The effects of cannabinoids on the endocrine system.

“Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil.

These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells.

Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads.

Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.”

Cannabinoids-induced peripheral analgesia depends on activation of BK channels.

 Brain Research“The endogenous cannabinoid system is involved in the physiological inhibitory control of pain and is of particular interest for the development of therapeutic approaches for pain management.

Selective activation of the peripheral CB1 cannabinoid receptor has been shown to suppress the heightened firing of primary afferents, which is the peripheral mechanism underlying neuropathic pain after nerve injury. However, the mechanism underlying this effect of CB1 receptor remains unclear.

The large-conductance calcium-activated potassium (BK) channels have been reported to participate in anticonvulsant and vasorelaxant effects of cannabinoids. We asked whether BK channels participate in cannabinoids-induced analgesia and firing-suppressing effects in primary afferents after nerve injury.

Here, using mice with chronic constriction injury(CCI)-induced neuropathic pain, antinociception action and firing-suppressing effect of HU210 were measured before and after BK channel blocker application. We found that local peripheral application of HU210 alleviated CCI-induced pain behavior and suppressed the heightened firing of injured fibers. Co-administration of IBTX with HU210 significantly reversed the analgesia and the firing-suppressing effect of HU210.

This result indicated that the peripheral analgesic effects of cannabinoids depends on activation of BK channels.”

https://www.ncbi.nlm.nih.gov/pubmed/30615887

https://www.sciencedirect.com/science/article/pii/S0006899319300071?via%3Dihub

Practical Perspectives in the Treatment of Nausea and Vomiting.

Image result for J Clin Gastroenterol.

“Nausea and vomiting result from complex interactions between afferent and efferent pathways of the gastrointestinal tract, central nervous system, and autonomic nervous system. Afferent pathways from the vagus nerve, vestibular system, and chemoreceptor trigger zone project to nucleus tractus solitarius, which in turn relays signals to the central pattern generator to initiate multiple downstream pathways resulting in symptoms of nausea and vomiting. There is increasing evidence that the central pathway of chronic nausea is different from that of acute nausea and vomiting-and closely resembles that of neuropathic pain. This improved understanding of chronic nausea has resulted in a paradigm shift with regard to management strategy. Although conventional therapies such as antiemetics and prokinetics are commonly used to manage acute nausea and vomiting, they are historically not as effective in treating chronic nausea. Recently, neuromodulator agents, such as tricyclic antidepressants, gabapentin, olanzapine, mirtazapine, and benzodiazepines, and cannabinoids have been shown to be efficacious in the treatment of nausea and vomiting, and may be useful in the treatment of chronic symptoms. There is a need to study these agents, especially in the management of chronic functional nausea. Improved understanding of the central and peripheral circuitry of nausea and vomiting symptoms will allow for enhanced utilization of the currently available medications, and the development of novel therapeutic options.”

https://www.ncbi.nlm.nih.gov/pubmed/30614944

https://insights.ovid.com/crossref?an=00004836-900000000-97784

Progress in Brain Cannabinoid CB2 Receptor Research: From Genes to Behavior.

Neuroscience & Biobehavioral Reviews

“The type 2 cannabinoid receptor (CB2R) was initially regarded as a peripheral cannabinoid receptor. However, recent technological advances in gene detection, alongside the availability of transgenic mouse lines, indicate that CB2Rs are expressed in both neurons and glial cells in the brain under physiological and pathological conditions, and are involved in multiple functions at cellular and behavioral levels. Brain CB2Rs are inducible and neuroprotective via up-regulation in response to various insults, but display species differences in gene and receptor structures, CB2R expression, and receptor responses to various CB2R ligands. CB2R transcripts also differ between the brain and spleen. In the brain, CB2A is the major transcript isoform, while CB2A and CB2B transcripts are present at higher levels in the spleen. These new findings regarding brain versus spleen CB2R isoforms may in part explain why early studies failed to detect brain CB2R gene expression. Here, we review evidence supporting the expression and function of brain CB2R from gene and receptor levels to cellular functioning, neural circuitry, and animal behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30611802

https://www.sciencedirect.com/science/article/pii/S0149763418308297?via%3Dihub

Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ9-Tetrahydrocannabinol-Induced Cognitive Impairment

“At present, clinical interest in the plant-derived cannabinoid compound cannabidiol (CBD) is rising exponentially, since it displays multiple therapeutic properties. In addition, CBD can counteract the undesirable effects of the psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) that hinder clinical development of cannabis-based therapies. Here, by combining in vivo and complementary molecular techniques, we demonstrate for the first time that CBD blunts the Δ9-THC-induced cognitive impairment in an adenosine A2A receptor (A2AR)-dependent manner. Overall, these data provide new evidence regarding the mechanisms of action of CBD and the nature of A2AR-CB1R interactions in the brain.”

Cannabinoid Receptor Type 1 Agonist ACEA Improves Cognitive Deficit on STZ-Induced Neurotoxicity Through Apoptosis Pathway and NO Modulation.

“The cannabinoid system has the ability to modulate cellular and molecular mechanisms, including excitotoxicity, oxidative stress, apoptosis, and inflammation, acting as a neuroprotective agent, by its relationship with signaling pathways associated to the control of cell proliferation, differentiation, and survival. Recent reports have raised new perspectives on the possible role of cannabinoid system in neurodegenerative diseases like Alzheimer disease’s (AD).

Our study has demonstrated a participation of the cannabinoid system in cellular survival, involving the CB1 receptor, which occurs by positive regulation of the anti-apoptotic proteins, suggesting the participation of this system in neurodegenerative processes. Our data suggest that the cannabinoid system is an interesting therapeutic target for the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/30607903

https://link.springer.com/article/10.1007%2Fs12640-018-9991-2

Cannabidiol.

Chemical structure

“Cannabidiol has not been studied in nursing women taking the pharmaceutical product.

Cannabidiol has been detected in the breastmilk of some mothers who used cannabis products recreationally.

If cannabidiol is required by the mother, it is not a reason to discontinue breastfeeding.

However, since no information is available on the use of cannabidiol during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.”

Cannabinoid-mediated retinal rescue correlates with improved circadian parameters in retinal dystrophic rats.

 Experimental Eye Research“Ocular pathologies and blindness have been linked to circadian disorders. In previous studies, our group has demonstrated that retinitis pigmentosa is associated with degenerative changes in the melanopsin system and weaker circadian patterns.

We have also shown that cannabinoids preserve retinal structure and function in dystrophic P23H rats.

This study is consequently aimed at examining whether the morphologic and functional rescue of retinal degeneration by cannabinoids is associated with amelioration of circadian parameters.

The synthetic cannabinoid HU210 (100 μg/kg, i.p.) or vehicle were administered to transgenic P23H rats three times per week, from postnatal day 24-90. Sprague-Dawley rats were used as a healthy control group. Locomotor activity and scotopic electroretinograms were recorded, and the retinal structure was analyzed at the end of the experiment. The ERG a- and b-wave amplitudes and photoreceptor cell number were more deteriorated in vehicle-administered P23H rats as compared to P23H rats treated with HU210. In cannabinoid-administered P23H rats, the locomotor activity circadian rhythms showed less disturbance than that observed in vehicle-administered P23H rats, the latter showing lower values for mesor, amplitude, acrophase, percentage of variance and non-parametric variables. A positive linear correlation was found between retinal values and circadian parameters of locomotor activity from P23H rats.

This study thus provides evidence of a positive correlation between cannabinoid-mediated rescue of retinal structure and function and improvement of circadian rhythmicity.”

https://www.ncbi.nlm.nih.gov/pubmed/30605663

https://www.sciencedirect.com/science/article/pii/S0014483518306511?via%3Dihub

Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies.

“Aversive learning and memory are essential to cope with dangerous and stressful stimuli present in an ever-changing environment. When this process is dysfunctional, however, it is associated with posttraumatic stress disorder (PTSD). The endocannabinoid (eCB) system has been implicated in synaptic plasticity associated with physiological and pathological aversive learning and memory.

OBJECTIVE AND METHODS:

The objective of this study was to review and discuss evidence on how and where in the brain genetic or pharmacological interventions targeting the eCB system would attenuate aversive/traumatic memories through extinction facilitation in laboratory animals and humans. The effect size of the experimental intervention under investigation was also calculated.

RESULTS:

Currently available data indicate that direct or indirect activation of cannabinoid type-1 (CB1) receptor facilitates the extinction of aversive/traumatic memories. Activating CB1 receptors around the formation of aversive/traumatic memories or their reminders can potentiate their subsequent extinction. In most cases, the effect size has been large (Cohen’s d ≥ 1.0). The brain areas responsible for the above mentioned effects include the medial prefrontal cortex, amygdala, and/or hippocampus. The potential role of cannabinoid type-2 (CB2) receptors in extinction learning is now under investigation.

CONCLUSION:

Drugs augmenting the brain eCB activity can temper the impact of aversive/traumatic experiences by diverse mechanisms depending on the moment of their administration. Considering the pivotal role the extinction process plays in PTSD, the therapeutic potential of these drugs is evident. The sparse number of clinical trials testing these compounds in stress-related disorders is a gap in the literature that needs to be addressed.”

https://www.ncbi.nlm.nih.gov/pubmed/30604182

https://link.springer.com/article/10.1007%2Fs00213-018-5127-x

The Anti-Inflammatory Properties of Terpenoids from Cannabis.

View details for Cannabis and Cannabinoid Research cover image

“Cannabinoids are well known to have anti-inflammatory effects in mammalians; however, the Cannabis plant also contains other compounds such as terpenoids, whose biological effects have not yet been characterized. The aim of this study was to compare the anti-inflammatory properties of terpenoids with those of cannabidiol (CBD).

Materials and Methods: Essential oils prepared from three monoecious nonpsychoactive chemotypes of Cannabis were analyzed for their terpenoid content and subsequently studied pharmacologically for their anti-inflammatory properties in vitro and in vivo.

Results: In vitro, the three essential oils rich in terpenoids partly inhibited reactive oxygen intermediate and nitric oxide radical (NO) production in RAW 264.7 stimulated macrophages. The three terpenoid-rich oils exerted moderate anti-inflammatory activities in an in vivo anti-inflammatory model without affecting tumor necrosis factor alpha (TNFα) serum levels.

Conclusions: The different Cannabis chemotypes showed distinct compositions of terpenoids. The terpenoid-rich essential oils exert anti-inflammatory and antinociceptive activities in vitro and in vivo, which vary according to their composition. Their effects seem to act independent of TNFα. None of the essential oils was as effective as purified CBD. In contrast to CBD that exerts prolonged immunosuppression and might be used in chronic inflammation, the terpenoids showed only a transient immunosuppression and might thus be used to relieve acute inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30596146

https://www.liebertpub.com/doi/10.1089/can.2018.0014