Healing autism spectrum disorder with cannabinoids: a neuroinflammatory story

 Neuroscience & Biobehavioral Reviews“Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a multifactorial etiology. Latest researches are raising the hypothesis of a link between the onset of the main behavioral symptoms of ASD and the chronic neuroinflammatory condition of the autistic brain; increasing evidence of this connection is shedding light on new possible players in the pathogenesis of ASD.

The endocannabinoid system (ECS) has a key role in neurodevelopment as well as in normal inflammatory responses and it is not surprising that many preclinical and clinical studies account for alterations of the endocannabinoid signaling in ASD. These findings lay the foundation for a better understanding of the neurochemical mechanisms underlying ASD and for new therapeutic attempts aimed at exploiting the renowned anti-inflammatory properties of cannabinoids to treat pathologies encompassed in the autistic spectrum.

This review discusses the current preclinical and clinical evidence supporting a key role of the ECS in the neuroinflammatory state that characterizes ASD, providing hints to identify new biomarkers in ASD and promising therapies for the future.”

https://pubmed.ncbi.nlm.nih.gov/33358985/

“Autism spectrum disorder has a multifactorial and complex etiology. Changes in the endocannabinoid system are found in autistic patients. Neuroinflammation is detected in autistic patients. The endocannabinoid system has a key role in neuroinflammation. Future therapies exploiting cannabinoid drugs.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763420306850?via%3Dihub

Role of marijuana components on the regenerative ability of stem cells

“Stem cell therapy promotes tissue regeneration and wound healing. Efforts have been made to prime stem cells to enhance their regenerative abilities.

Certain marijuana components, namely the non-psychoactive cannabidiol (CBD) and psychoactive tetrahydrocannabinol (THC), are defined as immunomodulators.9 We test whether two sources of stem cells, primed with CBD or THC, would demonstrate improved regenerative abilities.

Human adipose-derived stem cells (ASCs) and bone marrow-derived stem cells (BMDSCs), not obtained from the same individual, were treated with low (300 nM) or high (3 μM) concentration CBD. Porcine ASCs and BMDSCs were isolated from a single pig, and treated with either low or high concentrations of CBD or THC. Transwell migration and MTT proliferation assays were performed on the human ASCs and BMDSCs. Also, transwell migration assay was performed on the porcine ASCs and BMDSCs. Finally, a wound healing scratch assay in porcine primary fibroblasts (PFs) was performed, co-cultured with the cannabinoid-treated ASCs.

CBD priming at low concentration induces migration by 180% (P < .01) in porcine ASCs, and by only 93% (P < .02) in porcine BMDSCs. In porcine stem cells, THC priming at low concentration induces migration by 91.6% (P < .01) in ASCs but by only 44.3% (P < .03) in BMDSCs. Compared to PFs co-cultured with untreated ASCs, PFs co-cultured with low CBD-primed ASCs had 75% faster wound closure at 18 hours (P < .01).

CBD and THC priming of ASCs and BMDSCs, particularly at lower doses, enhances a number of regenerative parameters, suggesting that these major marijuana components may improve stem cell-based therapies.

SIGNIFICANCE OF THE STUDY: Our study demonstrates that cannabinoids can enhance the regenerative capacity of two major sources of stem cells, adipose- and bone marrow-derived, from human and porcine donors. Stem cell isolation and expansion is invasive, costly and time consuming. Stem cells with improved regenerative properties may be effective in the treatment of acute or chronic wounds. This is the first study to compare the priming potential of two sources of stem cells from the same animal, with the same genetic and epigenetic profile, as well as the first to prime with THC.”

https://pubmed.ncbi.nlm.nih.gov/33349985/

https://onlinelibrary.wiley.com/doi/10.1002/cbf.3609

Effects of standardized Cannabis sativa extract and ionizing radiation in melanoma cells in vitro

Journal of Cancer Research and Therapeutics “Melanoma causes the highest number of skin cancer-related deaths worldwide. New treatment methods are essential for the management of this life-threatening disease.

Aims: In this study, we investigated the efficacy of a standardized Cannabis sativa extract alone or in combination with single radiation dose (6 Gy) in B16F10 mouse melanoma cells in an extract dose-dependent manner.

Results: Administration of the extract alone or alongside radiation substantially inhibited melanoma cell viability and proliferation in the extract dose response-dependent manner. The inhibition of melanoma cell viability was paralleled by an increase in necrosis but not apoptosis when melanoma cells were treated with the extract alone. Radiation alone did not have any antiproliferative effects, and radiation also did not synergize antiproliferative effects of the extract when the extract and radiation were combined.

Conclusion: Our data suggest that C. sativa extract may have significant health and physiological implications for the treatment of melanoma. The results of this study also indicate that B16F10 mouse melanoma cells are radioresistant. Taken together, these findings may lead to the identification of new therapeutic strategy for the management of melanoma.”

https://pubmed.ncbi.nlm.nih.gov/33342819/

“This study provides the first evidence of antitumor effects of C. sativa extract, when administered alone or in combination with radiation, to mouse melanoma cells in vitro. Our results may verify the value of C. sativa extract for the treatment of melanoma and may complement the therapeutic profile of C. sativa extracts administration in the future.”

https://www.cancerjournal.net/article.asp?issn=0973-1482;year=2020;volume=16;issue=6;spage=1495;epage=1499;aulast=Naderi

Cannabinoid control of neurogenic inflammation

 British Journal of Pharmacology“A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.”

https://pubmed.ncbi.nlm.nih.gov/33289534/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15208

Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches

International Journal of Biological Macromolecules“Effective treatment choices to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited because of the absence of effective target-based therapeutics. The main object of the current research was to estimate the antiviral activity of cannabinoids (CBDs) against the human coronavirus SARS-CoV-2.

In the presented research work, we performed in silico and in vitro experiments to aid the sighting of lead CBDs for treating the viral infections of SARS-CoV-2. Virtual screening was carried out for interactions between 32 CBDs and the SARS-CoV-2 Mpro enzyme. Afterward, in vitro antiviral activity was carried out of five CBDs molecules against SARS-CoV-2.

Interestingly, among them, two CBDs molecules namely Δ (Yu et al., 2020 [9])-tetrahydrocannabinol (IC50 = 10.25 μM) and cannabidiol (IC50 = 7.91 μM) were observed to be more potent antiviral molecules against SARS-CoV-2 compared to the reference drugs lopinavir, chloroquine, and remdesivir (IC50 ranges of 8.16-13.15 μM). These molecules were found to have stable conformations with the active binding pocket of the SARS-CoV-2 Mpro by molecular dynamic simulation and density functional theory.

Our findings suggest cannabidiol and Δ (Yu et al., 2020 [9])-tetrahydrocannabinol are possible drugs against human coronavirus that might be used in combination or with other drug molecules to treat COVID-19 patients.”

https://pubmed.ncbi.nlm.nih.gov/33290767/

“In summary, this report demonstrates the antiviral potencies of CBD and Δ9-THC against SARS-CoV-2. Based on privileged safety index CBD and Δ9-THC in human and their current in vitro potencies against SARS-CoV-2, it can be concluded that these compounds are potential antiviral molecules towards SARS-CoV-2 and may have worked as dual-acting against SARS-CoV-2, not only block the viral translation procedure by inhibiting SARS-CoV-2 Mpro but also reduce pro-inflammatory cytokines levels in lung cells by acting as agonists of CB-2 receptor. The successful in vitro work here of CBD and Δ9-THC lays the framework for their application in human clinical trials for the treatment of human coronavirus infections. Thus, CBD and Δ9-THC may be used in combination or with other drugs to treat COVID-19 patients.”

https://www.sciencedirect.com/science/article/pii/S0141813020351783?via%3Dihub

Fig. 1

L-Theanine Prevents Long-Term Affective and Cognitive Side-Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry

Journal of Neuroscience“Chronic adolescent exposure to Δ-9-Tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioural abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathological alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations.

L-theanine is an amino acid analogue of L-glutamate and L-glutamine derived from various plant sources, including green tea leaves. L-theanine has previously been shown to modulate levels of GABA, DA and glutamate in various neural regions and to possess neuroprotective properties.

Using a pre-clinical model of adolescent THC exposure in male rats, we report that L-theanine pre-treatment prior to adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect which persists into adulthood. In addition, pre-treatment with L-theanine blocked THC-induced downregulation of local GSK-3 and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and sub-cortical DAergic dysregulation.

Finally, L-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of L-theanine in the mesocorticolimbic system.

SIGNIFICANCE STATEMENT With the increasing trend of cannabis legalization and consumption during adolescence, it is essential to expand knowledge on the potential effects of adolescent cannabis exposure on brain development and identify potential pharmacological strategies to minimize THC-induced neuropathology. Previous evidence demonstrates that adolescent THC exposure induces long-lasting affective and cognitive abnormalities, mesocorticolimbic dysregulation and schizophrenia-like molecular biomarkers that persist into adulthood.

We demonstrate for the first time that L-theanine, an amino acid analogue of L-glutamate and L-glutamine, is capable of preventing long-term THC side-effects. L-theanine prevented development of THC-induced behavioral aberrations, blocked cortical downregulation of local GSK-3 and Akt signaling pathways and normalized dysregulation of both PFC and VTA DAergic activity, demonstrating powerful and functional neuroprotective effects against THC-induced developmental neuropathology.”

https://pubmed.ncbi.nlm.nih.gov/33268546/

https://www.jneurosci.org/content/early/2020/11/24/JNEUROSCI.1050-20.2020

Medicinal Applications of Cannabinoids Extracted from Cannabis sativa (L.): A new Route to Fight against COVID-19?

 “Cannabis sativa is a well-known plant which has been of benefit since ancient times in several medicinal systems, including Chinese, Indian, Greek and Egyptian ones.

Although C. sativa is one of the most investigated medicinal plants in the world, it faces the most controversial of issues for its legalization as a medication. C. sativa contains several hundreds of phytoconstituents including the infamous «cannabinoid.” It is necessary to properly understand the medicinal importance of these phytochemicals and spread awareness among the countries where it’s still facing legal complexities.

The current review is focusing on most recent literature pertaining to the various applications of cannabinoids with a special focus on medicinal aspect of the phytochemicals. Peer reviewed articles focusing on the importance of cannabis and cannabinoids were the target of this review. Articles were selected based on the relevance to the general scope of the work i.e. application of cannabinoids.

Cannabinoids can truly be regarded as wonder drug keeping their immense diversity of usage but unfortunately, many of the mares never researched biologically or pharmacologically due to their low yield in the plant. However, the approval of some cannabinoids by the FDA (along with other recognized national medical health systems) has opened the horizons for the explicit use of these natural drugs in medicines such as Epidiolex® (cannabidiol used for the treatment of severe forms of epilepsy) and Sativex®(‘Δ9 -tetrahydrocannabinol and cannabidiol’ used for the treatment of spasticity caused by multiple sclerosis, aka: MS.)

Many pharmacological properties of C. sativa are attributed to cannabidiol (CBD), a non-psychoactive component, along with Δ9 -tetrahydrocannabinol (Δ9 -THC), a psychoactive component. This review addresses the most important application or current utilization of cannabinoids in a variety of treatments such as: chronic pain, cancer, emesis, anorexia, irritable bowel syndrome, communicative diseases, glaucoma and central nervous system disorders. The biosynthetic pathway of cannabinoids is also discussed. In short, this plant has a myriad of bioactive compounds which have the potential to increase the list of approved cannabinoids suitable for therapy.”

https://pubmed.ncbi.nlm.nih.gov/33267756/

https://www.eurekaselect.com/188617/article

Short-Term Medical Cannabis Treatment Regimens Produced Beneficial Effects among Palliative Cancer Patients

pharmaceuticals-logo“In the last decade the use of medical cannabis (MC) for palliative cancer treatment has risen. However, the choice between products is arbitrary and most patients are using Tetrahydrocannabinol (THC)-dominant cannabis products.

In this study, we aimed to assess the short-term outcomes of MC treatment prescribed by oncologists in relation to the type of cannabis they receive.

A comparative analysis was used to assess the differences in treatment effectiveness and safety between THC-dominant (n = 56, 52%), cannabidiol (CBD)-dominant (n = 19, 18%), and mixed (n = 33, 30%) MC treatments. Oncology patients (n = 108) reported on multiple symptoms in baseline questionnaires, initiated MC treatment, and completed a one-month follow-up.

Most parameters improved significantly from baseline, including pain intensity, affective and sensory pain, sleep quality and duration, cancer distress, and both physical and psychological symptom burden. There was no significant difference between the three MC treatments in the MC-related safety profile. Generally, there were no differences between the three MC treatments in pain intensity and in most secondary outcomes.

Unexpectedly, CBD-dominant oil treatments were similar to THC-dominant treatments in their beneficial effects for most secondary outcomes. THC-dominant treatments showed significant superiority in their beneficial effect only in sleep duration compared to CBD-dominant treatments.

This work provides evidence that, though patients usually consume THC-dominant products, caregivers should also consider CBD-dominant products as a useful treatment for cancer-related symptoms.”

https://pubmed.ncbi.nlm.nih.gov/33265945/

https://www.mdpi.com/1424-8247/13/12/435

Perioperative Cannabis as a Potential Solution for Reducing Opioid and Benzodiazepine Dependence

See the source image“Cannabis is increasingly being used for medicinal purposes but remains outside Western medical practice. Data on perioperative use and outcomes are scarce. Few surgeons receive training regarding legal endorsement, reported medicinal benefits, and potential risks, making it difficult to advise patients. Guidelines and additional research are needed.

Observations: It is legal to recommend cannabis, which can be obtained in states with medical cannabis programs. There are many methods of consumption, oral being the safest. Activity is primarily through Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) via cannabinoid receptors, which may be potentiated when taken together in the plant or plant extract. The known effects of cannabis on inflammation and malignancy are largely limited to laboratory experiments. However, there are higher-quality data to support adjunctive use of cannabis for relief of pain, nausea, and insomnia, which may be useful postoperatively and could potentially decrease reliance on opiates and benzodiazepines. There are prospective trials in surgical patients, but no reported data regarding surgical complications or other surgical outcomes. Currently, cannabis is regulated differently than other controlled substances, and there are issues with purity/homogeneity, making it difficult for surgeons to accept or significantly explore its medical benefits.

Conclusions and relevance: Recommendations are made for surgeons advising patients who use cannabis based on the limited existing data. While cannabis likely has some therapeutic benefits, it must be treated as other medical controlled substances to truly elucidate its role in surgical patient care.”

https://pubmed.ncbi.nlm.nih.gov/33263719/

https://jamanetwork.com/journals/jamasurgery/article-abstract/2773526

Natural Salicylates and Their Roles in Human Health

ijms-logo“Salicylic acid (SA) is a plant hormone which plays a crucial role in the plant defense against various pathogens and abiotic stresses. Increasing reports suggest that this phenolic compound and its derivatives, collectively termed salicylates, not only regulate plant defense but also have beneficial effects on human health. Both natural and synthetic salicylates are known to have multiple targets in humans, thereby exhibiting various appreciating pharmacological roles, including anti-inflammatory, anticancer, neuroprotective, antidiabetic effects, and so on. The role of some salicylates, such as acetylsalicylic acid (aspirin), 5-aminosalicylic acid (mesalazine), and amorfrutins in human diseases has been well studied in vitro. However, their clinical significance in different diseases is largely unknown. Based on recent studies, five natural salicylates, including amorfrutin, ginkgolic acid, grifolic acid, tetrahydrocannabinolic acid, and cannabidiolic acid, showed potential roles in different challenging human diseases. This review summarizes together some of the recent information on multitarget regulatory activities of these natural salicylates and their pharmacological roles in human health.”

https://pubmed.ncbi.nlm.nih.gov/33260759/

https://www.mdpi.com/1422-0067/21/23/9049