Medicinal Cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway

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“Background: Post-traumatic stress disorder (PTSD) refers to a chronic impairing psychiatric disorder occurring after exposure to the severe traumatic event. Studies have demonstrated that medicinal cannabis oil plays an important role in neuroprotection, but the mechanism by which it exerts anti-PTSD effects remains unclear.

Methods: The chronic complex stress (CCS) simulating the conditions of long voyage stress for 4 weeks was used to establish the PTSD mice model. After that, behavioral tests were used to evaluate PTSD-like behaviors in mice. Mouse brain tissue index was detected and hematoxylin-eosin staining was used to assess pathological changes in the hippocampus. The indicators of cell apoptosis and the BDNF/TRPC6 signaling activation in the mice hippocampus were detected by western blotting or real-time quantitative reverse transcription PCR experiments.

Results: We established the PTSD mice model induced by CCS, which exhibited significant PTSD-like phenotypes, including increased anxiety-like and depression-like behaviors. Medicinal cannabis oil treatment significantly ameliorated PTSD-like behaviors and improved brain histomorphological abnormalities in CCS mice. Mechanistically, medicinal cannabis oil reduced CCS-induced cell apoptosis and enhanced the activation of BDNF/TRPC6 signaling pathway.

Conclusions: We constructed a PTSD model with CCS and medicinal cannabis oil that significantly improved anxiety-like and depressive-like behaviors in CCS mice, which may play an anti-PTSD role by stimulating the BDNF/TRPC6 signaling pathway.”

Cannabidiol improves maternal obesity-induced behavioral, neuroinflammatory and neurochemical dysfunctions in the juvenile offspring

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“Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established.

We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams.

Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus.

CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes.

Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.”

How depression and antidepressant drugs affect endocannabinoid system?-review of clinical and preclinical studies

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“As major depressive disorder is becoming a more and more common issue in modern society, it is crucial to discover new possible grip points for its diagnosis and antidepressive therapy.

One of them is endocannabinoid system, which has been proposed as a manager of emotional homeostasis, and thus, endocannabinoid alterations have been found in animals undergoing various preclinical models of depression procedures as well as in humans suffering from depressive-like disorders.

In this review article, studies regarding those alterations have been summed up and analyzed. Another important issue raised by the researchers is the impact of currently used antidepressive drugs on endocannabinoid system so that it would be possible to predict reversibility of endocannabinoid alterations following stress exposure and, in the future, to be able to design individually personalized therapies.

Preclinical studies investigating this topic have been analyzed and described in this article. Unfortunately, too few clinical studies in this field exist, what indicates an urgent need for collecting such data, so that it would be possible to compare them with preclinical outcomes and draw reliable conclusions.”

Effectiveness of Medical Cannabis for the Treatment of Depression: A Naturalistic Outpatient Study

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“Background: There is a lack of studies on the course and effectiveness of medical cannabis in the treatment of major depressive disorder (MDD).

Methods: Retrospective longitudinal (18 weeks) study of n=59 outpatients with MDD, treated with medical cannabis via a telemedical platform. Previous treatment with antidepressant medication was required for inclusion into the study. Standardized data collection was carried out at entry and during monthly consultations. Severity of depression was measured on a 0-10 point rating scale. Side-effects were assessed by a checklist.

Results: Patients were 20-54 years old; 72.9% were male; one third reported times of regular cannabis consumption within the previous five years. Drop-out rate was 22% after 18 weeks. Mean severity of depression decreased from 6.9 points (SD 1.5) at entry to 3.8 points (2.7) at week 18 (baseline observation carried forward; 95% CI for the mean difference: 2.4 to 3.8; p<0.001). A treatment response (>50% reduction of the initial score) was seen in 50.8% at week 18. One third of patients complained about side effects, none was considered as severe. Concomitant antidepressant medication (31% of patients) was not associated with outcome.

Conclusions: Medical cannabis was well tolerated and dropout rate was comparable to those in clinical trials of antidepressant medication. Patients reported a clinically significant reduction of depression severity. Further research on the effectiveness of medical cannabis for MDD seems warranted. Risks of this medication, such as sustaining or inducing a cannabis use disorder, or side effects such as poor concentration, must be taken into consideration.”

The psychedelic effects of cannabis: A review of the literature

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“Cannabis and classic psychedelics are controlled substances with emerging evidence of efficacy in the treatment of a variety of psychiatric illnesses. Cannabis has largely not been regarded as having psychedelic effects in contemporary literature, despite many examples of historical use along with classic psychedelics to attain altered states of consciousness.

Research into the “psychedelic” effects of cannabis, and delta-9-tetrahydrocannabinol (THC) in particular, could prove helpful for assessing potential therapeutic indications and elucidating the mechanism of action of both cannabis and classic psychedelics.

This review aggregates and evaluates the literature assessing the capacity of cannabis to yield the perceptual changes, aversiveness, and mystical experiences more typically associated with classic psychedelics such as psilocybin. This review also provides a brief contrast of neuroimaging findings associated with the acute effects of cannabis and psychedelics.

The available evidence suggests that high-THC cannabis may be able to elicit psychedelic effects, but that these effects may not have been observed in recent controlled research studies due to the doses, set, and settings commonly used. Research is needed to investigate the effects of high doses of THC in the context utilized in therapeutic studies of psychedelics aimed to occasion psychedelic and/or therapeutic experiences.

If cannabis can reliably generate psychedelic experiences under these conditions, high-THC dose cannabis treatments should be explored as potential adjunctive treatments for psychiatric disorders and be considered as an active comparator in clinical trials involving traditional psychedelic medications.”

“Psychedelic drugs in the treatment of psychiatric disorders”

Under the umbrella of depression and Alzheimer’s disease physiopathology: can cannabinoids be a dual-pleiotropic therapy?

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“Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60% to 80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises.

Herein, we discuss the current state-of-art regarding the contribution of the endocannabinoid system (ECS) in synaptic transmission processes, synapses plasticity and neurogenesis and consequently the use of exogenous cannabinoids in the treatment of depression and on delaying the progression of AD. Besides the well-known imbalance of neurotransmitter levels, including serotonin, noradrenaline, dopamine and glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation of neurotrophic factor levels and formation of amyloid beta (Aβ) peptides, as the main physiopathological mechanisms compromised in depression and AD. The contribution of the ECS in these mechanisms is herein specified as well as the pleiotropic effects of phytocannabinoids.

At the end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin and Cannabichromene may act in novel therapeutic targets, presenting high potential in the pharmacotherapy of both diseases.”

“Endocannabinoid system is dysregulated in depression and AD.

Cannabinoids have potential to modulate the physiopathological mechanisms common in both diseases.”

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).”