"The aim of this review is to describe the historical development of research on cannabidiol". (Department of Neurology, Psychiatry and Medical Psychology, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto (SP), Brazil)
After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis. In the 1970's the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with THC and its antiepileptic and sedative effects.
The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects.
The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer.
Introduction
In the tip of secreting hairs located mainly on female-plant flowers and, in a smaller amount, in the leaves of cannabis plant, there are resin glands that have a considerable amount of chemically related active compounds, called cannabinoids. In some varieties of cannabis the main cannabinoid is the psychoactive component of the plant, THC. Cannabis varieties typically bred for fiber are nearly always relatively low in THC, cannabidiol (CBD) being the predominant cannabinoid in these plants.
Although CBD was isolated from marijuana extract in 1940 by Adams et al. for almost 25 years no further work has been reported, except for a few early works about its isolation. Only in 1963 its exact chemical structure was elucidated by Mechoulam and Shvo. Over the following few years Mechoulam's group was responsible for the structure and stereochemistry determination of the main cannabinoids, which opened a new research field on pharmacological activity of cannabis constituents.
Only a few pharmacological studies on CBD were reported before the early 1970's, showing that CBD had no cannabis-like activity. The number of publications increased in this decade and reached a first peak around 1975. In this period, a Brazilian research group led by Carlini, gave an important contribution, especially about the interactions of delta9-THC with other cannabinoids, including CBD. Then, the number of publications declined and remained stabilized until a few years ago. The interest in studies about cannabis was renewed in the early 1990's, by the description and cloning of specific receptors for the cannabinoids in the nervous system and the subsequent isolation of anandamide, an endogenous cannabinoid.
Afterwards, the number of publications about cannabis has been continuously growing, but the reports on CBD remained stable until the early 2000's. In the last five years there has been an explosive increase in publications on CBD, with the confirmation of a plethora of pharmacological effects, many of them with therapeutic potential. Now, there are some recent and very good reviews on CBD
Inactive cannabinoid that interact with delta9-THC
The early pharmacological tests on isolated cannabinoids had evidenced that except for THC, no other major psychotomimetically active compounds were present in cannabis.During this period, several reports attested that CBD was unable to mimic the effects of cannabis both in animals and in humans, leading to the thought that it was an inactive cannabinoid.
Early evidence on CBD pharmacological activity
1. Antiepileptic action
The first pharmacological actions of CBD described were the antiepileptic and the sedative ones. In 1973, a Brazilian group reported that CBD was active in reducing or blocking convulsions produced in experimental animals by a variety of procedures, which was confirmed by another group one year later.
2. Sedative action
In the early 1970's, suggestive evidence of a sedative action appeared, based on the observation that CBD reduced ambulation in and, with higher doses, operant behavior .In humans with insomnia, increased sleep duration compared to placebo.Sedative effect was also observed in healthy volunteers with high CBD dose.
Previous reports of subjective feelings by healthy volunteers showed a significant increase in "clear minded" and "quick- witted" feelings, in contrast with THC that induced an increase in "muzzy" feelings.
CBD effects on anxiety, psychoses and movement disorders
After the peak of reports on CBD in the 1970's, the next two decades the publication rate remained stabilized, indicating a lower degree of interest on the study of therapeutic actions of CBD. The reports in this field were maintained mainly by Brazilian researchers investigating the anxiolytic and antipsychotic properties of CBD and by a few studies about its effects in motor diseases conducted by Consroe et al.
1. Anxiolytic action
In 1974, an interactive study between CBD and THC, gave the first clue that CBD could act as an anxiolytic drug. This study showed that CBD changed the symptoms induced by THC alone in such a way that the subjects receiving the mixture showed less anxiety and more pleasurable effects.
The anxiolytic-like effect of CBD in healthy volunteers was also observed in a more recent double-blind study.
2. Antipsychotic action
The first evidence that CBD could have antipsychotic effects was obtained in the interactive study of CBD and delta9-THC in healthy volunteers published in 1982.
This study demonstrated that CBD could inhibit THC-induced subjective changes that resembled symptoms of psychotic diseases such as: disconnected thought, perceptual disturbance, depersonalization and resistance to communication.
The therapeutic use of CBD in psychotic patients was tested for the first time in 1995. In a case study, a schizophrenic patient, who presented serious side effects after treatment with conventional antipsychotics. A significant improvement was observed during CBD treatment.
3. Action on movement disorders
The possible therapeutic effect of CBD on movement disorders came from anecdotal accounts and preliminary reports of open trials, in the middle 1980's. CBD had antidystonic effects in humans when administered along with standard medication.
CBD's neuroprotective effects began to be reported in animal models of Parkinson's disease.
CBD as a drug with a wide spectrum of action
The interest in studies about cannabis was renewed in the early 1990's, with the description and cloning of specific receptors for the cannabinoids CB1 and CB2 in the nervous system and the subsequent isolation of anandamide, an endogenous cannabinoid.
After that, the number of publications about cannabis has been continuously growing, attesting the great interest in research involving the herb. However, the number of studies on CBD has increased only in the last five years , mainly stimulated by discoveries of the anti-inflammatory, anti-oxidative and neuroprotective actions of CBD.
CBD: a drug with multiple mechanisms of action
The plethora of CBD effects described above can be explained by its multiple mechanisms of action. The description and cloning of specific receptors for the cannabinoids in the nervous system have been a great contribution to the understanding of the mechanism of actions of cannabinoids. However, in contrast to THC, CBD has little affinity to CB1 and CB2 receptors.
Conclusion
In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials. It is important to highlight that many effects of CBD draw a bell-shaped dose-response curve, suggesting that the dose is a pivotal factor in CBD research. The wide range of CBD effects can be explained by the multiple mechanisms through which CBD acts, although further research is needed to clarify the precise mechanisms that underlie some of the potentially beneficial effects of CBD.
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