Unveiling behavioral and molecular neuroadaptations related to the antidepressant action of cannabidiol in the unpredictable chronic mild stress model

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“Introduction: This study aims to further characterize cannabidiol’s pharmacological and molecular profile as an antidepressant. 

Methods: Effects of cannabidiol (CBD), alone or combined with sertraline (STR), were evaluated in male CD1 mice (n = 48) exposed to an unpredictable chronic mild stress (UCMS) procedure. Once the model was established (4 weeks), mice received CBD (20 mg·kg-1, i.p.), STR (10 mg·kg-1, p.o.) or its combination for 28 days. The efficacy of CBD was evaluated using the light-dark box (LDB), elevated plus maze (EPM), tail suspension (TS), sucrose consumption (SC) and novel object recognition (NOR) tests. Gene expression changes in the serotonin transporter, 5-HT1A and 5-HT2A receptors, BDNF, VGlut1 and PPARdelta, were evaluated in the dorsal raphe, hippocampus (Hipp) and amygdala by real-time PCR. Besides, BDNF, NeuN and caspase-3 immunoreactivity were assessed in the Hipp. 

Results: CBD exerted anxiolytic and antidepressant-like effects at 4 and 7 days of treatment in the LDB and TS tests, respectively. In contrast, STR required 14 days of treatment to show efficacy. CBD improved cognitive impairment and anhedonia more significantly than STR. CBD plus STR showed a similar effect than CBD in the LBD, TST and EPM. However, a worse outcome was observed in the NOR and SI tests. CBD modulates all molecular disturbances induced by UCMS, whereas STR and the combination could not restore 5-HT1A, BDNF and PPARdelta in the Hipp. 

Discussion: These results pointed out CBD as a potential new antidepressant with faster action and efficiency than STR. Particular attention should be given to the combination of CBD with current SSRI since it appears to produce a negative impact on treatment.”



Δ8-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis


“Alzheimer’s disease (AD) represents the most common form of dementia, characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). It is characterized by neuroinflammation, the accumulation of misfolded protein, ER stress and neuronal apoptosis. It is of main importance to find new therapeutic strategies because AD prevalence is increasing worldwide.

Cannabinoids are arising as promising neuroprotective phytocompounds. In this study, we evaluated the neuroprotective potential of Δ8-THC pretreatment in an in vitro model of AD through transcriptomic analysis.

We found that Δ8-THC pretreatment restored the loss of cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells treated with Aβ1-42. Moreover, the transcriptomic analysis provided evidence that the enriched biological processes of gene ontology were related to ER functions and proteostasis. In particular, Aβ1-42 upregulated genes involved in ER stress and unfolded protein response, leading to apoptosis as demonstrated by the increase in Bax and the decrease in Bcl-2 both at gene and protein expression levels. Moreover, genes involved in protein folding and degradation were also deregulated. On the contrary, Δ8-THC pretreatment reduced ER stress and, as a consequence, neuronal apoptosis.

Then, the results demonstrated that Δ8-THC might represent a new neuroprotective agent in AD.”


“The results suggested that Δ8-THC may represent a novel neuroprotective agent in AD but also in other neurodegenerative diseases characterized by the accumulation of misfolded proteins.”


Cannabidiol Modulates Alterations in PFC microRNAs in a Rat Model of Depression


“Cannabidiol (CBD) is a potential antidepressant agent.

We examined the association between the antidepressant effects of CBD and alterations in brain microRNAs in the unpredictable chronic mild stress (UCMS) model for depression. UCMS male rats were injected with vehicle or CBD (10 mg/kg) and tested for immobility time in the forced swim test. Alterations in miRNAs (miR16, miR124, miR135a) and genes that encode for the 5HT1a receptor, the serotonergic transporter SERT, β-catenin, and CB1 were examined. UCMS increased immobility time in a forced swim test (i.e., depressive-like behavior) and altered the expression of miRNAs and mRNA in the ventromedial prefrontal cortex (vmPFC), raphe nucleus, and nucleus accumbens.

Importantly, CBD restored UCMS-induced upregulation in miR-16 and miR-135 in the vmPFC as well as the increase in immobility time. CBD also restored the UCMS-induced decrease in htr1a, the gene that encodes for the serotonergic 5HT1a receptor; using a pharmacological approach, we found that the 5HT1a receptor antagonist WAY100135 blocked the antidepressant-like effect of CBD on immobility time.

Our findings suggest that the antidepressant effects of CBD in a rat model for depression are associated with alterations in miR-16 and miR-135 in the vmPFC and are mediated by the 5HT1a receptor.”


“We show for the first time that CBD can prevent UCMS-induced increases in vmPFC miR-16 and miR-135. The antidepressant effects of CBD in rats exposed to the UCMS model for depression were mediated by the 5HT1a receptor.CBD seems to have positive effects of diminishing depressive-like behaviors with the advantage of not being addictive or having many side effects.”


Assessment of clinical outcomes of medicinal cannabis therapy for depression: Analysis from the UK Medical Cannabis Registry

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“Background: Although pre-clinical experiments associate cannabinoids with reduced depressive symptoms, there is a paucity of clinical evidence. This study aimed to analyze the health-related quality of life changes and safety outcomes in patients prescribed cannabis-based medicinal products (CBMPs) for depression.

Methods: An uncontrolled case series of the UK Medical Cannabis Registry was analyzed. Primary outcomes were changes from baseline in the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Sleep Quality Scale (SQS), and EQ-5D-5L at 1, 3, and 6 months. Secondary outcomes included adverse events incidence.

Results: 129 patients were identified for inclusion. Median PHQ-9 at baseline was 16.0 (IQR: 9.0-21.0). There were reductions in PHQ-9 at 1-month (median: 8.0; IQR: 4.0-14.0; p<0.001), 3-months (7.0; 2.3-12.8; p<0.001), and 6-months (7.0; 2.0-9.5; p<0.001). Improvements were also observed in GAD-7, SQS, and EQ-5D-5L Index Value at 1, 3, and 6 months (p<0.050). 153 (118.6%) adverse events were recorded by 14.0% (n=18) of participants, 87% (n=133) of which were mild or moderate.

Conclusion: CBMP treatment was associated with reductions in depression severity at 1, 3, and 6 months. Limitations of the study design mean that a causal relationship cannot be proven. This analysis provides insights for further study within clinical trial settings.”


“This study reports that treatment with CBMPs was associated with improvements in PHQ-9 (p<0.050) after 1, 3, and 6 months in a case series of patients with a primary diagnosis of depression on the UKMCR. This suggests that CBMPs could have antidepressant effects, although the limitations of the study design mean that a causal relationship cannot be proven. CBMP use was also associated with improvements in anxiety, sleep quality, and overall HRQoL (p<0.050).”


A Novel Anti-Inflammatory Formulation Comprising Celecoxib and Cannabidiol Exerts Antidepressant and Anxiolytic Effects

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“Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib’s usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. 

Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. 

Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. 

Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.”



Regulation of DNA Methylation by Cannabidiol and Its Implications for Psychiatry: New Insights from In Vivo and In Silico Models


“Cannabidiol (CBD) is a non-psychotomimetic compound present in cannabis sativa. Many recent studies have indicated that CBD has a promising therapeutic profile for stress-related psychiatric disorders, such as anxiety, schizophrenia and depression. Such a diverse profile has been associated with its complex pharmacology, since CBD can target different neurotransmitter receptors, enzymes, transporters and ion channels. However, the precise contribution of each of those mechanisms for CBD effects is still not yet completely understood. Considering that epigenetic changes make the bridge between gene expression and environment interactions, we review and discuss herein how CBD affects one of the main epigenetic mechanisms associated with the development of stress-related psychiatric disorders: DNA methylation (DNAm). Evidence from in vivo and in silico studies indicate that CBD can regulate the activity of the enzymes responsible for DNAm, due to directly binding to the enzymes and/or by indirectly regulating their activities as a consequence of neurotransmitter-mediated signaling. The implications of this new potential pharmacological target for CBD are discussed in light of its therapeutic and neurodevelopmental effects.”



Hippocampal CB1 Receptor mediates antidepressant-like effect of Synthetic Cannabinoid-HU210 in Acute Despair Reaction model in mice

Neuroscience Letters

“Growing evidence suggests that stress may contribute to the pathophysiology of depression. The alleviation of depressive symptoms is one of the most attractive medical applications of cannabis. Here, we investigated the antidepressant-like actions of synthetic cannabinoid-HU210 in acute despair response and explored the possible underlying mechanisms. Acute stress, induced by forced-swimming, induced depression-like behavior in the sucrose preference test (SPT). HU-210 (50 μg/kg) displayed anti-depressant like effect in the forced swim test in naïve mice and decreased depression-like behavior in the SPT, induced by forced swim stress. Pretreatment with AM251, an inhibitor of CB1R or inhibition of long-term depression (LTD) at hippocampal CA3-CA1 synapses by Tat-GluR2 attenuated the antidepressant like action of HU-210. These results indicate that HU210 produces antidepressant-like effects in acute stress and its underlying mechanism may be related to CB1R activation and hence hippocampal LTD production invivo. Synthetic cannabis or cannabis-related drugs may be used as an early intervention after acute stress exposure to prevent or at least reduce depression-like behaviors.”



Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice

Biomedicine & Pharmacotherapy

“Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety.

Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM.

Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration.

Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration.

Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine.

In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.”


“In the present study, it was possible to observe that, regardless of the route of administration, broad-spectrum cannabis oil proved to be effective in reversing the mechanical hyperalgesia effects of the reserpine-induced fibromyalgia model. Furthermore, chronic treatment with broad-spectrum cannabis oil showed analgesic effects on mechanical hyperalgesia and heat allodynia and mitigated reserpine-induced passive stress-coping behavior and lower-self-care behavior in mice. Conjointly, our results point to broad-spectrum cannabis oil as a therapeutic alternative for the disorders caused by FM.”


Dose-Dependent Antidepressant-Like Effects of Cannabidiol in Aged Rats

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“Aging predisposes to late-life depression and since antidepressants are known to change their efficacy with age, novel treatment options are needed for our increased aged population. In this context, the goal of the present study was to evaluate the potential antidepressant-like effect of cannabidiol in aged rats.

For this purpose, 19-21-month-old Sprague-Dawley rats were treated for 7 days with cannabidiol (dose range: 3-30 mg/kg) and scored under the stress of the forced-swim test. Hippocampal cannabinoid receptors and cell proliferation were evaluated as potential molecular markers underlying cannabidiol’s actions.

The main results of the present study demonstrated that cannabidiol exerted a dose-dependent antidepressant-like effect in aged rats (U-shaped, effective at the intermediate dose of 10 mg/kg as compared to the other doses tested), without affecting body weight. None of the molecular markers analyzed in the hippocampus were altered by cannabidiol’s treatment.

Overall, this study demonstrated a dose-dependent antidepressant-like response for cannabidiol at this age-window (aged rats up to 21 months old) and in line with other studies suggesting a beneficial role for this drug in age-related behavioral deficits.”


“In conclusion, this study increased the age-window at which cannabidiol exerted dose-dependent responses in this behavioral test, to include aged rats (up to 21 months old), at which it could be considered as a potential antidepressant, and in line with other studies suggesting a beneficial role for this drug in age-related behavioral deficits.”


Tetrahydrocannabinol and cannabidiol medicines for chronic pain and mental health conditions


“Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells.

The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain.

THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.”


“Tetrahydrocannabinol (THC) and cannabidiol (CBD) combination medicines and CBD-only medicines are prospective new treatments for chronic pain, stress, anxiety, depression, and insomnia, which are all medical conditions in need of better therapeutics. Both THC/CBD combination and CBD-only medicines could provide effective new treatment options for pain and mental health, respectively, and both have good safety and tolerability profiles relative to the current treatments.

THC and CBD combination medicines have a good safety and tolerability profile that is appropriate for opioid stage (stage 2–3) treatment of chronic pain. Low-dose CBD could be used as an initial treatment for chronic pain and for stress, anxiety, depression, and insomnia. High quality efficacy evidence is best for THC/CBD combination medicines for chronic pain and CBD-only medicines for stress and anxiety. “