The Impact of Marijuana on Antidepressant Treatment in Adolescents: Clinical and Pharmacologic Considerations

Abstract

The neuropharmacology of marijuana, including its effects on selective serotonin reuptake inhibitor (SSRI)/antidepressant metabolism and the subsequent response and tolerability in youth, has received limited attention. We sought to (1) review clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) interactions between cannabinoids and selected SSRIs, (2) use PK models to examine the impact of cannabinoids on SSRI exposure (area under curve (AUC)) and maximum concentration (CMAX) in adolescents, and (3) examine the frequency of adverse events reported when SSRIs and cannabinoids are used concomitantly. Cannabinoid metabolism, interactions with SSRIs, impact on relevant PK/PD pathways and known drug–drug interactions were reviewed. Then, the impact of tetrahydrocannabinol (THC) and cannabidiol (CBD) on exposure (AUC24) and CMAX for escitalopram and sertraline was modeled using pediatric PK data. Using data from the Food and Drug Administration Adverse Events Reporting System (FAERS), the relationship between CBD and CYP2C19-metabolized SSRIs and side effects was examined. Cannabis and CBD inhibit cytochrome activity, alter serotonergic transmission, and modulate SSRI response. In PK models, CBD and/or THC increases sertraline and es/citalopram concentrations in adolescents, and coadministration of CBD and CYP2C19-metabolized SSRIs increases the risk of cough, diarrhea, dizziness, and fatigue. Given the significant SSRI–cannabinoid interactions, clinicians should discuss THC and CBD use in youth prescribed SSRIs and be aware of the impact of initiating, stopping, or decreasing cannabinoid use as this may significantly affect es/citalopram and sertraline exposure.

Unveiling behavioral and molecular neuroadaptations related to the antidepressant action of cannabidiol in the unpredictable chronic mild stress model

“…This would increase plasma STR concentration and serotonin concentrations, reducing tolerability secondary to activation. Thus, the combined use of CBD plus STR appears to increase the risk of concentration-related SSRI side effects ( Jakubovski et al, 2016 ; Vaughn et al, 2021 ). A recent case report showed a pharmacokinetic interaction between CBD and STR in a patient treated with STR for depression and anxiety.…”

Adverse Effects of Antidepressant Medications and their Management in Children and Adolescents

“…In a small study of es/citalopram‐treated adolescents/young adults aged 17–24 years, CBD significantly increased citalopram plasma concentration 27 , and in pharmacokinetic models of adolescents treated with sertraline or escitalopram, CBD and THC increase sertraline and es/citalopram C MAX and AUC 0‐24 . Finally, it is noteworthy that a recent examination of the Food and Drug Administration Adverse Event Reporting System database revealed that co‐administration of CBD and CYP2C19‐metabolized SSRIs increased the risk of some SSRI‐related side effects (e.g., diarrhea, dizziness, and fatigue), which may relate to SSRI concentrations 28 …”

Examining the Use of Antidepressants for Adolescents with Depression/Anxiety Who Regularly Use Cannabis: A Narrative Review

“…To our knowledge, only one study has examined this possible interaction of marijuana and AD use among adolescents [ 182 ]. Nevertheless, this matter warrants intensive research before a definitive conclusion can be drawn.…”

“…This issue has not been explored fully; yet, a few similarities between these compounds’ mechanisms of action can point to a competitive effect. Although there are limited studies of direct SSRI–cannabinoid interactions, accumulating data suggest the potential for interactions [ 182 ].…”