Journal of Disease and Global Health

Background: Cannabis sativa and its principal constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), engage an endogenous lipid signalling network, the endocannabinoid system, that has emerged as a pervasive regulator of innate and adaptive immunity. Although the immunosuppressive properties of THC were first described experimentally several decades ago, the molecular pathways linking cannabinoid receptor engagement to specific immune cell fates, cytokine programmes, epigenetic states, and tissue-level outcomes have not been consolidated into a single critical synthesis that distinguishes well-supported mechanisms from preliminary or contradictory findings.

Purpose and Scope: This critical narrative review synthesises evidence on the molecular mechanisms through which phytocannabinoids, synthetic cannabinoid receptor ligands, and endogenous cannabinoids influence immune cell development, activation, and effector function. Attention is given to receptor-dependent and receptor-independent pathways, epigenetic and microRNA-mediated regulation, mucosal and pulmonary immune consequences, and the clinical correlates of these mechanisms in autoimmune disease and infection susceptibility.

Approach: Evidence was drawn from peer-reviewed primary research, mechanistic reviews, and clinical trials identified through structured searching of general and subject-specific bibliographic and citation-indexing platforms, supplemented by backward and forward citation tracing and restricted to sources whose bibliographic identity and relevance to the cited claim could be verified.

Principal Findings: The evidence base supports a model in which cannabinoid type 2 receptor (CB2) engagement on leukocytes constitutes the dominant, though not exclusive, route by which cannabinoids suppress lymphocyte proliferation, skew cytokine networks, induce apoptosis in activated T cells and dendritic cells, and mobilise myeloid-derived suppressor cells through epigenetically mediated mechanisms. Cannabinoid type 1 receptor (CB1) signalling contributes principally through neuro-immune circuits, while the atypical receptor GPR55 and peroxisome proliferator-activated receptor gamma (PPARγ) generate context-dependent, occasionally opposing, effects that complicate a simple anti-inflammatory narrative. CBD acts substantially through CB2-independent and PPARγ-dependent routes, with effects on macrophage polarisation and inflammasome activity that diverge mechanistically from those of THC. Confidence in these mechanisms is highest for rodent and in vitro human leukocyte systems and comparatively limited for chronic human exposure, where epidemiological and clinical trial evidence remains heterogeneous and often underpowered.

Conclusions and Implications: The molecular evidence positions the endocannabinoid system as a genuine node of immune homeostatic control rather than a uniformly immunosuppressive or anti-inflammatory pathway. Reconciling laboratory mechanism with the modest and inconsistent clinical signal for infection risk and autoimmune disease modification requires dose-, route-, and context-sensitive research designs that are largely absent from the current literature.