Effects of β-caryophyllene, A dDietary Cannabinoid, in Animal Models of Drug Addiction

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“Background: β-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in Cannabis and other plants. BCP is currently used as a food additive, although pharmacological studies suggest its potential therapeutic application for the treatment of certain brain disorders. The mechanisms of action of BCP remain uncertain, possibly including full agonism at the cannabinoid CB 2 receptor (CB 2 R).

Objective: The study aims to investigate the BCP’s potential as a new drug for the treatment of substance use disorders, by reviewing preclinical studies with animal models.

Results: BCP has been investigated in behavioral paradigms, including drug self-administration, conditioned place preference, and intracranial self-stimulation; the drugs tested were cocaine, nicotine, alcohol, and methamphetamine. Remarkably, BCP prevented or reversed behavioral changes resulting from drug exposure. As expected, the mechanism of action entails CB 2 R activation, although this is unlikely to constitute the only molecular target to explain such effects. Another potential target is the peroxisome proliferator-activated receptor.

Conclusion: Preclinical studies report promising results with BCP in animal models of substance use disorders. Further research, including studies in humans, are warranted to establish its therapeutic potential and its mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/36173065/

https://www.eurekaselect.com/article/126579

Natural vs. artificial cannabinoid oils: the comparison of their antioxidant activities

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SpringerLink

“In the wide range of products containing hemp ingredients, cannabinoid oils are the most popular. They have gained popularity not only among people struggling with various health ailments, but also those who search for a neutral way of taking care of their body and mind.

The antioxidant activities of cannabinoid oils differing in the type of their main cannabinoid [i.e., Cannabigerol (CBG), Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (Δ9-THC), Cannabigerolic acid (CBGA), Cannabidiolic acid (CBDA) or Δ9-Tetrahydrocannabinolic acid (Δ9-THCA)] are compared and discussed in the paper. The oils with the same concentration of their main cannabinoid but prepared in different ways were applied in the experiments.

Following the presented results, cannabinoid oils obtained from the plant extracts are characterized by evidently greater antioxidant activity than those prepared from pure cannabinoids. The essential difference in the antioxidant activity of the oils containing the neutral or acidic form of a given cannabinoid is observed only in the case of THC and THCA oils.”

https://pubmed.ncbi.nlm.nih.gov/36164439/

“Cannabinoid oils obtained from the plant extracts have the greatest antioxidant activity.”

https://link.springer.com/article/10.1007/s00217-022-04121-9

Evaluation of two different Cannabis sativa L. extracts as antioxidant and neuroprotective agents

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“Cannabis sativa L. is a plant that contains numerous chemically active compounds including cannabinoids such as trans-Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and flavone derivatives, such as luteolin-7-O-glucuronide and apigenin glucuronide. In particular, the polar fraction of hemp including many phenolic compounds has been overlooked when compared with the more lipophilic fraction containing cannabinoids. Therefore, the aim of this study was to assess two extracts of industrial hemp (C. sativa) of different polarity (aqueous and hexane) by evaluating their antioxidant profile and their neuroprotective potential on pharmacological targets in the central nervous system (CNS). Several assays on in vitro antioxidant capacity (DPPH, superoxide radical, FRAP, ORAC), as well as inhibition of physiological enzymes such as acetylcholinesterase (AChE) and monoaminooxidase A (MAO-A) were carried out in order to find out how these extracts may be helpful to prevent neurodegenerative disorders. Neuro-2a cell line was selected to test the cytotoxic and neuroprotective potential of these extracts. Both extracts showed striking antioxidant capacity in the FRAP and ORAC assays, particularly the hexane extract, and interesting results for the DPPH and superoxide radical uptake assays, with the aqueous extract standing out especially in the latter. In enzyme inhibition assays, the aqueous extract showed AChE and MAO-A inhibitory activity, while the hexane extract only reached IC50 value for AChE inhibitory bioassay. Neuro-2a assays demonstrated that polyphenolic extract was not cytotoxic and exhibited cytoprotective properties against hydrogen peroxide and antioxidant response decreasing reactive oxygen species (ROS) production. These extracts could be a source of compounds with potential benefit on human health, especially related to neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/36176449/

“In conclusion, this study provided new insights into the biological activities of two different extracts of C. sativa. It was revealed that these extracts constitute a valuable and interesting natural source of bioactive molecules with great antioxidant properties, potentially capable of preventing neurodegenerative diseases.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.1009868/full

The role of cannabinoids in neurodevelopmental disorders of children and adolescents

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PubMed | MIT Libraries News

“Introduction: Neurodevelopmental disorders have a multifactorial etiology that results from the interaction between biological and environmental factors. The biological basis of many of these disorders is only partially understood, which makes therapeutic interventions, especially pharmacological ones, particularly difficult. The impact of medical cannabis on neurological and psychiatric disorders has been studied for a long time. This study aimed to review the currently available clinical and pre-clinical studies regarding the use of cannabinoids in pediatric neurodevelopmental disorders and to draw attention to the potential therapeutic role of cannabidiol in this field.

Development: Cannabidiol is an endocannabinoid system modulator and exerts its effects on both developing and mature brains through numerous mechanisms. Cannabidiol holds a relatively high toxicity limit and current literature suggests that it may have anxiolytic, antipsychotic, and neuroprotective properties. Clinical evidence suggests that early treatment with cannabidiol might be a promising therapy for neurodevelopmental disorders, including intellectual disability, autism spectrum disorders, tics, and attention/deficit hyperactivity disorder.

Conclusions: This review hopefully draws attention to an emerging body of evidence concerning cannabidiol’s significant potential to safely improve many of the common symptoms affecting children and adolescents with neurodevelopmental disorders, especially autism spectrum disorder.”

https://pubmed.ncbi.nlm.nih.gov/36169325/

Cannabidiol in Treatment of Autism Spectrum Disorder: A Case Study

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Archive of "Cureus". - PMC

“This case study aims to demonstrate the use of cannabidiol (CBD) with low-dose tetrahydrocannabinol (THC) in managing symptoms associated with autism spectrum disorder (ASD) to increase the overall quality of life for these individuals and their families.

ASD is a neurodevelopmental disorder affecting cognitive development, behavior, social communication, and motor skills. Despite the increasing awareness of ASD, there is still a lack of safe and effective treatment options.

The study includes a nine-year-old male patient who was diagnosed with nonverbal ASD. He exhibited emotional outbursts, inappropriate behaviors, and social deficits including challenges in communicating his needs with others. Since the patient was unable to attain independence at school and at home, his condition was a significant burden to his caregivers.

The patient was treated with full-spectrum high CBD and low THC oil formulation, with each milliliter containing 20 mg of CBD and <1 mg of THC. CBD oil starting dose was 0.1ml twice daily, increased every three to four days to 0.5ml twice daily.

Overall, the patient experienced a reduction in negative behaviors, including violent outbursts, self-injurious behaviors, and sleep disruptions. There was an improvement in social interactions, concentration, and emotional stability.

A combination of high CBD and low-dose THC oil was demonstrated to be an effective treatment option for managing symptoms associated with autism, leading to a better quality of life for both the patient and the caregivers.”

https://pubmed.ncbi.nlm.nih.gov/36176817/

“In this case, the child patient responded positively to the introduction of CBD oil treatment with reduced negative behaviors, better sleep, and improved communication. With the increasing clinical studies on the use of cannabidiol in treating patients with mood disorders, anxiety, chronic pain conditions, and other behavioral problems, it should be considered as a treatment option in managing symptoms related to autism. In the case study presented, the child patient has shown behavioral and cognitive improvements with no side effects reported. Altogether, this study presents a case that motivates further research and clinical studies to understand the molecular mechanism of CBD as well as the dosing regimes for pediatric populations, the etiology of ASD, and how various dosing affect different demographics.”

https://www.cureus.com/articles/109585-cannabidiol-in-treatment-of-autism-spectrum-disorder-a-case-study


Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

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iScience journal (@iScience_CP) / Twitter

“Epilepsy and neurodevelopmental disorders can arise from pathogenic variants of KCNQ (Kv7) channels. A patient with developmental and epileptic encephalopathy exhibited an in-frame deletion of histidine 260 on Kv7.2. Coexpression of Kv7.2 mutant (mut) subunits with Kv7.3 invoked a decrease in current density, a depolarizing shift in voltage for activation, and a decrease in membrane conductance. Biotinylation revealed an increased level of surface Kv7.2mut compared to Kv7.3 with no change in total membrane protein expression. Super-resolution and FRET imaging confirmed heteromeric channel formation and a higher expression density of Kv7.2mut. Cannabidiol (1 μM) offset the effects of Kv7.2mut by inducing a hyperpolarizing shift in voltage for activation independent of CB1 or CB2 receptors. These data reveal that the ability for cannabidiol to reduce the effects of a pathogenic Kv7.2 variant supports its use as a potential therapeutic to reduce seizure activity.”

https://pubmed.ncbi.nlm.nih.gov/36157585/

“Control of seizure activity has been increasingly gained through use of cannabinoids, with cannabidiol (CBD) specifically approved for clinical use.”

https://www.cell.com/iscience/fulltext/S2589-0042(22)01364-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004222013645%3Fshowall%3Dtrue

Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome

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Nature Reviews Gastroenterology & Hepatology

“The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options.

Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease.

The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome.

Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.”

https://pubmed.ncbi.nlm.nih.gov/36168049/

https://www.nature.com/articles/s41575-022-00682-y

Medical Cannabis Patients Report Improvements in Health Functioning and Reductions in Opiate Use

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“Purpose: Opioid use rates have dropped as North American patients gain access to medical cannabis, indicating a harm reduction role, yet health outcomes remain mostly unexplored. This study presents self-reported medical cannabis use, perceptions of health functioning, and changes in opioid pain medication use in Florida medical cannabis patients.

Methods: Patients (n = 2,183) recruited from medical dispensaries across Florida completed a 66-item cross-sectional survey that included demographic, health, and medication usage items, along with items from the Medical Outcomes Survey (SF-36) to assess health functioning before and after cannabis initiation.

Results: Most participants were between the ages of 20 and 70 years of age (95%), over 54% were female, 47% were employed, and most (85%) were white. Commonly reported ailment groups were Pain and Mental Health combined (47.92%), Mental Health (28.86%) or Pain (9.07%). Health domains of bodily pain, physical functioning, and social functioning improved while limitations due to physical and emotional problems were unchanged. Most patients rated medical cannabis as being important to their quality of life. Many (60.98%) reported using pain medications prior to medical cannabis, 93.36% of these reported a change in pain medication after medical cannabis. The majority of participants (79%) reported either cessation or reduction in pain medication use following initiation of medical cannabis and 11.47% described improved functioning.

Conclusions: The findings suggest that some medical cannabis patients decreased opioid use without harming quality of life or health functioning, soon after the legalization of medical cannabis. The public health implications of medical cannabis as an alternative pain medication are discussed.”

https://pubmed.ncbi.nlm.nih.gov/36168127/

“In conclusion, some patients may reduce or even cease use of OBPM upon access to medical cannabis, potentially without harming quality of life or health functioning. This is suggestive of the harm reduction role and opioid-sparing effects of medical cannabis in a quality-controlled and regulated medical-use only state. Given the great individual and societal costs associated with the opioid crisis (Florence et al., 2021; National Institute on Drug Abuse, n.d.), the public health implications of these findings are important to consider.”

https://www.tandfonline.com/doi/full/10.1080/10826084.2022.2107673

Endocannabinoid-Binding Receptors as Drug Targets

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Book cover

“Cannabis plant has been used from ancient times with therapeutic purposes for treating human pathologies, but the identification of the cellular and molecular mechanisms underlying the therapeutic properties of the phytocannabinoids, the active compounds in this plant, occurred in the last years of the past century.

In the late 1980s and early 1990s, seminal studies demonstrated the existence of cannabinoid receptors and other elements of the so-called endocannabinoid system. These G protein-coupled receptors (GPCRs) are a key element in the functions assigned to endocannabinoids and appear to serve as promising pharmacological targets. They include CB1, CB2, and GPR55, but also non-GPCRs can be activated by endocannabinoids, like ionotropic receptor TRPV1 and even nuclear receptors of the PPAR family.

Their activation, inhibition, or simply modulation have been associated with numerous physiological effects at both central and peripheral levels, which may have therapeutic value in different human pathologies, then providing a solid experimental explanation for both the ancient medicinal uses of Cannabis plant and the recent advances in the development of cannabinoid-based specific therapies.

This chapter will review the scientific knowledge generated in the last years around the research on the different endocannabinoid-binding receptors and their signaling mechanisms. Our intention is that this knowledge may help readers to understand the relevance of these receptors in health and disease conditions, as well as it may serve as the theoretical basis for the different experimental protocols to investigate these receptors and their signaling mechanisms that will be described in the following chapters.”

https://pubmed.ncbi.nlm.nih.gov/36152178/

https://link.springer.com/protocol/10.1007/978-1-0716-2728-0_6

Endocannabinoid Metabolism and Transport as Drug Targets

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“The wide distribution of the endocannabinoid system (ECS) throughout the body and its pivotal pathophysiological role offer promising opportunities for the development of novel therapeutic drugs for treating several diseases. However, the need for strategies to circumvent the unwanted psychotropic and immunosuppressive effects associated with cannabinoid receptor agonism/antagonism has led to considerable research in the field of molecular alternatives, other than type-1 and type-2 (CB1/2) receptors, as therapeutic targets to indirectly manipulate this pro-homeostatic system. In this context, the use of selective inhibitors of proteins involved in endocannabinoid (eCB) transport and metabolism allows for an increase or decrease of the levels of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the sites where these major eCBs are indeed needed. This chapter will briefly review some preclinical and clinical evidence for the therapeutic potential of ECS pharmacological manipulation.”

https://pubmed.ncbi.nlm.nih.gov/36152188/

https://link.springer.com/protocol/10.1007/978-1-0716-2728-0_16