Laurel Foster

Background: Prenatal cannabis exposure (PCE) is an increasingly relevant concern due to growing acceptance, legalization, and decriminalization of cannabis. As societal attitudes delineate marijuana as a “harmless” drug and women seek relief from morning sickness, nausea, vomiting, and anxiety, cannabis use during pregnancy has consequently increased in the United States.^1,2,3 THC, a psychoactive substance in cannabis, crosses the placenta and acts on the endocannabinoid system receptors expressed early in human fetal development. Under the multi-hit model of psychiatric disorders, PCE is implicated as a risk factor in predisposing offspring to psychotic-like states. Specifically, PCE acts as a “first hit” in which a “second hit” such as life adversity, drug abuse, or psychosocial stress, manifests the full onset of psychiatric disorders such as schizophrenia.^2,4,5 By altering endocannabinoid signaling during fetal development, PCE induces a hyperdopaminergic state that is akin to a psychotic-like endotype.⁶ There is an unmet need to further investigate PCE and its underlying biological mechanisms. Importantly, the development of drug targets and therapeutic strategies are needed to mitigate the risk of psychopathology in children and adolescents.

Objectives: This review focuses on the CB₁ receptor (CB₁R) of the endocannabinoid pathway as a mechanistic link between PCE and psychiatric disorders. Neurobehavioral outcomes were also investigated to better understand the implications of PCE in childhood and adolescence.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: “prenatal cannabis exposure”, “fetal development”, and “psychiatric disorders”.

Results: PCE leads to a hyperdopaminergic state in the ventral tegmental area (VTA), characterized by increased tonically active dopamine neurons and increased firing frequency of dopamine neurons in response to acute THC administration.⁵ By activating CB₁R, PCE decreases GABA release which reduces synaptic inhibition of dopamine neurons.⁶ PCE is associated with remodeling CB₁R synaptic connections allowing fewer CB₁R to control more GABA release channels.⁶ Additionally, PCE delays upregulation of KCC2, which is crucial for the switch of GABA to inhibitory in fetal development. Administration of a CB₁R antagonist prevented the GABA switch delay indicating these effects are CB₁R mediated.⁷  PCE is associated with deleterious neurobehavioral effects. In rats, PCE was linked to disrupted pre-pulse inhibition (PPI), increased vulnerability to acute stress, diminished weight gain, and impaired early-life communication.^5,6,7 Cannabis use after maternal knowledge of pregnancy is linked to increased attention, cognition, social, and self-control problems and increased occurrence of psychotic-like experiences in children.⁴ One potential treatment is pregnenolone, a negative regulator of CB₁R, which rescued the THC-induced remodeling of excitatory and inhibitory inputs on dopamine cells, enhancement of dopamine levels, and disruption of PPI.⁶

Conclusion: Studies have characterized a THC-mediated excitability of fetal neurons via aberrant CB₁R signaling in the endocannabinoid pathway. This disruption manifests as negative neurobehavioral and psychiatric outcomes. Understanding the role of CB₁R in the development of psychopathology can lead to new therapeutic strategies. Importantly, exploring additional mechanisms of PCE is essential. Enhanced understanding can reduce the risk of psychiatric disorders in children and improve outcomes in those previously vulnerable to illness due to PCE.

Works Cited:

1. Little B, Sud N, Nobile Z, Bhattacharya D. Teratogenic effects of maternal drug abuse on developing brain and underlying neurotransmitter mechanisms. NeuroToxicology. 2021;86:172-179. doi:10.1016/j.neuro.2021.08.007
2. Frau R, Melis M. Sex-specific susceptibility to psychotic-like states provoked by prenatal THC exposure: Reversal by pregnenolone. J Neuroendocrinol. 2023;35(2):e13240. doi:10.1111/jne.13240
3. Hurd YL, Manzoni OJ, Pletnikov MV, Lee FS, Bhattacharyya S, Melis M. Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects. J Neurosci. 2019;39(42):8250-8258. doi:10.1523/JNEUROSCI.1165-19.2019
4. Paul SE, Hatoum AS, Fine JD, et al. Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study. JAMA Psychiatry. 2021;78(1):64-76. doi:10.1001/jamapsychiatry.2020.2902
5. Sagheddu C, Traccis F, Serra V, et al. Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure. Prog Neuropsychopharmacol Biol Psychiatry. 2021;105:110128. doi:10.1016/j.pnpbp.2020.110128
6. Frau R, Miczán V, Traccis F, et al. Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone. Nat Neurosci. 2019;22(12):1975-1985. doi:10.1038/s41593-019-0512-2
7. Scheyer AF, Borsoi M, Wager-Miller J, et al. Cannabinoid exposure via lactation in rats disrupts perinatal programming of the GABA trajectory and select early-life behaviors. Biol Psychiatry. 2020;87(7):666-677. doi:10.1016/j.biopsych.2019.08.023