CBD Oil Withdrawal Symptoms

The cannabis withdrawal syndrome: current insights Correspondence: Udo Bonnet, Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Over 50% of medical marijuana users were shown to experience clusters of withdrawal symptoms when they were between uses in a new, detailed study There is disagreement over whether or not there is such a thing as a cannabis withdrawal syndrome, but it’s definitely real, and with increased availability of legal marijuana and other products, even those who use it medicinally need to be aware of the symptoms, and what to do …

The cannabis withdrawal syndrome: current insights

Correspondence: Udo Bonnet, Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, D-44577 Castrop-Rauxel, Grutholzallee 21, Germany, Email [email protected]

Copyright © 2017 Bonnet and Preuss. This work is published and licensed by Dove Medical Press Limited

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Abstract

The cannabis withdrawal syndrome (CWS) is a criterion of cannabis use disorders (CUDs) (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and 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. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, 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 cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. 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 treatment of CWS. The up-to-date ICD-11 Beta Draft is recommended to be expanded by physical CWS symptoms, the specification of CWS intensity and duration as well as gender effects.

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 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 trials10,11 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 outpatient12,13,20,24–26 and inpatient laboratory studies27–30 ( 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

Authors Study design Sample CWS-measurement and characteristics CWS type Subjects reporting CWS (%) Gender effects Comorbidity Other clues
Wiesbeck et al (USA)10 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 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)38 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)24 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)28 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)27 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)41 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)25 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)26 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)37 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 seekers24
Arendt et al (Denmark)20 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 199924
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)17 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 199924
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)39 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 Diagnoses27 (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)22 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)21 Part of NESARC (Hasin et al)22 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 al22
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 al14 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,24 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)79 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)23 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)11 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)34 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)24
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)15 Plus 1 month follow-up: Allsop et al (Australia)16 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 al24 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)19 (secondary analyses of the population of Levin et al)11 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 al11
Type A 40.9% of subjects met the DSM-5 CWS criterion31 (at least 3–7 symptoms), 30.0% met the Budney and Hughes (2006)13 4-symptom criterion (at least 4 of 11 symptoms), and 57.3% met the Budney et al.12 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)35 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),28 12-item Marijuana Craving Questionnaire, Symptom Checklist-90 revised (SCL-90R)129
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 CWS31 on admission, increasing to 55% (day 1), 38% day 2), 56% (day 3) During days 4–30, 20%–50% of the participants met these criteria31 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)36 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),24 Clinical Global Impression Scale – Severity (CGI-S)80
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)42 Prospective outpatient cohort study plus 1-year follow-up Modified version of the Customary Drinking and Drug Use Record (CDDR, Brown et al),78 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 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)76 Prospective outpatient study N=136 treatment-seeking frequent cannabis users Female 26.5% Adults >80% African–American Marijuana Withdrawal Checklist (Budney et al),24 14-item Withdrawal Discomfort Scale (WDS, Budney et al)26
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:
Soenksen et al (USA)40 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:24 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)109 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 CWS31
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

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)56 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)15
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.

Using CBD oil for pain management? Watch out for withdrawal

Over 50% of medical marijuana users were shown to experience clusters of withdrawal symptoms when they were between uses in a new, detailed study

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Washington [US], January 9 (ANI): More than half of people who use medical marijuana products to ease pain also experience clusters of multiple withdrawal symptoms when they’re between uses, a new study finds.

About 10% of the patients taking part in the study experienced worsening changes to their sleep, mood, mental state, energy, and appetite over the next two years as they continued to use cannabis.

Many of them may not recognize that these symptoms come not from their underlying condition, but from their brain and body’s reaction to the absence of substances in the cannabis products they’re smoking, vaping, eating, or applying to their skin, says the University of Michigan Addiction Center psychologist who led the study.

When someone experiences more than a few such symptoms, it’s called cannabis withdrawal syndrome, and it can mean a higher risk of developing even more serious issues such as a cannabis use disorder.

In the new research published in the journal Addiction, a team from the U-M Medical School and the VA Ann Arbor Healthcare System reports findings from detailed surveys across two years of 527 Michigan residents. All were participating in the state’s system to certify people with certain conditions for use of medical cannabis and had non-cancer-related pain.

“Some people report experiencing significant benefits from medical cannabis, but our findings suggest a real need to increase awareness about the signs of withdrawal symptoms developing to decrease the potential downsides of cannabis use, especially among those who experience severe or worsening symptoms over time,” says Lara Coughlin, Ph.D., the addiction psychologist who led the analysis.

A long-term study in medical cannabis use

The researchers asked the patients whether they had experienced any of 15 different symptoms – ranging from trouble sleeping and nausea to irritability and aggression – when they had gone a significant time without using cannabis.

The researchers used an analytic method to empirically group the patients into those who had no symptoms or mild symptoms at the start of the study, those who had moderate symptoms (meaning they experienced multiple withdrawal symptoms), and those who had severe withdrawal issues that included most or all of the symptoms.

They then looked at how things changed over time, surveying the patients one year and two years after their first survey.

At baseline, 41% of the study participants fell into the mild symptoms group, 34% were in the moderate group and 25% were classed as severe.

Misconceptions about medical cannabis

Many people who turn to medical cannabis for pain do so because other pain relievers haven’t worked, says Coughlin, an assistant professor in the Department of Psychiatry who sees patients as part of U-M Addiction Treatment Services. They may also want to avoid long-term use of opioid pain medications because they pose a risk of misuse and other adverse health consequences.

She notes that people who experience issues related to their cannabis use for pain should talk with their health care providers about receiving other pain treatments including psychosocial treatments such as cognitive-behavioral therapy.

The perception of cannabis as “harmless” is not correct, she says. It contains substances called cannabinoids that act on the brain – and that over time can lead the brain to react when those substances are absent.

In addition to a general craving to use cannabis, withdrawal symptoms can include anxiety, sleep difficulties, decreased appetite, restlessness, depressed mood, aggression, irritability, nausea, sweating, headache, stomach pain, strange dreams, increased anger, and shakiness.

Previous research has shown that the more symptoms and greater severity of symptoms a person has, the less likely they are to be able to reduce their use of cannabis, quit using it, or stay away from it once they quit.

They may mistakenly think that the symptoms happen because of their underlying medical conditions, and may even increase the amount or frequency of their cannabis use to try to counteract the effect – leading to a cycle of increasing use and increasing withdrawal.

Coughlin says people who decide to use a cannabis product for a medical purpose should discuss the amount, route of administration, frequency, and type of cannabis product with their regular health provider. They should also familiarize themselves with the symptoms of cannabis withdrawal and tell their provider if they’re experiencing them.

Feeling the urge to use cannabis after a period without use, such as soon after waking up, can be a sign of withdrawal syndrome, she notes. So can the inability to cut back on use without experiencing craving or other symptoms of withdrawal.

Because there is no medically accepted standard for medical cannabis dosing for different conditions, patients are often faced with a wide array of cannabis products that vary in strength and route of administration. Some products could pose more risk for the development of withdrawal symptoms than others, Coughlin says.

For example, people who smoked cannabis tended to have more severe withdrawal symptoms than others, while people who vaped cannabis reported symptoms that tended to stay the same or get worse but generally did not improve, over time.

As more states legalize cannabis for medical or general use, including several states that will legalize its use based on the results of last November’s election, use is expected to grow.

More about the study

The researchers asked the patients about how they used cannabis products, how often, and how long they’d been using them, as well as about their mental and physical health, their education, and employment status.

Over time, those who had started off in the mild withdrawal symptom group were likely to stay there, but some did progress to moderate withdrawal symptoms.

People in the moderate withdrawal group were more likely to go down in symptoms than up, and by the end of the study, the number of people in the severe category had dropped to 17 percent. In all, 13 percent of the patients had gone up to the next level of symptoms by the end of the first year, and 8 percent had transitioned upward by the end of two years.

Sleep problems were the most common symptom across all three groups, and many in the mild group also reported cravings for cannabis. In the moderate group, the most common withdrawal symptoms were sleep problems, depressed mood, decreased appetite, craving, restlessness, anxiety, and irritability.

The severe withdrawal symptom group was much more likely to report all the symptoms except sweatiness. Nearly all the participants in this group reported irritability, anxiety, and sleep problems. They were also more likely to be longtime and frequent users of cannabis.

Those in the severe group were more likely to be younger and to have worse mental health. Older adults were less likely to go up in withdrawal symptom severity, while those who vaped cannabis were less likely to transition to a lower withdrawal-severity group.

The study didn’t assess nicotine use or try to distinguish between symptoms that could also be related to breakthrough pain or diagnosed/undiagnosed mental health conditions during abstinence.

Future directions

Coughlin and her colleagues hope future research can explore cannabis withdrawal symptoms among medical cannabis patients further, including the impact of different attempts to abstain, different types of use and administration routes, and interaction with other physical and mental health factors. Most research on cannabis withdrawal has been in recreational users, or “snapshot” looks at medical cannabis patients at a single point in time.

Further research could help identify those most at risk of developing problems, and reduce the risk of progression to cannabis use disorder, which is when someone uses cannabis repeatedly despite major impacts on their lives and ability to function. (ANI)

If cannabis becomes a problem: How to manage withdrawal

Proponents of cannabis generally dismiss the idea that there is a cannabis withdrawal syndrome. One routinely hears statements such as, “I smoked weed every day for 30 years and then just walked away from it without any problems. It’s not addictive.” Some cannabis researchers, on the other hand, describe serious withdrawal symptoms that can include aggression, anger, irritability, anxiety, insomnia, anorexia, depression, restlessness, headaches, vomiting, and abdominal pain. Given this long list of withdrawal symptoms, it’s a wonder that anyone tries to reduce or stop using cannabis. Why is there such a disconnect between researchers’ findings and the lived reality of cannabis users?

New research highlights the problems of withdrawal, but provides an incomplete picture

A recent meta-analysis published in JAMA cites the overall prevalence of cannabis withdrawal syndrome as 47% among “individuals with regular or dependent use of cannabinoids.” The authors of the study raise the alarm that “many professionals and members of the general public may not be aware of cannabis withdrawal, potentially leading to confusion about the benefits of cannabis to treat or self-medicate symptoms of anxiety or depressive disorders.” In other words, many patients using medical cannabis to “treat” their symptoms are merely caught up in a cycle of self-treating their cannabis withdrawal. Is it possible that almost half of cannabis consumers are actually experiencing a severe cannabis withdrawal syndrome — to the point that it is successfully masquerading as medicinal use of marijuana — and they don’t know it?

Unfortunately, the study in JAMA doesn’t seem particularly generalizable to actual cannabis users. This study is a meta-analysis: a study which includes many studies that are deemed similar enough to lump together, in order to increase the numerical power of the study and, ideally, the strength of the conclusions. The authors included studies that go all the way back to the mid-1990s — a time when cannabis was illegal in the US, different in potency, and when there was no choice or control over strains or cannabinoid compositions, as there is now. One of the studies in the meta-analysis included “cannabis-dependent inpatients” in a German psychiatric hospital in which 118 patients were being detoxified from cannabis. Another was from 1998 and is titled, “Patterns and correlates of cannabis dependence among long-term users in an Australian rural area.” It is not a great leap to surmise that Australians in the countryside smoking whatever marijuana was available to them illegally in 1998, or patients in a psychiatric hospital, might be substantively different from current American cannabis users.

Medical cannabis use is different from recreational use

Moreover, the JAMA study doesn’t distinguish between medical and recreational cannabis, which are actually quite different in their physiological and cognitive effects, as Harvard researcher Dr. Staci Gruber’s work tells us. Medical cannabis patients, under the guidance of a medical cannabis specialist, are buying legal, regulated cannabis from a licensed dispensary; it might be lower in THC (the psychoactive component that gives you the high) and higher in CBD (a nonintoxicating, more medicinal component), and the cannabis they end up using often results in them ingesting a lower dose of THC.

Cannabis withdrawal symptoms are real

All of this is not to say that there is no such thing as a cannabis withdrawal syndrome. It isn’t life-threatening or medically dangerous, but it certainly does exist. It makes absolute sense that there would be a withdrawal syndrome because, as is the case with many other medicines, if you use cannabis every day, the natural receptors by which cannabis works on the body “down-regulate,” or thin out, in response to chronic external stimulation. When the external chemical is withdrawn after prolonged use, the body is left in the lurch, and forced to rely on natural stores of these chemicals, but it takes time for the natural receptors to grow back to their baseline levels. In the meantime, the brain and the body are hungry for these chemicals, and the result is withdrawal symptoms.

Getting support for withdrawal symptoms

Uncomfortable withdrawal symptoms can prevent people who are dependent on or addicted to cannabis from remaining abstinent. The commonly used treatments for cannabis withdrawal are either cognitive behavioral therapy or medication therapy, neither of which has been shown to be particularly effective. Common medications that have been used are dronabinol (which is synthetic THC); nabiximols (which is cannabis in a mucosal spray, so you aren’t actually treating the withdrawal); gabapentin for anxiety (which has a host of side effects); and zolpidem for the sleep disturbance (which also has a list of side effects). Some researchers are looking at CBD, the nonintoxicating component of cannabis, as a treatment for cannabis withdrawal.

Some people get into serious trouble with cannabis, and use it addictively to avoid reality. Others depend on it to an unhealthy degree. Again, the number of people who become addicted or dependent is somewhere between the 0% that cannabis advocates believe and the 100% that cannabis opponents cite. We don’t know the actual number, because the definitions and studies have been plagued with a lack of real-world relevance that many studies about cannabis suffer from, and because the nature of both cannabis use and cannabis itself have been changing rapidly.

How do you know if your cannabis use is a problem?

The standard definition of cannabis use disorder is based on having at least two of 11 criteria, such as: taking more than was intended, spending a lot of time using it, craving it, having problems because of it, using it in high-risk situations, getting into trouble because of it, and having tolerance or withdrawal from discontinuation. As cannabis becomes legalized and more widely accepted, and as we understand that you can be tolerant and have physical or psychological withdrawal from many medicines without necessarily being addicted to them (such as opiates, benzodiazepines, and some antidepressants), I think this definition seems obsolete and overly inclusive.

For example, if one substituted “coffee” for “cannabis,” many of the 160 million Americans who guzzle coffee on a daily basis would have “caffeine use disorder,” as evidenced by the heartburn and insomnia that I see every day as a primary care doctor. Many of the patients that psychiatrists label as having cannabis use disorder believe that they are fruitfully using cannabis to treat their medical conditions — without problems — and recoil at being labeled as having a disorder in the first place. This is perhaps a good indication that the definition doesn’t fit the disease.

Perhaps a simpler, more colloquial definition of cannabis addiction would be more helpful in assessing your use of cannabis: persistent use despite negative consequences. If your cannabis use is harming your health, disrupting your relationships, or interfering with your job performance, it is likely time to quit or cut down drastically, and consult your doctor. As part of this process, you may need to get support or treatment if you experience uncomfortable withdrawal symptoms, which may make it significantly harder to stop using.

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