The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users, Valentina Lorenzetti et al., 2016

The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users

Valentina Lorenzetti, Nadia Solowij, and Murat Yücel

Biological Psychiatry, 2016, 79:e17-e31


The past few decades have seen a marked change in the composition of commonly smoked cannabis. These changes primarily involve an increase of the psychoactive compound Δ9-tetrahydrocannabinol (THC) and a decrease of the potentially therapeutic compound cannabidiol (CBD). This altered composition of cannabis may be linked to persistent neuroanatomic alterations typically seen in regular cannabis users. In this review, we summarize recent findings from human structural neuroimaging investigations. We examine whether neuroanatomic alterations are 1) consistently observed in samples of regular cannabis users, particularly in cannabinoid receptor–high areas, which are vulnerable to the effects of high circulating levels of THC, and 2) associated either with greater levels of cannabis use (e.g., higher dosage, longer duration, and earlier age of onset) or with distinct cannabinoid compounds (i.e., THC and CBD). Across the 31 studies selected for inclusion in this review, neuroanatomic alterations emerged across regions that are high in cannabinoid receptors (i.e., hippocampus, prefrontal cortex, amygdala, cerebellum). Greater dose and earlier age of onset were associated with these alterations. Preliminary evidence shows that THC exacerbates, whereas CBD protects from, such harmful effects. Methodologic differences in the quantification of levels of cannabis use prevent accurate assessment of cannabis exposure and direct comparison of findings across studies. Consequently, the field lacks large “consortium-style” data sets that can be used to develop reliable neurobiological models of cannabis-related harm, recovery, and protection. To move the field forward, we encourage a coordinated approach and suggest the urgent development of consensus-based guidelines to accurately and comprehensively quantify cannabis use and exposure in human studies.

Keywords : Cannabidiol, Cannabinoids, Cannabis, CBD, Hippocampus, Prefrontal, THC


Although cannabis has existed for thousands of years, the past few decades have seen a marked increase in the prevalence of highly potent cannabis strains (1). These strains have a high proportion of the psychoactive constituent Δ9- tetrahydrocannabinol (THC) (2), which exerts persistent adverse effects on cognition, mental health, and the brain (3,4). In parallel, there are decreasing levels of other constituent cannabis compounds, such as cannabidiol (CBD), which has been touted as a potential therapeutic agent for conditions ranging from chronic pain and seizures to psychiatric symptoms (5–7). These recent changes in the composition of “street” cannabis create a new and complex landscape for investigators endeavoring to understand the neurobiological harm and the therapeutic potential of cannabis products.

Specific cannabinoid compounds have distinct effects on mental health and brain function. The psychoactive and addictive properties of cannabis are primarily due to THC (8). Increased availability of cannabis varieties that are high in THC (e.g., “skunk”) have been consistently linked to accelerated onset of psychosis (9,10), increased cannabis-related hospital admissions (11), and increased anxiety symptoms and psychotic-like experiences (12–15). Preclinical studies showed that THC is neurotoxic to brain areas rich in cannabinoid type 1 receptors, including the hippocampus (16–20), amygdala (20), striatum (21), and prefrontal cortex (PFC) (21–23). In contrast, CBD has been found to have anxiolytic, antipsychotic, and therapeutic properties (24–27). There is evidence suggesting that CBD is neuroprotective, mitigating the neurotoxic effects of THC (28–30).

The compounds THC and CBD have also been shown to have opposing effects on the functional activity and connectivity between brain regions that are high in cannabinoid receptors, such as the hippocampus, amygdala, striatum, cerebellum, and PFC (12–14,31–36). These changes in brain function, documented using functional magnetic resonance imaging (MRI), may modulate the effects of THC on anxiety and psychotic-like experiences in humans (5,32,37). Similar processes may underpin the protective effects of CBD on such experiences (5,6,27,32,37). Participants pretreated with CBD do not experience the psychotogenic and anxiogenic effects of THC (12–14,32–37).

The recent changes in the relative composition of cannabinoids found within commonly available cannabis increase the potential for psychological and neurobiological harm in the current generation of cannabis users. However, the relative contribution of the two major compounds of cannabis (i.e.,THC and CBD) to such damage is unclear (37). In this review, we summarize the current literature on neuroanatomic alterations reported in regular cannabis users, which includes nine additional studies relative to the most recent review on the topic, reflecting an increased focus on this field of research and warranting a need to integrate the most recent findings (38–46). We present a novel focus on the emerging evidence for differential roles of specific cannabinoids in neuroanatomic abnormalities (41,43,47,48). First, we provide an overview of findings and stratify them according to brain regions. Second, we examine the link between neuroanatomic alterations and levels of cannabis use, with a specific focus on the cannabinoid compounds THC and CBD. Finally, we identify major limitations of current research, particularly in relation to the measurement of cannabis use and cannabinoid compounds. These methodologic inadequacies limit the ability to develop evidence-based models of the effects of cannabis on neuroanatomy, whereby specific patterns (and types) of cannabis use are associated with discrete alterations in defined neural circuits. We suggest that a coordinated approach is required to move the field forward, and we offer preliminary guidelines to develop a standardized protocol to measure levels of cannabis use.