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Try out PMC Labs and tell us what you think. Learn More. Cannabis is the most frequently used illegal psychoactive substance in the world. There is a ificant increase in the of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis-dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population.
So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal e. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre-clinical studies suggest the potential of fatty acid amide hydrolase FAAH inhibitors such as URB, endocannabinoid-metabolizing enzymes, and nicotinic alpha7 receptor antagonists such as methyllycaconitine MLA.
Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications. Cannabis is the most frequently used illegal substance in the world [ 1 — 3 ]. In the United States, the of individuals with disorders associated with cannabis use is twice that of any other illicit drug [ 1 ], with approximately 4 million adults meeting criteria for a life-time diagnosis of cannabis dependence [ 6 ].
Relapse rates for cannabis users in treatment are comparable to those found for other drugs of abuse [ 7 — 11 ]. CB1 receptors are located primarily in pre-synaptic neurons of the CNS and are responsible for the acute psychological and cardiovascular effects of cannabis.
CB2 receptors are located largely in the periphery and modulate immune function and inflammatory response. Endocannabinoids endogenous ligands at CB receptors such as anandamide serve as retrograde neuromodulators of synaptic activity. They are released postsynaptically by a variety of stimuli upon demand, travel across the synaptic cleft, and then activate presynaptic CB receptors.
A membrane transporter actively takes anandamide into the cell. Anandamide is then broken down by fatty acid amide hydrolase FAAH [ 13 — 15 ]. The neuropharmacological mechanism of cannabis dependence may involve interactions of the endocannabinoid system with the dopaminergic and opioid systems. Chronic administration of cannabinoids le to down-regulation of the CB receptor and receptor function desensitization [ 16 ]. THC like other drugs of abuse, releases DA in the mesocortico-limbic regions of animal brains [ 17 — 19 ].
PET brain imaging studies in healthy human volunteers provide inconsistent evidence for this action in humans. One study showed modest THC-induced dopamine release in the ventral striatum and dorsal putamen using [ 11 C] raclopride [ 20 ]. Another study found no ificant effect of THC on [ 11 C] raclopride binding, although THC markedly increased psychosis-like symptoms [ 21 ].
A subsequent study using the same methodology found ificant decreases in frontal and temporal lobe [ 11 C] raclopride binding after THC challenges, but no changes in the striatum, which is also part of the dopamine reward pathway [ 22 ]. Decreased frontal lobe binding ificantly correlated with catechol-O-methyltransferase COMT status.
Therefore, medications that target the brain dopamine reward system may have a role in the treatment of cannabis dependence, as they may for other drugs of abuse. Cannabis intoxication is a syndrome recognized in DSM-IV [ 4 ] and ICD [ 5 ], with both psychological and behavioral euphoria, relaxation, increased appetite, impaired memory and concentration , and physical motor incoordination, tachycardia, orthostatic hypotension , manifestations.
Intoxication is usually mild and self-limiting, not requiring pharmacological treatment [ 23 ]. The most severe effects anxiety, panic, psychosis are best treated symptomatically with a benzodiazepine or second-generation atypical anti-psychotic medication. No medication is approved specifically for treatment of cannabis intoxication. In a double-blind, placebo-controlled study of 63 healthy men with a history of cannabis use, single oral doses of rimonabant produced ificant dose-dependent blockade of the subjective intoxication and tachycardia caused by smoking an active 2.
Rimonabant alone produced no ificant physiological or psychological effects and did not affect peak THC plasma concentration or its time course. This pattern of findings suggests that the observed attenuation of cannabis effects was specifically due to CB1 receptor blockade, and not to reduction in brain THC concentration or counteracting effects of rimonabant. CB receptor antagonists such as rimonabant might be useful in treating acute cannabis intoxication, in the way that the mu-opioid receptor mOR antagonists naloxone and naltrexone are used to treat opiate intoxication.
However, such medications are no longer available for clinical use. Rimonant and similar CB1 receptor antagonists were withdrawn from clinical development and use because of psychiatric side-effects associated with their long-term use [ 25 ]. Both human laboratory and clinical outpatient studies have established the reliability, validity and time course of the cannabis withdrawal syndrome [ 26 , 27 ] and the cannabis withdrawal syndrome has been proposed for inclusion in DSM-V [ 28 ].
Some US studies suggest that about half of patients in treatment have reported symptoms of the cannabis withdrawal syndrome [ 23 , 29 — 33 ]. The main symptoms of cannabis withdrawal are anxiety, irritability, depressed mood, restlessness, disturbed sleep, G-I symptoms, and decreased appetite. Most symptoms begin during the first week of abstinence and resolve after a few weeks. Because symptoms of cannabis withdrawal may serve as negative reinforcement for relapse to cannabis use in individuals trying to abstain [ 27 , 34 ], pharmacological treatment aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence.
Several studies have tested the effects of medications on cannabis withdrawal [ 35 — 37 ]. These medications are either CB receptor agonists that directly suppress the withdrawal syndrome analogous to using an opiate to suppress heroin withdrawal or are deed to indirectly alleviate symptoms of cannabis withdrawal e.
No medication has regulatory approval for the treatment of cannabis withdrawal. The CB receptor agonist THC has shown efficacy in several human laboratory studies and open-label case series. See Table 1 for description of all pharmacological treatment trials for cannabis dependence. Most published studies have been human laboratory studies of short duration typically 3—4 days , using an inpatient human laboratory model developed at Columbia University New York, US [ 35 ].
Participants were non-treatment-seeking volunteers who smoked cannabis many times a day. They smoked cannabis active or placebo and received oral medication active or placebo each day under double-blind conditions. The protocols used a within-subjects crossover de so that each participant received each active and placebo combination of cannabis and medication [ 38 ].
The early laboratory studies evaluated divalproex, an anticonvulsant which is used clinically as a mood stabilizer and to treat epilepsy and migraine headaches [ 39 ] buproprion, which is used clinically as an antidepressant and for smoking cessation; and nefazodone, an antidepressant that blocks post-synaptic 5HT-2a receptors and inhibits pre-synaptic 5HT and NE reuptake [ 40 ].
Bupropion is thought to exert its clinical effects by inhibiting reuptake of norepinephrine NE and dopamine DA and possibly by acting as a nicotine receptor antagonist [ 41 ]. Oral THC was also more effective than placebo in an outpatient study in which oral THC was given to 8 adult, daily cannabis users who were not seeking treatment in a day, within-subject de study [ 44 ].
Comparison of measures of withdrawal symptoms across conditions indicated a dose-dependent reduction of withdrawal discomfort by THC. Minimal adverse effects were associated with either THC dose. This demonstration of dose-response effect replicates and extends prior findings of the pharmacological specificity of the cannabis withdrawal syndrome [ 43 ].
More recently, the Columbia group has evaluated medications in a more complicated human laboratory de that models both withdrawal and relapse. Regular cannabis users were maintained on each medication condition for 7 inpatient days.
Each medication phase was separated by an outpatient washout phase. During the first three inpatient days, placebo cannabis was available for self-administration withdrawal. For the next 4 days, active cannabis was available for self-administration. Participants paid for self-administered cannabis using study earnings. The first such study evaluated lofexidine, an agonist at the alpha2-adrenergic receptor that is used to treat opiate withdrawal [ 46 ]. Lofexidine was tested both alone and in combination with THC [ 47 ].
THC reversed the anorexia and weight loss associated with cannabis withdrawal, and decreased some withdrawal symptoms, but increased sleep onset latency, and did not decrease the resumption of cannabis use when active cannabis was available. Lofexidine, which was sedating, worsened withdrawal-related anorexia and did not robustly attenuate mood symptoms associated with withdrawal, but improved sleep and decreased cannabis relapse.
The combination of lofexidine and THC produced the most robust improvements in sleep and decreased cannabis withdrawal, craving, and relapse in daily cannabis smokers relative to either medication alone. The second such study evaluated baclofen, a GABA B receptor agonist and antispasmodic medication that reduces mood symptoms in heroin withdrawal [ 48 ], and mirtazapine, an antidepressant that enhances noradrenergic and serotonergic transmission and decreases withdrawal symptoms in alcohol-dependent patients [ 49 ], especially agitation and insomnia [ 50 ].
On the first inpatient day of each medication condition, participants smoked active cannabis baclofen group : 3. For the next 3 days, participants could self-administer placebo cannabis withdrawal phase , followed by 4 days in which they could self-administer active cannabis relapse phase. During active cannabis smoking, baclofen dose-dependently decreased craving for tobacco and cannabis, but had little effect on mood during abstinence and did not decrease relapse.
Mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease cannabis relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine show promise for the treatment of cannabis withdrawal.
One strategy to treat drug dependence is long-term treatment with the same agonist drug or with a cross-tolerant drug to suppress withdrawal and drug craving. This approach is successfully used in the treatment of tobacco nicotine dependence nicotine itself and opiate dependence methadone, buprenorphine. It is being studied for treatment of cannabis dependence using synthetic THC which is legally marketed in many countries as an oral medication for appetite stimulation and suppression of nausea and vomiting due to chemotherapy.
Questions of medication abuse and diversion must be addressed, as with opiate agonist substitution treatment. Use of oral synthetic THC in outpatients was reported in a study that showed the potential benefit, as well as questions that arise from the use of this medication in cannabis-abusing populations [ 52 ]. Controlled clinical trials of oral THC are currently underway www. The antagonist approach uses long-term treatment with a CB1 antagonist to prevent patients from experiencing the pleasurable reinforcing effects of cannabis use, resulting in extinction of drug-seeking and drug-taking behavior.
This approach has been used successfully with the mOR antagonist naltrexone in the treatment of opiate dependence [ 53 ]. It could be implemented should a CB1 receptor antagonist again become available for human use. A recent randomized, double blind, parallel group study investigated whether subacute 2-week treatment with the CB1 receptor antagonist rimonabant 40 mg daily attenuated the effects of smoked cannabis in 42 healthy men with a history of cannabis use [ 54 ]. The repeated daily rimonabant doses attenuated the acute cardiovascular effects of a cannabis cigarette 2.
Rimonabant did not ificantly affect THC pharmacokinetics, suggesting that the observed effects were due to receptor blockade and not reduced THC levels in the brain. Alternative pharmacotherapy approaches may arise from improved understanding of the neuropharmacology of cannabis use disorders, including the recognition that i frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid aling, and ii genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence [ 55 ].
These findings suggest that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters anandamide and 2-arachidonoylglycerol 2-AG might alleviate cannabis withdrawal and dependence.
Preclinical studies showed that URB produced analgesic, anxiolytic-like, and antidepressant-like effects in rodents, which were not accompanied by overt s of abuse liability. This evidence suggests that FAAH inhibitors such as URB might offer a possible therapeutic avenue for the treatment of cannabis withdrawal [ 55 ]. Because animal studies show that mOR antagonists block effects of THC, several human laboratory studies have investigated whether the mOR antagonist naltrexone can reduce the subjective effects of cannabinoids in humans. In cannabis users, pretreatment with high doses of naltrexone 50— mg failed to attenuate or enhanced the subjective effects of THC [ 56 , 57 ] or smoked cannabis [ 58 ].
However, a lower, more mOR-selective dose of naltrexone 12 mg decreased the intoxicating effects of 20 mg, but not 40 mg, of THC [ 59 ]. A recent placebo-controlled study in 29 heavy cannabis smokers found that opioid-receptor blockade by naltrexone 12, 25, 50, or mg daily enhanced the subjective and cardiovascular effects of cannabis [ 60 ]. This pattern of human experimental findings is not completely consistent, but suggests that clinically used doses of naltrexone would not be effective as treatment for cannabis dependence, and might actually increase the abuse liability of cannabis.
Catechol-O-methyl transferase COMT is an enzyme that inactivates catecholamine neurotransmitters and plays a pivotal role in regulating homeostatic levels of DA neurotransmitter in the inter-synaptic cleft. COMT inhibitors would increase synaptic DA activity, perhaps counteracting the DA deficiency considered to play a role in drug compulsion and craving.
The gene for COMT is located on chromosome 22q However, these findings were not replicated in a later study [ 66 ]. As mentioned earlier, THC, like other drugs of abuse, releases DA in the meso-cortico-limbic regions of animal brains. PET brain imaging studies in healthy volunteers so far seems to suggest that THC administration in modest dopamine release in some human brain regions, but the role of this action in the rewarding effects of THC remains unclear. Therefore, the place in treatment of medications that target the brain dopamine reward system also remains unclear.
Entacapone both short-term and long-term ificantly decreased craving for cannabis in Entacapone was well tolerated and there was no serious adverse event [ 67 ]. The neurotransmitter glutamate has emerged as a potential target in the treatment of addictions, such as cocaine, nicotine, and cannabis dependence. In animal studies, N -acetylcysteine NAC reverses drug-induced down-regulation of the cystine-glutamate exchanger, which restores normal regulation of glutamate release, reducing compulsive drug-seeking behaviors [ 68 ].
Consistent with this evidence, preliminary studies have demonstrated ificant reductions in cocaine craving [ 69 ] and cigarette use [ 70 ] during NAC treatment. A recent open-label study gave NAC 1, mg twice daily for 4 weeks to 24 cannabis-dependent males and females who were interested in reducing their cannabis use [ 71 ].
Treatment with NAC was well tolerated and associated with ificant decreases in self-report measures of cannabis use and craving, but no change in semi-quantitative urine cannabinoid levels. Cannabis users demonstrate time and dose-dependent impairments in attention, memory, executive function and response inhibition that resemble deficits in patients with attention deficit hyperactivity disorder ADHD and share morbidity with this disorder [ 72 ].
For the eight participants who completed the study, there was a trend towards reduction in cannabis use and increase in percent days of abstinence. The majority of patients experienced gastrointestinal adverse events. Buspirone shares some of the properties of the benzodiazepines and the neuroleptics; it is a 5-HT 1A receptor agonist [ 75 ] and a D 2 receptor antagonist [ 76 ].
A preliminary week, open-label study in 10 cannabis-dependent men found that buspirone maximum 60 mg per day in a week open-label trial ificantly reduced frequency and duration of cannabis craving and use and reduced irritability and depression [ 77 ]. These findings support the promise of buspirone as a treatment for cannabis dependence. Lithium is a mood stabilizer used primarily in the treatment of bipolar disorder depression and mania , both acutely and chronically. A preclinical study showing that lithium attenuated cannabis withdrawal in rats [ 79 ] prompted two small open-label clinical studies.
However, cannabis was admittedly smoked during this period by one of these 4 participants and cannabis abstinence was not verified in the others. Twelve participants completed the 7-day inpatient detoxification. Five participants reported continuous abstinence that was corroborated with urine toxicology tests on Day These provide limited support for a double-blind trial of lithium as treatment for cannabis dependence. These suggest that nefazodone and bupropion-sustained release are not effective in treating cannabis dependence. Cannabis users frequently have co-morbid mood symptoms, especially depression [ 84 , 85 ].
The prevalence of depression in this population suggested that anti-depressant medication might promote abstinence in this population. Two studies evaluated the selective serotonin reuptake inhibitor SSRI anti-depressant medication fluoxetine in this population. A post hoc analysis of 13 cannabis-using patients among a larger sample of alcohol-abusing, depressed adolescents treated with fluoxetine 20—40 mg daily showed reduction in cannabis and alcohol dependence and depressive symptoms [ 86 ].
Five-year follow-up of 10 patients showed that cannabis and alcohol dependence were reduced and academic ability improved, but clinical depression remained problematic. A later week, controlled clinical trial in 70 adolescents and young adults with comorbid major depression and cannabis use disorder found fluoxetine 20 mg daily no better than placebo in treating either the depressive symptoms or the cannabis- related symptoms [ 87 ].Cannabis withdrawal medication
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