700 A.H. Lichtman and B.R. Martin
was quite prolonged (i.e., 4–14 days). The protracted nature of marijuana with-
drawal may contribute to the difficulties in maintaining abstinence. Collectively,
this pattern of results is consistent with the hypothesis that cannabis withdrawal
symptoms contribute to continued marijuana use.
4.2
Investigation of Cannabinoid Withdrawal in Laboratory Animal Models
Two general categories of dependent measures are used to assess withdrawal in
laboratory animals: (1) recording the occurrence of behavioral and physiological
changes and (2) the use of operant procedures. In the former approach, subjects
are observed for alterations in behavior, and these behaviors are generally either
scored as quantal responses or quantified. In the latter approach, animals that had
been previously trained to emit an operant response (e.g., lever pressing) for food
reinforcement will exhibit decreases in response rates during withdrawal. In both
cases, readministration of the drug results in response rates returning to normal.
Below, we will first discuss the results of abstinence withdrawal studies conducted
in laboratory animals followed by precipitated withdrawal studies.
There are two types of procedures that are used to induce withdrawal in drug-
dependent organisms, abstinence withdrawal and precipitated withdrawal. Ab-
stinence withdrawal occurs when drug administration is abruptly discontinued
or reduced, following prolonged exposure to the drug. As the body metabolizes
and/or excretes the agent, physiological symptoms ranging from mild rebound to
severe life-threatening effects can emerge. The pharmacokinetic and pharmaco-
dynamic characteristics of the drug, as well as the degree of dependence, influence
the specific withdrawal syndrome, its intensity, and the onset of withdrawal re-
sponses. In contrast, a second procedure used to induce withdrawal is the use of
a receptor antagonist that precipitates withdrawal in a drug-dependent organism.
The antagonist displaces the agonist from the receptor, immediately eliciting with-
drawal effects. A typical clinical example of precipitated withdrawal is the treat-
ment of an opioid overdose with naloxone or other opioid receptor antagonist.
Upon near instantaneous reversal of respiratory depression and other overdose
symptoms, an opioid-dependent individual will present with opioid withdrawal
effects. The precipitated withdrawal procedure has been particularly useful in in-
vestigating cannabinoid withdrawal symptoms in laboratory animals; however,
there are currently no published reports in which this procedure has been used
in humans. Below, we will review studies examining cannabinoid dependence in
humans and laboratory animals, as well discuss potential pharmacotherapies to
alleviate cannabinoid withdrawal symptoms.
4.2.1
Abstinence Withdrawal Versus Precipitated Withdrawal in Laboratory Animals
Research investigating abstinence withdrawal following repeated cannabinoid ad-
ministration in laboratory animals has led to mixed results. A variety of uncon-