Nicolas J. Schlienz and Ryan Vandrey
I. D. Montoya, S. R. B. Weiss (eds.), Cannabis Use Disorders,
Drug withdrawal refers to a constellation of symptoms that occur following abrupt cessation of chronic drug use. Though drug withdrawal can occur from stopping use of medication, it is most often encountered within the context of illicit, non-medicinal, drug use. The withdrawal symptoms that emerge following extended and frequent use of abused drugs are a key feature of what define substance use disorders [4, 85]. Further, there is accumulating neurobiological evidence that withdrawal drives the maintenance of problematic substance misuse through a mechanism of reward dysfunction and negative reinforcement . Historically, there was debate and controversy regarding the existence of a valid and clinically meaningful cannabis withdrawal syndrome. However, extensive translational research has now firmly established that cannabis withdrawal occurs reliably in a subset of cannabis users, that it is pharmacologically specific to the use of cannabis, and that it is clinically meaningful within the context
of treating cannabis use disorder (CUD). As a result, mitigating cannabis withdrawal has been targeted in several studies aiming to develop improved treatments for CUD (discussed in detail in other chapters of this book). There are also individual characteristics, such as sex, genetics, and co-occurring
psychiatric disorders that have been associated with differences in the type or severity of cannabis withdrawal. This chapter will provide a detailed overview of the etiology and characterization of cannabis withdrawal with emphasis on its importance within the context of CUD.
Following an extended period of daily heavy use, termination of cannabis use is associated with the onset of a cannabis withdrawal syndrome that has been well-documented; has been observed in humans, rodents, and nonhuman primates; and has been reported in inpatient, outpatient, and clinical research settings [12, 14, 42].
Symptoms and Time Course
Symptoms : Early controlled laboratory studies of cannabis withdrawal reported the onset of a series of withdrawal symptoms that emerged after a period of unrestricted cannabis self-administration. Following cessation from cannabis use in a controlled residential research unit, an inpatient sample of heavy users reported increased ratings of “anxiety,” “irritability,” and “stomach pain” . Findings from multiple outpatient studies documented symptoms that also included anger, aggression, physical tension, nervousness, restlessness, depression, sleep difficulties, and loss of appetite [16, 55, 56]. The set of cannabis withdrawal symptoms that are most common, elicited reliably, and constitute DSM-5 cannabis withdrawal syndrome symptomatology  are outlined in Table 11.1 and include the following: irritability, anger/aggression, anxiety, sleep disturbance, appetite decline or weight loss, restlessness, and depressed mood. Less common symptoms include shakiness, chills, sweating, nausea/stomach pain, and tension [15, 43, 45, 55].
Time Course : Findings from early investigations of cannabis withdrawal provided an initial understanding of symptom characteristics and demonstrated that symptoms generally emerge within 24–72 h following cessation from cannabis  and reach peak magnitude 2–5 days post-cessation [15, 44, 45, 55]. Studies conducted by Budney and colleagues  and Kouri and Pope  provided a broader understanding of the time course of cannabis withdrawal based on self-reported symptoms during an extended period of abstinence. Most withdrawal symptoms resolve within 2–3 weeks and return to baseline levels [15, 55]. However, abstinence-induced insomnia may continue to persist, and
reports of abstinence-related increases in vivid or strange dreams failed to return to baseline levels at the end of a 45-day abstinence period .
Validity, Reliability, and Clinical Significance
For years, the proposed existence of a cannabis withdrawal syndrome was met with great skepticism, and one early review of the literature concluded that the combination of methodological limitations of published findings and lack of controlled research rendered the recognition of a cannabis withdrawal syndrome as being premature . However, an extensive body of research has now clearly demonstrated that the cannabis withdrawal syndrome is valid, reliable, and pharmacologically specific and produces distress and impairment in important areas of functioning [12, 14, 42].
Reliability : Core symptoms of cannabis withdrawal have been consistently documented in adults [13, 16, 43, 45, 55], adolescents [25, 26, 30, 32, 41, 68, 69, 77], and individuals with polysubstance use and comorbid psychopathology [9, 19, 49, 54, 82], and within incarcerated samples [70, 71, 76]. Further, cannabis withdrawal symptoms have been documented in treatment-seeking and non-treatment-seeking populations and across inpatient and outpatient settings. Thus, cannabis withdrawal is consistently observed across a variety of daily cannabis users and differs from data obtained from control samples of individuals who do not use cannabis [15, 55].