Author Archives: David Worrell

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

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“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.”

https://pubmed.ncbi.nlm.nih.gov/37047608/

“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.”

https://www.mdpi.com/1422-0067/24/7/6598

The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer’s Disease-like Mouse Model

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“Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA.

In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system.

The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer’s disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ1-42-treated mouse model. We observed that Aβ1-42-treated mice had more hippocampal Aβ and p-tau levels, pathological markers of AD, and loss of cognitive function compared with PBS-treated mice. However, CBDA- and THCA-treated mice showed decreased hippocampal Aβ and p-tau and superior cognitive function compared with Aβ1-42-treated mice. In addition, CBDA and THCA lowered Aβ and p-tau levels, alleviated calcium dyshomeostasis, and exhibited neuroprotective effects in primary neurons.

Our results suggest that CBDA and THCA have anti-AD effects and mitigate memory loss and resilience to increased hippocampal Ca2+, Aβ, and p-tau levels. Together, CBDA and THCA may be useful therapeutic agents for treating AD.”

https://pubmed.ncbi.nlm.nih.gov/37047798/

https://www.mdpi.com/1422-0067/24/7/6827

The impact of cannabinoids on inflammasome signaling in HIV-1 infection

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NeuroImmune Pharmacology and Therapeutics

“Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver.

Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.”

https://pubmed.ncbi.nlm.nih.gov/37027347/

“It is evident from the literature that cannabinoids show protective effects against inflammation associated with HIV-1. In both human and animal studies, THC/cannabis treatment has been shown to reduce inflammatory markers, including NLRP3-associated cytokine signaling and T-cell activation and proliferation. Studies also implicate a neuroprotective effect against NO-mediated cytotoxicity and BBB breakdown in rodents. Taken together, these findings suggest a role for cannabinoid receptor activation in reducing chronic inflammation and associated pathologies in PWH.”

https://www.degruyter.com/document/doi/10.1515/nipt-2023-0002/html

Risk of Motor Vehicle Collisions and Culpability among Older Drivers Using Cannabis: A Meta-Analysis

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“Limited studies have investigated the effects of cannabis use on driving among older adults, who represent the fastest growing segment of drivers globally. We conducted a systematic review and meta-analysis to evaluate the effects of delta-9-tetrahydrocannabinol (THC) exposure on risks of (1) motor vehicle collisions (MVC) and (2) culpability for MVCs among adults 50 years and older. Three reviewers screened 7022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO. Odds Ratios (OR) were calculated using the Mantel-Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I2. The National Heart, Lung, and Blood Institute tool was used to assess the quality of each study. Seven cross-sectional studies were included. Three studies evaluated culpability while four evaluated MVC.

The pooled risk of MVC was not significantly different between THC-positive and THC-negative older drivers (OR, 95% CI 1.15 [0.40, 3.31]; I2 = 72%). In culpability studies, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I2 = 0%). Inspection of funnel plots did not indicate publication bias.

Our review found that THC exposure was not associated with MVC involvement nor with culpability for MVCs.”

https://pubmed.ncbi.nlm.nih.gov/36979231/

https://www.mdpi.com/2076-3425/13/3/421

A Comprehensive Review on Cannabis sativa Ethnobotany, Phytochemistry, Molecular Docking and Biological Activities

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“For more than a century, Cannabis was considered a narcotic and has been banned by lawmakers all over the world. In recent years, interest in this plant has increased due to its therapeutic potential, in addition to a very interesting chemical composition, characterized by the presence of an atypical family of molecules known as phytocannabinoids. With this emerging interest, it is very important to take stock of what research has been conducted so far on the chemistry and biology of Cannabis sativa.

The aim of this review is to describe the traditional uses, chemical composition and biological activities of different parts of this plant, as well as the molecular docking studies. Information was collected from electronic databases, namely SciFinder, ScienceDirect, PubMed and Web of Science. 

Cannabis is mainly popular for its recreational use, but it is also traditionally used as remedy for the treatment of several diseases, including diabetes, digestive, circulatory, genital, nervous, urinary, skin and respiratory diseases.

These biological proprieties are mainly due to the presence of bioactive metabolites represented by more than 550 different molecules. Molecular docking simulations proved the presence of affinities between Cannabis compounds and several enzymes responsible for anti-inflammatory, antidiabetic, antiepileptic and anticancer activities.

Several biological activities have been evaluated on the metabolites of Cannabis sativa, and these works have shown the presence of antioxidant, antibacterial, anticoagulant, antifungal, anti-aflatoxigenic, insecticidal, anti-inflammatory, anticancer, neuroprotective and dermocosmetic activities. This paper presents the up-to-date reported investigations and opens many reflections and further research perspectives.”

https://pubmed.ncbi.nlm.nih.gov/36986932/

“At present, more than 545 phytochemicals have been described in the different parts of the Cannabis plant. The most represented metabolite class is the phytocannabinoids and they exhibit enormous structural diversity and bioactivities. Cannabis sativa is found in a wide variety of forms and environments on all continents and its pharmacological properties seem to go far beyond psychotic effects, with the ability to address needs such as the treatment and relief of many symptoms and diseases.”

https://www.mdpi.com/2223-7747/12/6/1245

Special Issue: Therapeutic Potential for Cannabis and Cannabinoids

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“The number of patients reporting the use of cannabis for medical purposes, whether through state-regulated medical marijuana programs or through over-the-counter hemp extracts, continues to grow. The growth in medicinal use of cannabis has in many ways surpassed the scientific data on the benefits and hazards of cannabis, and the scientific community has largely been left playing catch-up. Since 1996, when California became the first jurisdiction to legalize medical cannabis, the number of states following suit has grown and is currently at 37, while nearly 50 countries have legalized medical cannabis (and even more have decriminalized the plant) including Canada, Austria, Uruguay, Australia, South Korea, and Lesotho.

Cannabis sp. produces a number of phytochemicals with potential medical benefits including terpenes, flavonoids, and a unique class of molecules called cannabinoids, of which Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most studied. Amazingly, the plant produces over 100 different cannabinoids with different potential therapeutic targets and activities, and these remain understudied.

The therapeutic benefits of cannabinoids are due, in large part, to the endocannabinoid system that exists in the human body, in addition to the ability of cannabinoids to interact and signal through a large number of disparate receptor molecules.”

“Cannabis is a complicated plant that produces over 100 cannabinoids in addition to terpenes and flavonoids. Adding to the complexity of trying to address the mechanism of action for cannabis is the fact that the cannabinoids that have been studied have been reported to exhibit activity at a number of different receptors.

This makes cannabinoids (and cannabis) a promiscuous drug. While typically viewed as a negative, promiscuous drugs do offer some advantages, most notably the ability to target different pathways of a disease with one medication.

The field of medical cannabis is growing rapidly, and as patients continue to use this plant to treat their conditions, there will remain a growing need for the scientific and medical communities to better understand how cannabis can impact the body.”

https://www.mdpi.com/2227-9059/11/3/902

Role of Terpenophenolics in Modulating Inflammation and Apoptosis in Cardiovascular Diseases: A Review

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“One in every three deaths worldwide is caused by cardiovascular diseases (CVDs), estimating a total of 17.9 million deaths annually. By 2030, it is expected that more than 24 million people will die from CVDs related complications. The most common CVDs are coronary heart disease, myocardial infarction, stroke, and hypertension.

A plethora of studies has shown inflammation causing both short-term and long-term damage to the tissues in many organ systems, including the cardiovascular system. In parallel to inflammation processes, it has been discovered that apoptosis, a mode of programmed cell death, may also contribute to CVD development due to the loss of cardiomyocytes.

Terpenophenolic compounds are comprised of terpenes and natural phenols as secondary metabolites by plants and are commonly found in the genus Humulus and Cannabis. A growing body of evidence has shown that terpenophenolic compounds exhibit protective properties against inflammation and apoptosis within the cardiovascular system.

This review highlights the current evidence elucidating the molecular actions of terpenophenolic compounds in protecting the cardiovascular system, i.e., bakuchiol, ferruginol, carnosic acid, carnosol, carvacrol, thymol and hinokitiol. The potential of these compounds is discussed as the new nutraceutical drugs that may help to decrease the burden of cardiovascular disorders.”

https://pubmed.ncbi.nlm.nih.gov/36982410/

“In this review, we have summarised the evidence on the potential pharmacological activities of terpenophenolic compounds in regulating inflammation and apoptosis associated with CVDs. Treatment of various classes of terpenophenolic compounds has been shown effective in preventing and limiting the progression of heart failure. In addition, all terpenophenolics seem to be potent antioxidants, which are proven to upregulate the Nrf2 pathway and increase the endogenous antioxidant level.”

https://www.mdpi.com/1422-0067/24/6/5339

Combined non-psychoactive Cannabis components cannabidiol and β-caryophyllene reduce chronic pain via CB1 interaction in a rat spinal cord injury model

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Lopiccolo & Chang in PLoS ONE – BU Linguistics

“The most frequently reported use of medical marijuana is for pain relief. However, its psychoactive component Δ9-tetrahydrocannabinol (THC) causes significant side effects. Cannabidiol (CBD) and β-caryophyllene (BCP), two other cannabis constituents, possess more benign side effect profiles and are also reported to reduce neuropathic and inflammatory pain. We evaluated the analgesic potential of CBD and BCP individually and in combination in a rat spinal cord injury (SCI) clip compression chronic pain model. Individually, both phytocannabinoids produced dose-dependent reduction in tactile and cold hypersensitivity in male and female rats with SCI. When co-administered at fixed ratios based on individual A50s, CBD and BCP produced enhanced dose-dependent reduction in allodynic responses with synergistic effects observed for cold hypersensitivity in both sexes and additive effects for tactile hypersensitivity in males. Antinociceptive effects of both individual and combined treatment were generally less robust in females than males. CBD:BCP co-administration also partially reduced morphine-seeking behavior in a conditioned place preference (CPP) test. Minimal cannabinoidergic side effects were observed with high doses of the combination. The antinociceptive effects of the CBD:BCP co-administration were not altered by either CB2 or μ-opioid receptor antagonist pretreatment but, were nearly completely blocked by CB1 antagonist AM251. Since neither CBD or BCP are thought to mediate antinociception via CB1 activity, these findings suggest a novel CB1 interactive mechanism between these two phytocannabinoids in the SCI pain state. Together, these findings suggest that CBD:BCP co-administration may provide a safe and effective treatment option for the management of chronic SCI pain.”

https://pubmed.ncbi.nlm.nih.gov/36913400/

“In conclusion, the current findings indicate that the combination of readily accessible non-psychoactive cannabis components CBD oil and BCP may be particularly effective in reducing neuropathic pain resulting from spinal cord injury. In addition, cannabinoid-like side effects were minimal using this combination. Further, the observed decrease in opioid-seeking behavior suggest that this treatment may be useful as a supplemental therapeutic to reduce opioid needed for effective pain management. Together, these findings are supportive of the beneficial effects of combining cannabis components in the armamentarium for chronic pain management.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282920

Cannabidiol Recovers Dopaminergic Neuronal Damage Induced by Reserpine or α-synuclein in Caenorhabditis elegans

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SpringerLink

“Progressive neurodegenerative disorders such as Parkinson Disease (PD) lack curative or long-term treatments. At the same time, the increase of the worldwide elderly population and, consequently, the extension in the prevalence of age-related diseases have promoted research interest in neurodegenerative disorders. Caenorhabditis elegans is a free-living nematode widely used as an animal model in studies of human diseases.

Here we evaluated cannabidiol (CBD) as a possible neuroprotective compound in PD using the C. elegans models exposed to reserpine.

Our results demonstrated that CBD reversed the reserpine-induced locomotor alterations and this response was independent of the NPR-19 receptors, an orthologous receptor for central cannabinoid receptor type 1. Morphological alterations of cephalic sensilla (CEP) dopaminergic neurons indicated that CBD also protects neurons from reserpine-induced degeneration. That is, CBD attenuates the reserpine-induced increase of worms with shrunken soma and dendrites loss, increasing the number of worms with intact CEP neurons. Finally, we found that CBD also reduced ROS formation and α-syn protein accumulation in mutant worms.

Our findings collectively provide new evidence that CBD acts as neuroprotector in dopaminergic neurons, reducing neurotoxicity and α-syn accumulation highlighting its potential in the treatment of PD.”

https://pubmed.ncbi.nlm.nih.gov/36964823/

https://link.springer.com/article/10.1007/s11064-023-03905-z

Highly purified cannabidiol improves stability and postural tone in adult patients with Lennox-Gastaut Syndrome: a case series

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“Lennox-Gastaut Syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterising patients with LGS.

Highly purified cannabidiol (CBD) is a novel antiseizure medication recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous antiseizure medication treatment helps reduce seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait and stability are available.

In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected.

Our case series suggests that CBD may help manage patients with LGS regarding seizure control and improve other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug’s effect on the brain locomotor centres, as demonstrated in animal model studies.”

https://pubmed.ncbi.nlm.nih.gov/36946334/

https://onlinelibrary.wiley.com/doi/10.1002/epd2.20049