Abstract

Recently, the first publically-funded Latin American cannabinoid research network (CannaLatan, www.cyted.org/es/cannalatan), formed by academic investigators and pharma companies of different countries, was launched. CannaLatan aims to promote and boost the results obtained by the different partners of the consortium developing collaborative research and educational projects. The CannaLatan network is devoted to tackle the potential therapeutic applications of under-investigated phytocannabinoids and novel cannabinoid-based molecules, as well to clarify their undesired actions. Here we discuss one of the ongoing projects initiated by CannaLatan with the financial support of Fundación Canna (www.fundacion-canna.es/) , in which we address the anti-psychotic and cognitive actions of acidic forms of phytocannabinoids, namely THCa
The plant Cannabis sativa contains more than 160 molecules with a great diversity of chemical modifications based on a common scaffold structure (isoprenylated resorcinyl polyketide core) and known as phytocannabinoids (Hanuš et al., 2016). THC (delta-9- tetrahydrocannabinol) and CBD (cannabidiol) being by far the molecules that have been mostly investigated. The interest of the scientific community during the 20th century on the mechanism of action of THC was mostly propelled by anti-drug institutions, which aimed to demonstrate and disseminate its detrimental actions. In this regard, whereas THC use, like any other bioactive molecule, is not devoid of undesired actions (Ferland and Hurd, 2020), the scientists slowly embraced and investigated the wide variety of potential beneficial applications of THC known by humankind for millennia. THC is a psychoactive molecule that regulates neuronal function primarily via CB1 cannabinoid receptors, which were identified and cloned in the 1990s. In a different manner, the interest in CBD is much more recent. CBD was neglected by scientists as a “non-active” molecule, being one of the main reasons for this lack of interest, the absence of a receptor-mediated mechanism of action. Funny enough, CBD ostracism has lately turned into the preferred cannabinoid molecule as: i) it is a non-psychotomimetic compound (it does not induce psychosis, that is characteristic of CB1 receptor-targeting molecules such as THC; ii) CBD exerts anticonvulsive actions in various refractory epilepsy diseases, and this led FDA and EMA to approve its use as a medicament; and iii) the lack of pro-psychotic effects and cognitive impairment of CBD spares it from most of the access restrictions that apply to THC. Hence, CBD is a safe and very well tolerated compound that has exploded as the “gold” Cannabis molecule and has become the preferred compound for commercial marketing, now being added to many human consumption products and edibles (health-benefiting claimed products, nutritional supplements, and any other thing you can imagine). The efficacy of most CBD-containing products, not of pharmaceutical degree, with low or undetermined CBD concentrations, absence of bioavailability and pharmacodynamic data can be questioned in many cases. However, CBD is an interesting molecule for its purported therapeutic uses. Among other therapeutic actions (Fernández-Ruiz et al., 2020), CBD exerts an anticonvulsant action in epilepsy and relieves various neuropsychiatric disorders symptoms. In this regard, CBD has been repeatedly demonstrated to exert anxiolytic, antidepressive and antipsychotic actions in preclinical models of various pathological conditions (Fig. 1A). There is moderate evidence that CBD alleviates symptoms of schizophrenia, social anxiety disorder, comorbidities of autism spectrum disorder, and attention deficit hyperactivity disorder in humans (Crippa et al., 2020). Last, but not least, CBD is being explored for the management of non-motor symptoms of neurodegenerative diseases (i.e., Parkinson’s disease and Alzheimer’s disease), to mention some examples.