcohol use in the past 30 days, 39% tobacco smoker	Significant withdrawal discomfort ~4 weeks of abstinence
Vandrey et al (USA)^Citation37	Cross-sectional outpatient study	N=72 treatment seeking cannabis users, 10% female, 57% DSM-IV cannabis dependence Female 90% Adolescents 89% Caucasian	15-item Marijuana Withdrawal Checklist, Youth Self-Report (YSR) Typical symptoms: craving cannabis, depressed mood, irritability, sleep difficulty, increased anger, decreased appetite, increased aggression, nervousness/anxiety, headache Controlled abstinence period: 4 weeks	NA	78% reported two or more symptoms	NA	No current comorbidity other than nicotine dependence. Psychiatric symptoms: YSR – externalizing scale: 59.8±10.4, percent in clinical range (39%), YSR – internalizing scale. 51.5±12.4, percent in clinical range (16%)	Craving, depressed mood, irritability, and sleep difficulty were rated as being moderate or greater severity by at least one-third of the sample, the prevalence and magnitude of withdrawal symptoms were lower than that observed in the similar study with adult treatment seekers^Citation24
Arendt et al (Denmark)^Citation20	Prospective cohort study plus follow-up 26±4 months after baseline assessment	N=36 cannabis dependents (ICD-10) seeking treatment, at baseline, 29 and 7 subjects received outpatient and inpatient treatment, respectively Female 19.4% Young adults All Caucasian (putatively)	22-item Marijuana Withdrawal Checklist according to Budney et al 1999^Citation24 Clinical Assessment in Neuropsychiatry, computerized version (SCAN) Typical symptoms: significantly elevated after abstinence compared with follow-up: irritability, anger, depression, restlessness, craving, sleep problems, strange dreams, increased appetite, violent outbursts, sweating, hot flashes, chills, and shakiness Controlled abstinence period: median length of time from abstinence to the baseline interview was 6.5±11.3 weeks	Type A	More than half of the subjects reported symptoms in the moderate to severe range	No	No current comorbidity other than nicotine dependence, lifetime use of other substances was common (mostly amphetamine (91.7%)	Between baseline and follow-up, 24 subjects (67%) had used cannabis at some point. The following substances had also been used: benzodiazepines (5.6%), amphetamines (13.9%), cocaine (27.8%), ecstasy (2.8%), LSD (2.8%), and alcohol (abuse; 13.9%). Average withdrawal scores at baseline did not differ with gender, age, treatment type, extent of cannabis use, or a lifetime history of anxiety or affective disorders. Withdrawal scores at baseline did not predict relapse during follow-up
Cornelius et al (USA)^Citation17	Cross-sectional outpatient study	N=104 cannabis dependents (DSM-IV) recruited for the treatment of CUD and depression Female 49.0% Youths and adolescents 65.4% Caucasian, 27.9% African–American	22-item Marijuana Withdrawal Checklist according to Budney et al 1999^Citation24 Structured Clinical Interview for DSM-IV (SCID), modified for use with youths and adolescents Typical symptoms: craving cannabis, depressed mood, irritability, restlessness, anxiety, somatic symptoms were reported only rarely Controlled abstinence period: 4 weeks	NA	91% reported two or more symptoms	NA	80% current major depressive disorder (DSM-IV)	CWS was related with rapid relapse of cannabis use
Milin et al (Canada)^Citation39	Prospective outpatient study	N=21 cannabis dependents (DSM-IV) voluntarily entering a community youth addiction residential (N=13) or day/outpatient treatment program, female One-third female Youths and adolescents Ethnicity: NA	16-item Cannabis Withdrawal Scale developed by the authors by reviewing available literature Structured Clinical Interview for DSM-IV Childhood Diagnoses^Citation27 (KID-SCID) Typical symptoms: craving cannabis, irritability, depression, twitches and shakes, sleep difficulties, nervousness, perspiring, restlessness, appetite change, tension, body aches, nausea, and malaise Controlled abstinence period: 28 days	Type B	All	Males began to use cannabis regularly at an earlier age than females. Only few differences in reported withdrawal symptoms and severity between males and females	All self-reported high levels of psychiatric problems. Four of the 21 participants had a lifetime history of another substance dependence. 11 of 13 participants who had attained 2 weeks of abstinence were screened with KID-SCID: 4 were found to have at least one externalizing disorder, 1 had an internalizing disorder only, and 5 had both internalizing and externalizing disorders. One participant did not have any comorbid disorder.	CWS intensity was not related to the quantity of cannabis used, the frequency of exposure, the length of cannabis dependence, and the age at onset of daily cannabis use, or levels of psychiatric problems. 13 patients completed the study
Hasin et al (USA)^Citation22	Part of an epidemiologic study, representative for the civilians of the USA 2001–2002, the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC)	N=2,613 frequent cannabis users (≥3 times/week), and a “cannabis-only” subset (N =1,119) never binge-drank or used other drugs (≥3 times/week) Most of the 2,613 individuals used cannabis 5–7 days a week, and 57.2% and 16.2% were diagnosed with DSM-IV cannabis abuse and DSM-IV cannabis dependence, respectively Female 33.1% Adults, aged 18–99 years 75.4% Caucasian, 11.4% African–American, 7.3% Hispanic, 5.9% other ethnicities (N=2,613)	Structured in-person interviews covering substance history, DSM-IV Axis I and II disorders, and withdrawal symptoms after cessation of use Typical symptoms: 2 factors (symptom types) were found, one characterized by weakness, hypersomnia, and psychomotor retardation and the second by anxiety, restlessness, depression, and insomnia	NA	In the full sample (N=2,613), 57.7%, 44.3%, 34.4% reported ≥1 symptom, ≥2 symptoms, and ≥3 symptoms, respectively. These rates were nearly identical in the “cannabis-only” subset (N=1,119)	Gender was significantly associated with the anxiety/depression symptoms type only	Major depression was significantly associated with anxiety/depression symptoms type, the same was true for Panic Disorder. Generalized Anxiety Disorder was unrelated to CWS symptoms. Personality disorder was associated with both types of withdrawal symptoms	Both the symptom types were significantly associated with significant distress/impairment, substance use to relieve/avoid cannabis withdrawal symptoms, and quantity of cannabis use
Agrawal et al (USA)^Citation21	Part of NESARC (Hasin et al)^Citation22	Subsample of the past-12 month cannabis users (N=1,603), 12.2% met criteria for a lifetime history of DSM-IV Cannabis Dependence (not including withdrawal as a criterion) Female 38% Mean age 30.8 years Ethnicity of this subsample: NA	See Hasin et al^Citation22 Typical symptoms: >40% of those with a lifetime history of DSM-IV cannabis dependence reported weakness/tiredness and eating more than usual/weight gain. 20%–40% reported sleeping more than usual, feeling depressed, feeling anxious/nervous, and moving/speaking slowly	NA	In the full sample (N=1,603), >43% and ~29.4% reported ≥1 symptom and ≥2 symptoms, respectively. Mean number of withdrawal symptoms: 1.37 (range 0–18)	Nausea was more frequently reported in women, goosebumps/dilated pupils were more frequent in men, other symptoms were experienced in men and women with similar prevalence	Co-occurring tobacco use modestly increased the likelihood of reporting certain CWS symptoms (depressed mood, sweating/heart-racing, nausea, frequent yawning, unpleasant dreams, seeing/hearing things, and bad headaches), as did other illicit drug use (feeling weak/tired, depressed mood upon withdrawal, and frequent yawning)	After controlling for intensity of cannabis use, a history of parental alcohol/drug problems was associated with an increased likelihood of experiencing CWS The association between cannabis dependence and CWS was not mediated by a past-12-month diagnosis (DSM-IV) of Major Depressive Disorder, Generalized Anxiety Disorder, or Panic Disorder
Budney et al^Citation14	Naturalistic telephone survey study	N=67 daily cannabis users and N=54 daily tobacco cigarette smokers who made quit attempts during the prior 30 days Female 46% (cannabis group) Adults Ethnicity (cannabis group): 66% Caucasian, 30% African–American	Withdrawal Symptom Checklist,^Citation24 which includes common symptoms of both cannabis and tobacco withdrawal Typical symptoms: Withdrawal Discomfort Score (WDS) did not differ significantly between groups. Individual symptom severity ratings were also of similar magnitude, except craving and sweating were slightly higher for tobacco	NA	NA	No	NA	Both the groups reported that withdrawal contributed substantially to relapse, and the strength of these ratings was similar across groups
Vandrey et al (USA)^Citation79	Laboratory outpatient crossover study	Nontreatment-seeking heavy users (N=12) of cannabis and tobacco for 6 months prior to participating Female 50% Adults 100% Caucasian	Withdrawal Symptom Checklist, which includes common symptoms of both cannabis and tobacco withdrawal Typical symptoms: CWS: anxiety/nervousness, decreased appetite, difficulty concentrating, irritability, sleep difficulty, strange dreams, and WDS Tobacco withdrawal: anxiety/nervousness, increased anger, irritability, physical discomfort, restlessness, shakiness, sleep difficulty, tension, and WDS Controlled abstinence period: 5 days	Type A	All	NA	No current comorbidity other than nicotine dependence	Overall withdrawal severity (WDS) associated with cannabis alone and tobacco alone was of a similar magnitude. Withdrawal during simultaneous cessation of both substances was more severe than for each substance alone, but these differences were of short duration, and substantial individual differences were noted
Copersino et al (USA)^Citation23	Retrospective outpatient laboratory study	N=104 regular, nontreatment-seeking cannabis smokers, days used out of past 30 days: 23.9±7.8 Adults 52% Caucasian	176-item Marijuana Quit Questionnaire addressing 40 withdrawal symptoms, sociodemography characteristics, cannabis use history, and the “most difficult” cannabis quit attempt Typical symptoms: craving cannabis 66%, irritability 48%, and boredom 45%, increased anxiety 33%, difficulty sleeping 33%, increase in appetite 26%, decrease in appetite 24%, physical discomfort 10%	Type A The onset of physical withdrawal symptoms (means of 1–3 days after last use) was typically sooner than the onset of psychological symptoms (means of 2–10 days after last use)	98% of subjects reported experiencing at least one cannabis withdrawal symptom, 81% reported experiencing ≥2 symptoms, 49% reported experiencing ≥4 symptoms	No	No current comorbidity other than nicotine dependence	Physical withdrawal symptoms generally had a shorter duration (2–19 days) than psychological symptoms (5 weeks to >1 year)
Levin et al (USA)^Citation11	Retrospective outpatient laboratory study	N=469 subjects, 90.6% cannabis dependents (DSM-IV), lifetime, nontreatment seeking. The sample was generally of low socioeconomic status Female 42% Adults 79.5% African–Americans	176-item Marijuana Quit Questionnaire Typical symptoms: Psychological symptoms: cannabis craving (75.7%), mood changes (33.7%–50.1%), sleep disturbances (21.8%–46.9%), and decreased appetite (38.8%); Physical symptoms: weight gain (23.5%) and headache (23.2%) Controlled abstinence period: duration of withdrawal symptoms was highly variable, ranging from 1.5 weeks to >1 year: Physical symptoms and aggressive behaviors tended to have quicker onset, quicker peak intensity, and shorter duration than sleep disturbances or mood changes	Type A	42.4% of subjects had experienced a lifetime withdrawal syndrome, 95.5% of subjects reported ≥1 individual withdrawal symptom (median 9.0); 43.1% reported ≥10 symptoms	Nonsignificant trend for women and African–Americans to be more likely than other subjects to experience CWS	Most subjects used legal psychoactive substances over the 6 months prior to the quit attempt: 69.7% used caffeine (36.3% at least 5 days per week), 75.3% alcohol (15.3%), and 79.3% tobacco (62.0%). There was minimal use of medications or illegal drugs	Number of withdrawal symptoms was significantly associated with greater frequency and amount of cannabis use, symptoms were usually of ≥moderate intensity and often prompted actions to relieve them. Alcohol (41.5%) and tobacco (48.2%) were used more often than cannabis (33.3%) for this purpose. There was little change during withdrawal in use of other legal or illegal substances among subjects reporting at least 2,000 lifetime uses of cannabis
Preuss et al (Germany)^Citation34	Prospective inpatient study	N=118 treatment-seeking cannabis dependents (DSM-IV): The educational level was mostly low, almost two-thirds of the patients were unemployed, and more than half reported having been in detention Females 14.4% Age 16–36 years All Caucasian	Modified version of the Marijuana Withdrawal Checklist (Budney et al)^Citation24 Typical symptoms: The most frequently mentioned physical symptoms of strong or very strong intensity on the first day were sleeping problems (20.7%), sweating (28.2%), hot flashes (20.7%), and decreased appetite (15.4%). The most frequent “strong” or “very strong” ratings were given for craving (37.9%). Other often highly rated psychological symptoms: restlessness (19.8%), nervousness (19.7%), and sadness (19.2%). Proportions of the “very strong” response category did not exceed 13.8% on any physical item, 12.2% on any psychological item, or 14.7% for craving Controlled abstinence period: 10 days	Type B	68% reported withdrawal symptoms, four withdrawal symptoms of at least moderate intensity were reported by the majority of subjects (69.8%) on the first day	No	No current comorbidity other than nicotine dependence	Most withdrawal symptoms ranged on average between low to moderate intensity
Allsop et al (Australia)^Citation15 Plus 1 month follow-up: Allsop et al (Australia)^Citation16	Laboratory outpatient prospective study	DSM-IV-dependent nontreatment-seeking cannabis users (N=49), cannabis use on ≥5 days per week over the previous 3 months Cannabis dependence severity: mild 77%, moderate 23%, severe 0% Female 33% Ethnicity: NA	26-item Cannabis Withdrawal Scale (adapted from the Marijuana Withdrawal Checklist of Budney et al^Citation24 and a literature search of PubMed) Typical symptoms: nightmares and/or strange dreams = most valid item but caused relatively little associated distress. Angry outbursts were considered intense and caused much distress. Trouble getting to sleep is intense withdrawal symptom and caused significant distress Controlled abstinence period: 14 days	Type A	NA	No	Nicotine dependence and anxiety disorder 14%, mood disorder 14%, psychotic disorder 2%, alcohol/other SUD 4%
Gorelick et al (USA)^Citation19 (secondary analyses of the population of Levin et al)^Citation11	Retrospective outpatient laboratory cohort study	N=384 subjects, 92.4% lifetime cannabis dependents (DSM-IV), nontreatment seeking. The sample was generally of low socioeconomic status Female 42% Adults 82.3% African–American	176-item Marijuana Quit Questionnaire Typical symptoms: craving for cannabis 59.4%, sleep difficulties 50.5%, insomniaa 48.7%, feeling angry and/or aggressive and/or irritable 45.6%, physical symptoms 25.3%, feeling restless 21.9%,increased appetite 20.8%, decreased appetite 17.4% Controlled abstinence period: cf Levin et al^Citation11	Type A	40.9% of subjects met the DSM-5 CWS criterion^Citation31 (at least 3–7 symptoms), 30.0% met the Budney and Hughes (2006)^Citation13 4-symptom criterion (at least 4 of 11 symptoms), and 57.3% met the Budney et al.^Citation12 2-symptom criterion (at least 2 of 11 symptoms)	Women were significantly more likely than men to report a DSM-5 physical symptom (30.6% vs 21.4%,)	Among subjects using a drug class at least weekly prior to the quit attempt, only a minority within each class decreased their use during the cannabis quit attempt: 10.1% for caffeine (5.2% of all subjects), 15.4% for alcohol (5.5%), 12.4% for tobacco (8.3%), 44.0% for stimulants (2.9%), 19.1% for opiates (1.0%), 14.3% for sedative/hypnotics (0.5%), 33.3% for hallucinogens (0.3%), and 50% for phencyclidine (0.3%)	Total number of joints smoked in the month prior to the quit attempt was significantly correlated with total number of withdrawal symptoms experienced by a subject. There was no significant association between presence of CWS by any definition and outcome (relapse vs continued abstinence) of the quit attempt
Lee et al (USA)^Citation35	Prospective laboratory study at a closed research unit	N=29 nontreatment-seeking, chronic cannabis smokers, 79.3% cannabis dependents (DSM-IV), smoking for at least 1 year and ≥5 days per week for the last 6 months Female: 0% Adults 86.2% African–American	37-item cannabis withdrawal scale (adapted from Haney et al),^Citation28 12-item Marijuana Craving Questionnaire, Symptom Checklist-90 revised (SCL-90R)^Citation129 Typical symptoms: craving for marijuana 48.8%, irritable 36.8%, angry/aggressive 36.3%, depressed 31.0%, restless 26.8%, anxious 28.7%, strange/vivid dreams 14.3%, depth of sleep 15.8%, difficulty getting off to sleep 7.29% Residual cannabis symptoms at admission: feel thirsty 35.9%, dry mouth/throat 25.6%, feel hungry 23.8%, increased appetite 18.0%, high appetite 27.0%, stimulated appetite 27.0% Controlled abstinence period: 30 days	Type A	38% of the subjects met DSM-5 diagnostic criteria for CWS^Citation31 on admission, increasing to 55% (day 1), 38% day 2), 56% (day 3) During days 4–30, 20%–50% of the participants met these criteria^Citation31		No current comorbidity other than nicotine dependence	Severity of symptoms was generally mild to moderate. About 10% had at least moderate severity. Expected residual cannabis effects were positively correlated with plasma THC and 11-OH-THC. Expected withdrawal effects, “difficulty getting off to sleeping” and “anxious,” were negatively correlated with plasma THC
Bonnet et al (Germany)^Citation36	Prospective inpatient study	N=39 treatment-seeking chronic cannabis dependents (ICD-10), mostly lived alone (51.3%), unemployed (69.2%), and had a moderate education level (76.9%); detention history 15.4% Female 20.5% Adults 97.4% Caucasian	Modified version of the Marijuana Withdrawal Checklist (Budney et al),^Citation24 Clinical Global Impression Scale – Severity (CGI-S)^Citation80 Typical symptoms: mean intensity of irritability, nervousness, restlessness, and anger increased until day 4 and then decreased. Craving and sleeplessness peaked on day 2. Strange, ie, vivid and lucid dreams reached its maximum not until day 4 The intraindividual CWS peak was first observed on day 1 in 3 patients (7.7%), on day 2 in 12 patients (30.8%), on day 4 in 20 patients (51.3%), and on day 8 in 4 patients (10.3%) Controlled abstinence period: 16 days	Type A	All	Females had stronger CWS	No current comorbidity other than nicotine dependence	The maximum withdrawal severity according to CGI-S was 4 “moderately ill” in 7 patients (17.9%), 5 “markedly ill” in 16 patients (41%), and 6 “severely ill” in 16 patients (41.1%). On admission, THC and its metabolites did negatively correlate with the severity of CWS. There was no significant correlation afterward, 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 >1 g/mL (range: 1.3–6.4 ng/mL). Concerning the single withdrawal symptoms only for “strange dreams” a significant (negative) correlation with serum THC was found at day 4
Greene and Kelly (USA)^Citation42	Prospective outpatient cohort study plus 1-year follow-up		Modified version of the Customary Drinking and Drug Use Record (CDDR, Brown et al),^Citation78 a structured interview that assesses substance involvement, past 90-day withdrawal symptoms, and DSM-IV lifetime cannabis abuse/dependence Typical symptoms: difficulty sleeping 30.56%, headaches 13.89%; feeling irritable 13.89%; stomach upset, nausea, vomiting 11.11%, fatigue, excessive yawning 11.11%, feeling angry, hostile, or acting aggressive 11.11%; loss of appetite 11.1%, feeling depressed 8.33%, feeling anxious or nervous 8.33% Controlled abstinence period: 12 months	NA	40% (n=36) reported experiencing cannabis withdrawal. Twenty-four (66.67%) of these subjects reported using drugs to relieve or prevent withdrawal symptoms	No	Most patients had another SUD mostly alcohol use disorder (90%), tobacco (90%),amphetamine <10%, cocaine <10% Anxiety disorders 10%, mood disorders 17.7%, externalizing disorders 42.2%	Participants reporting withdrawal were more likely 1) to meet criteria for cannabis dependence, 2) to have a mood disorder, 3) have higher levels of substance use severity, 4) report more substance-related consequences. No main effect of withdrawal on percent days abstinent over the 12-month follow-up period. There was no longitudinal relationship between withdrawal and psychiatric symptoms
Herrmann et al (USA)^Citation76	Prospective outpatient study	N=136 treatment-seeking frequent cannabis users Female 26.5% Adults >80% African–American	Marijuana Withdrawal Checklist (Budney et al),^Citation24 14-item Withdrawal Discomfort Scale (WDS, Budney et al)^Citation26 Controlled abstinence period: NA	NA	NA	Women had significantly stronger CWS and more withdrawal symptoms than men. Women had significantly higher scores than men on six individual items. These items were in two domains: mood symptoms (irritability, increased anger, restlessness, and violent outbursts) and gastrointestinal symptoms (nausea and stomach pain)	No current comorbidity other than nicotine dependence Reported drinking: <20 standard drinks per week
Soenksen et al (USA)^Citation40	Cross-sectional study	N=93 pre-adjudicated males between 12 and 18 years of age who were detained at a state juvenile correctional facility: 50.5% of participants reported using cannabis at least once a day during the 3 months prior to detention Female 0% Youths 45.1% Caucasian; 21.5% African–American; 26.88%/5% Hispanic/Latino	Typical symptoms according to the Marijuana Withdrawal Checklist of Budney et al:^Citation24 sleep difficulty, nervousness/anxiety, depressed mood, restlessness, increased anger, decreased appetite, headache, and sweating. Three of these symptoms (sleep difficulty, depressed mood, and nervousness/anxiety) were reported to be of at least moderate severity by 30% of participants Controlled abstinence period: 5.7±12.7 days	NA	NA	–	51.6% reported using alcohol at least once a month	Significant main effect for level of marijuana use on the reported severity of two withdrawal symptoms: craving to smoke marijuana; and strange/wild dreams: significant main effect for the level of tobacco use on severity of irritability. African–Americans reporting lower withdrawal discomfort scores and experiencing less severe depressed mood, difficulty sleeping, nervousness/anxiety, and strange/wild dreams
Davis et al (USA)^Citation109	Prospective outpatient cohort plus 3-month follow-up	N=110 heavy and recent cannabis users (use ≥45 out of 90 days) seeking community outpatient substance abuse treatment. 28.2% of participants were diagnosed with past year cannabis dependence, and 53.4% reported any lifetime CUD Female 8.2% Young adults (18–25 years old) 34.6% Hispanic, 26.4% African–American, 21.8% Caucasian	22-item Current Withdrawal Scale. Individuals who reported ≥3 symptoms (eg, scores ≥3) were coded (cannabis withdrawal = 1) as having met criteria for a DSM-5 diagnosis of CWS^Citation31 Typical symptoms: feel sad, tense, angry 48.2%, feel nervous 26.4%, have trouble sleeping 40.0%, have trouble sitting still 33.6%, throw up or feel like throwing up (stomach) 10.0%, shaky hands 9.09%; sweat more/heart race/or goose bumps (chills) 11.8%, have a fever 2.73%, have muscle aches (headache) 12.7% Controlled abstinence period: 3 months	NA	NA	Gender, non-Caucasian, and previous days of substance use treatment were not significant predictors of abstinence in the community at 3 months	No current comorbidity other than nicotine dependence. Drinking alcohol <13 days out of the past 90 days. About 72% of participants reported smoking tobacco in the past week. Depression 3.7%, generalized anxiety disorder 20%, ADHD 7.7%	Of the 110 participants, 28.2% (n=31) reported being abstinent in the community at the 3-month follow-up assessment. Relative to those meeting cannabis withdrawal criteria, those not meeting the cannabis withdrawal criteria have 2.6 times higher odds of being abstinent in the community at 3 months
Synthetic cannabinoid receptor agonists
Macfarlane et al (New Zealand)^Citation56	Retrospective chart review	In the 12-month period, N=47 patients presented to detoxification services reporting problems withdrawing from synthetic cannabinoid receptor agonists. About 21 clients were admitted for medical management within an inpatient setting Female 37.5% 66% Caucasian, 25% Maori, 6% Indian, 3% Pacific Islander	Cannabis Withdrawal Assessment Scale (CWAS) scores (Allsop et al)^Citation15 Typical symptoms: inpatients (N=20): agitation 89%; irritability 83%, anxiety 55%, and mood swings 55%, nausea and vomiting 44%, and loss of appetite 17% Controlled abstinence period: 8 days (mean duration)	Type A The CWAS scores peaked on day 2 but remained at a similar level throughout the first 5 days	NA	NA	Coexisting substance dependence apart from nicotine dependence was low. About 30% inpatients had an Axis 1 psychiatric disorder (schizophrenia N=3, depression with psychosis N=1, bipolar disorder N=1, and anxiety disorder N=1)	87.2% of the clients reported difficulty to stop using due to the development of withdrawal symptoms

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)

Symptoms	None	Mild	Moderate	Severe
Cannabis craving
Irritability*
Nervousness/anxiety*
Increased aggression*
Restlessness*
Increased anger*
Sleep difficulty*
Strange/wild dreams*
Depressed mood*
Decreased appetite*
Sweating*
Shakiness/tremulousness*
Headaches*
Stomach pains*
Nausea
Other

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.

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 studies^24,26,37) 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 studies^24,26,37); 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

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

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