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Journal of Clinical and
Translational Research Cannabinoids for cannabis use disorder

Furthermore, by addressing cravings, these therapies might CBD has a low affinity for CB1 and CB2 receptors but can act
aid recovery efforts and help lower the rates of relapse. as an antagonist at CB1 receptors in the presence of THC,
Nabilone, a synthetic derivative of THC, and thereby mitigating its psychoactive effects. CBD enhances
dronabinol, a synthetic form of THC, are currently used the signaling of the endogenous CB AEA by inhibiting its
as a second-line treatment for patients with AIDS, cancer reuptake and degradation through the FAAH, leading to
cachexia, and chemotherapy patients experiencing nausea increased AEA levels in the brain, which contributes to its
or vomiting. 27,28 Both medications primarily act on the anxiolytic and anti-inflammatory effects. In addition, CBD
CB1 receptor. Nabiximols, a CB agonist containing interacts with other receptors such as transient receptor
approximately equal parts of THC and CBD, is used in potential vanilloid-1 channel, involved in pain perception,
the treatment of central neuropathic pain in multiple and 5-hydroxytryptamine receptor 1A, also known as
sclerosis and as an adjuvant analgesic in adults with serotonin receptor 1A, which influences serotonin signaling
advanced malignancy. CB agonists, particularly those and mood regulation. Through these interactions, CBD
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targeting CB1 and CB2 receptors, play a crucial role in exerts therapeutic effects that are beneficial in treating
the endocannabinoid system, influencing physiological CUD by stabilizing the endocannabinoid system, reducing
processes such as pain sensation, mood, appetite, and cravings, and alleviating withdrawal symptoms, thereby
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memory. CB1 receptors, primarily located in the central supporting recovery and reducing relapse rates.
nervous system, modulate neurotransmitter release According to our findings, CBD was effective in
through the inhibition of adenylyl cyclase, activation of reducing withdrawal symptoms at a dose of 800 mg. Both
the mitogen-activated protein kinase (MAPK) pathway, 400 mg and 800 mg CBD doses lengthened the period
and modulation of ion channels, leading to effects of abstinence and reduced cannabis use, but the 400 mg
such as analgesia, euphoria, and appetite stimulation. dose might be slightly more effective. However, one cannot
CB2 receptors, found mainly in peripheral tissues and conclude that there is a dose-response association since the
immune cells, also inhibit adenylyl cyclase and activate data are limited to only one study and should be analyzed
the MAPK pathway, contributing to anti-inflammatory carefully. Finally, regarding adverse events, there was no
and neuroprotective effects. In the context of cannabis significant difference between intervention and placebo
dependence, agonist substitution therapy leverages these reported in any study. Overall, the treatment was well
mechanisms to stabilize neurotransmitter levels, which tolerated in all studies.
might reduce cravings, and manage withdrawal symptoms, This study has some important limitations. First, the
thereby supporting recovery and reducing relapse rates. 30
small number of patients included in the studies, the great
In this study, dronabinol reported significantly heterogeneity of substances used, and the absence of data
higher retention in treatment compared to placebo, and from standardized questionnaires to evaluate baseline
nabilone reduced cravings early in the treatment, but characteristics and outcomes significantly increased bias
no improvements were seen after the 28-day follow-up. due to selection effects. Second, there was inconsistency
Nabiximols reduced self-reported cannabis use, whereas in follow-up periods and drug dosages across the included
nabilone and dronabinol alone, or combined with studies, leading to significant heterogeneity. In addition,
lofexidine, did not affect the magnitude of cannabis use most outcomes are self-reported, which can introduce
when compared with a placebo. Nabiximols were also reporting bias. However, all studies included urinary
effective in reducing withdrawal symptoms, reducing drug screening tests as a method to validate the self-
cannabis cravings, and had a higher rate of treatment report, confirming self-reporting as a reliable method
retention. As hypothesized by Lintzeris et al., the in determining ongoing drug use on grounds of a strong
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significant reductions observed in cannabis cravings with association between the urinary test results and self-
nabiximols can be attributed to several factors: adjustable report outcomes. While our systematic review is updated
dosage schedule, pharmacokinetic characteristics such and includes the albatross plot, which offers a stronger
as higher bioavailability and quicker onset of action, and methodological approach, it remains underpowered
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the combination of THC with CBD, which may provide to support any specific medication, let alone clinical
benefits to nabiximols recipients. 31-34 practice.
The modulation of the endocannabinoid system is a
relatively new approach to treating CUD. CBD modulates 5. Conclusion
the endocannabinoid system through a multifaceted This systematic review found that three studies highlighted
mechanism involving indirect interactions with CB the therapeutic potential of nabiximols in reducing
receptors, endogenous ligands, and enzymes. Unlike THC, cannabis use. One study with nabiximols also reported

Volume 11 Issue 1 (2025) 11 doi: 10.36922/jctr.24.00066