The Mapping of Physiological Conversion Pathways from the Major Acidic Cannabinoids

1. Introduction

This paper dives into the acidic cannabinoid metabolome cascade that happens through stomach, blood, and liver mechanisms, and the compound outcome from that process.

This preprint is part of a three-work integrated series examining (1) dietary inputs from the seeds of the hemp plant, (2) and the dietary inputs from the phytocannibinoids from the plants, (3) the mechanistic ECS pathways they activate, and the physiological outcomes.

2. Materials and Methods

This review series is a narrative synthesis of existing peer-reviewed literature on dietary inputs from Cannabis sativa L. (whole plant and seeds), endocannabinoid system (ECS) mechanisms, and physiological outcomes. No primary experimental data were generated.

A comprehensive literature search was conducted using PubMed, Google Scholar, Scopus, and Web of Science databases from inception through December 2025, with keywords including but not limited to: “hemp seed nutrition,” “acidic cannabinoids,” “THCA/CBDA/CBGA pharmacokinetics,” “endocannabinoid precursors,” “PUFA ECS modulation,” “raw cannabis consumption,” “entourage effect,” “clinical endocannabinoid deficiency,” and organ-specific terms (e.g., “hemp seed cardiovascular,” “cannabis neuroprotection”).References were selected for relevance, methodological rigor, and recency, prioritizing human studies, clinical trials, and mechanistic reviews where available, supplemented by preclinical and in vitro evidence. Inclusion focused on studies demonstrating direct links between cannabis/hemp constituents and ECS pathways or homeostasis outcomes.

Metabolite pathways (e.g., “The Acidic Cannabinoid Metabolome”) were constructed by integrating established pharmacokinetic data with logical chemical extensions based on known CYP450, UGT, and oxidative transformations. Speculative or trace compounds/metabolites were explicitly labeled as such, derived from structural analogy and rare reported pathways.

All claims are supported by cited sources; synthesis connects established findings to propose integrative models for dietary ECS modulation.

3. AI Disclosure

The comprehensive literature search spanning the past 13 years was systematically supported by [ChatGPT-4, Grok, and Gemini]. The tools were used for data extraction and collation, specifically to efficiently screen and categorize high-volume scientific databases and preprint servers for keywords related to the endocannabinoid system (ECS) and various nutritional compounds. The multiple AIs were then pitted against each other to test and validate the scientific data and theories.

This assistance was instrumental in managing the large dataset compiled over the research period. The identification of the novel conceptual framework—nutritional support for the ECS—was an original human-driven insight based on the author’s synthesis of the collated data, not a generative function of the AI tools. The author assumes full responsibility for all content, interpretation, and references cited in this manuscript.

5. Conclusions

The acidic cannabinoids THCA, CBDA, and CBGA anchor the biochemical framework of the cannabis plant and, through their diverse decarboxylation and metabolic conversion pathways, generate a wide spectrum of neutral cannabinoids and phase I/II metabolites with distinct physiological relevance. Mapping these cascades clarifies how whole-plant consumption delivers not only primary cannabinoids but also a dynamic ensemble of downstream molecules that contribute to endocannabinoid system modulation, metabolic adaptation, and homeostatic balance.

The patterns observed across the THCA, CBDA, and CBGA lineages reveal consistent principles: (1) precursor acids maintain unique bioactivity independent of their neutral forms; (2) hepatic metabolism produces secondary metabolites that often dominate systemic exposure; and (3) minor transformation routes—though present in trace amounts—add functional diversity that remains understudied. Collectively, these pathways challenge the conventional focus on isolated neutral cannabinoids and highlight the need to evaluate acidic and metabolite-driven signaling within physiological and dietary contexts.

As part of this three-paper series, these findings integrate with companion analyses on hemp seed nutrition and ECS-regulated metabolic mechanisms to provide a comprehensive framework for understanding cannabis as a dietary input. Together, they support the emerging view that acidic cannabinoids and their metabolites play central roles in maintaining homeostasis, adapting to internal stressors, and contributing to overall biological resilience. Targeted clinical and translational research is warranted to establish the full therapeutic potential of these compounds within human nutrition and regenerative health.