From Mechoulam to NegEnt: Historical, Regulatory and Clinical Evolution of Cannabidiol-Based Therapeutics for Psychological Distress

Cannabidiol (CBD) represents one of the most remarkable examples of the transformation of a natural compound into a modern therapeutic platform. From its chemical characterization by Raphael Mechoulam in the early 1960s, through the discovery of the endocannabinoid system and the later development of cannabinoid-based medicines such as Sativex® and Epidiolex®, scientific understanding of CBD has progressively expanded from phytochemistry to clinical pharmacology.The present article provides an epistemological and historical perspective on this evolution, focusing specifically on the Italian experience that led to the development of NegEnt, a medical device based on micellar water-soluble cannabidiol conceived for the management of psychological distress, particularly anxiety and insomnia. The article reconstructs the scientific, technological, clinical, entrepreneurial and regulatory milestones of the programme, from its theoretical origins in the Entropy of Mind model to the development of micellar cannabidiol, the registration of NegEnt as a medical device, systematic post-marketing clinical observation, and the subsequent evolution toward the Terpenolol platform.Particular attention is devoted to the interaction between theoretical psychiatry, technological innovation, clinical observation and regulatory change. Within this historical trajectory, the emergence of a biophysical interpretation of cannabinoid neuromodulation represents a further conceptual step, shifting attention from uniform pharmacological suppression toward state-dependent processes of functional regulation. The resulting history illustrates how a natural molecule may progressively become incorporated into a broader scientific programme centred on regulation, organization and resilience within complex mental systems.