Cannabis Sativa: a Dr Jekyll’s and Mr Hyde’s plant

It is common to associate the idea of Cannabis with the smoke that saturates the interior of a small Dutch coffee shop where the drug is openly sold and consumed; or with the new oils, lotions and the wide range of other products that are nowadays commercialized by the Cannabis industries, a market that, according to some analysts, could grow to reach $24.5 billion in sales in 2021 (Arcview Market Research). However, the use of this incredibly versatile plant goes far beyond the recreational use as it can be exploited for its great therapeutic potential.

The use of Cannabis for medical purposes is long-dated throughout history: we found the very first written witnesses back to 2800 BC in the Chinese herbarium Pen-ts’ao, and we also know from Pyramids texts that Cannabis was employed medicinally in Egypt at least since 2350 BC. Despite the extracts of this plant have been used to treat several conditions over centuries in many parts of the world, in Western medicine Cannabis has been introduced only during the 19thcentury by the Irish physician William Brooke O’Shaughnessy, who used it to treat rheumatism, seizures, and tetanus, and by the French physician Jean-Jacques Moreau de Tours for the treatment of mental disorders.

Nevertheless, the implementation of scientifically based medical Cannabis is relatively recent. Once that tetrahydrocannabinol (THC), the Cannabis psychoactive compound, was isolated in 1964 and finally cloned in 1967, and even more so when cannabinoid receptors were characterized in 1990s, the number of Cannabis-related publications increased exponentially.

The interest in THC properties was mainly linked to the social impact this product has had in past decades. But in parallel to this, medical research has been able to exploit its peculiarities to treat symptoms such as pain, insomnia and lack of appetite, among others.

Treatments with THC have caused a great deal of controversy within the scientific community, due to its various side effects. In the last 30 years, for example, a substantial literature has established that the use of Cannabis containing high percentage of THC is a significant risk factor for the onset and development of symptoms of schizophrenia.

For the aforementioned considerations, the attention has turned to other Cannabis components (more than 60 are the bioactive compounds) of particular interest. Indeed, cannabidiol (CBD), the second main molecule of the Cannabis Sativa, does not exert psychoactive action at the level of the central nervous system. Moreover, it seems that CBD has a favorable safety profile with only a few minor side effects, such as tiredness, diarrhea, and changes of appetite/weight.

From a molecular point of view, CBD lead to a variety of pharmacological outcomes, although its mechanism of action remains unknown. One of the proposed models hypothesizesits action as an inverse agonist (a type of agonist that produces an effect of opposite sign to that of the agonist) on the cannabinoid receptors. Consequently, in fact, CBD decreases anandamide (AEA, the main endogenous cannabinoid) hydrolysis (by inhibiting FAAH, the enzyme that catalyzes AEA degradation) and reuptake, facilitating so endocannabinoid-mediated neurotransmission.

This point is crucial, since imbalances against the delicate endocannabinoid system are associated with severe conditions, including schizophrenia. In this latter neurological condition, AEA levels are increased in the blood flow, and the severity of symptoms are negatively associated with AEA cerebrospinal levels. For this reason, CBD has been proposed as a potential alternative cure, for the attempt to both reducing the side effects of marketed antipsychotics, given also their weak efficacy on some schizophrenic symptoms, and to reconstitute the equilibrium of the altered endocannabinoid system.

The results of such experiments are related to the THC:CBD ratio. It has already been said that a higher proportion of THC is associated with an increased risk of a first psychotic episode of schizophrenia. On the other hand, Cannabis with higher CBD content was associated with fewer psychotic experiences. Moreover, when CBD was administered to rats as well as healthy human volunteers, it did show antipsychotic properties, improving both negative and positive symptoms of schizophrenia.

The improvements of clinical symptoms and serum AEA levels observed in CBD-treated schizophrenics, suggests that the ability of CBD to indirectly enhance AEA signaling might represent a possible mechanism contributing to its antipsychotic properties.

Other models indicate that CBD is also able to bind and activate TRPV1 receptors; to be a putative antagonist of a cannabinoid receptor called GPR55; and to act as an agonist of serotonin receptors. Thus, CBD could be able to ameliorate schizophrenic symptoms by combining simultaneously all these different mechanisms of actions, or some of them.

Even though a more significant literature on schizophrenia has been produced so far, other studies have investigated the effects of CBD on depression, bipolar and anxiety disorders, reaching similar outcomes in ameliorating the symptoms produced by these severe psychiatric conditions.

To conclude, more and more advanced research is being carried out on the use of Cannabis for therapeutic purposes. However, the use of CBD for medical reasons clashes with the legislation and the social traditions of different countries. These variables certainly make the approval of Cannabis very complicated for medical use. And despite the history and recent scientific evidence to show how undeniable its therapeutic potential is, it is known for certain that Cannabis increases the risk of developing schizophrenia or other diseases related to the central nervous system. Although these effects are attributable only to THC, while CBD would have no side effect, larger clinical investigations and assessing the chronic effects of CBD are still needed.

Paolo Masia holds a MSc in Neurosciences from the University of Trieste/SISSA.
He is currently a PhD fellow in Neurosciences at the University of Cagliari, and he studies the molecular basis of the “Gateway Hypothesis”, which postulates that early exposure to cannabinoids (as well as other soft drugs) in adolescence could cause neurobiological changes that affect the cerebral maturation leading to a major risk of vulnerability to abuse hard drugs during adulthood.