Does cannabidiol protect against adverse psychological effects of THC ?
Raymond J. M. Niesink and Margriet W. van Laar
Frontiers in Psychiatry, 2013, 4, 130
doi : 10.3389/fpsyt.2013.00130.
The recreational use of cannabis can have persistent adverse effects on mental health. Delta 9-tetrahydro-cannabinol (THC) is the main psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis are caused by THC. Recent studies have suggested a possible protective effect of another cannabinoid, cannabidiol (CBD). A literature search was performed in the bibliographic databases PubMed, PsycINFO, andWeb of Science using the keyword “cannabidiol.” After removing duplicate entries, 1295 unique titles remained. Based on the titles and abstracts, an initial selection was made.The reference lists of the publications identified in this manner were examined for additional references. Cannabis is not a safe drug. Depending on how often someone uses, the age of onset, the potency of the cannabis that is used and someone’s individual sensitivity, the recreational use of cannabis may cause permanent psychological disorders. Most recreational users will never be faced with such persistent mental illness, but in some individuals cannabis use leads to undesirable effects : cognitive impairment, anxiety, paranoia, and increased risks of developing chronic psychosis or drug addiction. Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC. However, the question remains of how the laboratory results translate to the types of cannabis that are encountered by real-world recreational users.
Keywords : tetrahydrocannabinol, cannabidiol, cannabis, psychosis, anxiety, drug dependence, cognition
Tetrahydrocannabinol (THC) is the main psychoactive substance in cannabis. Cannabidiol (CBD) is a cannabinoid that appears in cannabis resin but rarely in herbal cannabis. In recent years, many positive attributes have been ascribed toCBD. Is cannabis that contains CBD less harmful than cannabis without CBD? Are people who smoke cannabis resin, therefore, less susceptible to psychosis or less likely to become addicted than are peoplewho smoke herbal marijuana? In this article, several of the health aspects of CBD will be reviewed. The article will focus on the role played by CBD in contributing to the psychological effects that are experienced during recreational cannabis use.
Cannabis sativa contains more than 80 different cannabinoids, of which THC is principally responsible for the pharmacological actions, including the psychoactive effects. THC binds to specific proteins in the brain – the cannabinoid receptors (CB-Rs) (1). Two different receptors have been discovered: the CB1 and CB2 receptors (2, 3). CB1-R is mainly found in the central nervous system (CNS); CB2-R is predominantly present in the immune system (3–5). Endocannabinoids are naturally occurring substances that attach to these receptors (6–8).
Cannabinoid receptors, endocannabinoids, and the enzymes involved in the synthesis and degradation of these substances together form the endocannabinoid system (9). The activation of the CB-Rs affects the actions of various neurotransmitters, such as acetylcholine, dopamine, GABA, glutamate, serotonin, norepinephrine, and endogenous opioids (10, 11). Under normal physiological circumstances, CB-Rs are activated by endocannabinoids (12). The activation of CB-Rs by endocannabinoids inhibits excessive neurotransmitter release. Endocannabinoids are lipid-soluble compounds,which prevent themfromtraveling long distances within the brain. As a consequence of this feature, endocannabinoids are ideally suited for small-scale, local physiological processes (13).
Tetrahydrocannabinol mimics the effect of endocannabinoids. In contrast to these substances, THC is not rapidly broken down at the site of operation, and it not only works at specific locations but simultaneously activates all CB receptors throughout the brain (14).
The mechanisms by which CBD exerts its effect are not precisely known, but it is clear that the pharmacological actions of CBD follow from many different mechanisms [for reviews, see Ref. (15, 16)]. CBD weakly binds to CB-Rs but is capable of antagonizing the effects of THC, even when the former is present in low doses. By inhibiting the degradation of the endogenous cannabinoid anandamide, CBD intensifies, and prolongs its effect (17). The (extended) presence of anandamide prevents THC from interacting with CB-Rs. CBD also interacts with several other recently discovered CB Rs, and it is an agonist for the 5-HT1A receptor (18, 19), which may explain some of the antipsychotic and anxiolytic effects of CBD (20). Through its effect on intracellular calcium concentrations, CBD might protect neurons against the possible neurotoxic effects of THC (21). CBD itself has almost no effect on normal physiological processes. Only when a stimulus (such as pain or ashock reaction) or another cannabinoid (such as THC) upsets the normal “tone” of the endocannabinoid system is the effect of CBD expressed (12).
The amount of CBD administered, the ratio of CBD to THC and the timing of administration all seem to be important in determining the possible effects of CBD (22, 23). Most clinical studies on the effects of CBD are not relevant for generalizing to the effects of CBD in “recreational” cannabis users. In many of these studies, the doses that have been used are not relevant to the situation typically encountered by recreational cannabis users.
Clinical research has focused on the physical effects of cannabis use, such as pain relief, appetite promotion, and inflammation. For recreational cannabis users, the substance’s psychological effects
are the most important. In many experimental studies, the routes of administration used for both THC and CBD are not comparable to the routes of administration found in recreational cannabis use. The high dosages of CBD that have been used in experimental studies increase the concentration of CBD in the blood to levels that can never be reached by smoking a joint. The method that is most comparable to smoking is exposure through a vaporizer, but little research has been conducted involving the administration of cannabis, THC, or CBD via a vaporizer (24, 25). Therefore, it is unknown to what extent the effects of a single administration procedure can be extrapolated to recreational cannabis users given such differences in usage patterns.
TOXICOLOGY OF CBD
Research on the pharmacological and toxicological properties of CBD has been performed on different types of animals. In general, the metabolism of CBD indifferent species seems similar to that observed in humans, but some differences exist (26). It is possible that differences in metabolism and kinetics among different species have been responsible for some of the observed differences in pharmacological and toxicological effects.
Little research has focused on the safety and side effects of CBD in humans. However, several studies have described the effects of CBD for therapeutic applications in clinical trials. Only a few,generally mild side effects have been observed after administration of CBD in these human studies, though a wide range of effects over a wide dose range, including acute and chronic administration, have been examined. Few undesirable effects are reported, and tolerance for CBD does not seem to occur.
Based on an extensive literature review, Bergamaschi and colleagues concluded that CBD, to the extent that it has been studied, is a substance with low toxicity (27). Notably, however, the absence of harmful effects of CBD in humans has been described in research that was not primarily aimed at investigating these same side effects or toxicities of CBD. Because no specific research on these issues has been performed, it is currently impossible to draw conclusions about differences in toxicity between hashish and marijuana.
Chronic cannabis use is associated with psychiatric toxicity and cannabis has been implicated in the etiology of long-term psychiatric conditions (28). Several in vivo brain scanning techniques have been conducted to investigate whether chronic, heavy cannabis use leads to structural changes in the brain [forreviews, seeRef.(29, 30)]. The results oft hese studies have been relatively inconsistent. Ingeneral, no differences in total brain volume between cannabis users and non-users have been found. With respect to CB1 receptor concentrations in different parts of the brain, it can be expected that structural changes after chronic intensive cannabis use would most likely eventually be situated in the orbito frontal cortex (OCC), the anterior cingulate cortex (ACC), the striatum, the amygdala, and the hippocampus (31–33). In some structural magnetic resonance imaging (sMRI) studies, reductions in the volumes of the hippocampus, the amygdala, and the cerebellum have been found in adult heavy cannabis users when compared with healthy controls (21, 34, 35). Using a PET scan technique, Wilson and colleagues found age-dependent morphological changes in early-onset cannabis users. In subjects who started their cannabis use before the age of 17, it has been found that the ratio of cortical gray to white matter is smaller when compared with subjects who had started using cannabis after their 17th birthdays (36). Structural abnormalities due to chronic cannabis use have been most consistently identified in the hippocampus (21, 34, 35). Using a voxel-based morphometry (VBM) approach, Demirakca and colleagues studied gray matter (GM) concentrations and volumes of the hippocampus in 11 chronic recreational cannabis users and13 healthy controls and correlated their findings with THC and CBD measurements made from hair analyses. They found that cannabis users showed lower GM volume in the right anterior hippocampus. Higher THC and lower CBD were associated with this hippocampal volume reduction, suggesting neurotoxic effects of THC and neuroprotective effects of CBD.
The conflicting results among volumetric brain studies seem to result from differences in time span (e.g., age of onset), patterns of cannabisuse (e.g.,frequency, duration of use, cumulative lifetime use), and type of cannabis used (e.g., potency, CBD/THC ratio) (29, 30).