Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders, Alline C. Campos et al.,

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

Alline C. Campos, Manoela V. Fogaça, Franciele F. Scarante, Sâmia R. L. Joca, Amanda J. Sales, Felipe V. Gomes, Andreza B. Sonego, Naielly S. Rodrigues, Ismael Galve-Roperh, and Francisco S. Guimarães

Frontiers in Pharmacology, 2017.

doi: 10.3389/fphar.2017.00269


Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD
treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here.

Keywords : cannabinoids, anxiety, depression, schizophrenia, neurogenesis, synaptic remodeling, autophagy



Plasticity relates to the particular characteristic of a material that undergoes deformation under a
load (Lubliner, 2005). In neuroscience, the term neuroplasticity applies to the capacity of the brain
to adapt and change in response to experience (Fuchs and Flugge, 2014). William James was the
first to propose this term in 1890, defending the idea that brain functions are not fixed during life
(James, 1890). Several neuroscientists denied this concept for decades. Santiago Ramón y Cajal,
however, used the term neuroplasticity to describe changes in the brain that were a consequence
of, or related to, pathology. He also suggested that small protrusions in the dendrites of neurons
stained with Golgi’s method, which he later named as dendritic spines, are involved in synaptic
connectivity and function (Stahnisch and Nitsch, 2002).

Nowadays, the idea that brain continually changes along our lifetime is well accepted. Notably, the concept of neuroplasticity has expanded to include not only changes at a morphological level but also biochemical and pharmacological adaptations (intracellular pathways, receptors, synaptic proteins), alterations in neuronal networks (changes in connectivity, dendritic remodeling, and number andmorphology of dendritic spines), as well as the generation of new neurons (i.e., adult neurogenesis) (Fuchs and Flugge, 2014). These neuroplastic modifications, moreover, can be either adaptive or maladaptive. Therefore, the mechanisms responsible for these changes may be a great window of opportunity for understanding the pathophysiology and treatment of mental illness (Kays et al., 2012).

Neuroplasticity and Psychotropic Drugs

Psychiatric disorders may result from significant neuroplastic changes that lead to new set points of brain functions (Pallanti, 2016). For instance, several neuropsychiatric conditions have been associated with stress-induced changes in dendritic remodeling and decreased adult hippocampal neurogenesis
(Bessa et al., 2009; Campos et al., 2013b). Corroborating this proposal, decreased hippocampal volume and reduced proliferative activity of neurogenic niches have been described in mood disorders, posttraumatic stress disorder (PTSD) and schizophrenia (Reif et al., 2006; Dhikav and Anand, 2007;
Lucassen et al., 2010).

The therapeutic effects of several psychotropic drugs usually need 2–6 weeks to be clinically recognized. It suggests that time-dependent structural reorganization of neuronal circuits and biochemical synaptic changes are required for the pharmacological action of these drugs (Konradi and Heckers, 2001; Fogaça et al., 2013).

Antidepressants are probably the most studied class of medication associated with plastic brain changes. For example, chronic, but not acute, treatment with antidepressants such as serotonin selective uptake inhibitors (SSRIs) and tricyclics increases the expression of Brain-derived Neurotrophic Factor (BDNF) in the hippocampus and prefrontal cortex (PFC) (Castren et al., 2007). Repeated antidepressant treatment also prevents stress-induced hippocampal dendritic atrophy (Bessa et al., 2009) and facilitates adult hippocampal neurogenesis in rodents (Malberg et al., 2000; Santarelli et al., 2003).

In addition to standard antidepressant drugs, the rapid and sustained antidepressant effects induced by ketamine also seem to depend on neuroplastic events (Duman et al., 2016). Ketamine appears to act in the PFC and hippocampus modifying the number of dendritic spines and BDNF expression by facilitating mTOR (mechanistic Target of Rapamycin) intracellular pathway (Duman et al., 2016).

Neuroplastic changes have also been associated with the effects of antipsychotic drugs. Haloperidol modifies the number/shape of dendritic spines and synaptic strength and increases expression of synaptic proteins (Eastwood et al., 1997; Harris, 1999; Matus, 1999; Nakahara et al., 1999). Regarding adult hippocampal neurogenesis, the results are contradictory. Whereas Malberg et al. (2000) found no changes in haloperidol-treated adult rats, in gerbils haloperidol seems to facilitate neurogenesis (Dawirs et al., 1998). In the case of atypical antipsychotic drugs, clozapine induces proliferation in the subgranular zone of the rodent dentate gyrus 24-h after the treatment (Halim et al., 2004) and prevents the phencyclidine-induced decrease in hippocampal neurogenesis (Maeda et al., 2007).