Cannabis-Based Medicinal Products in the Management of Emotionally Unstable Personality Disorder (EUPD): A Narrative Review and Case Series

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“Emotionally unstable personality disorder (EUPD) is a common mental health disorder, manifesting with a range of chronic and debilitating symptoms, including impaired social functioning, unstable mood, and risky impulsive or self-injurious behaviour. Whilst the exact aetiology has not been fully elucidated, implicated factors seem to include genetic factors, environmental causes such as trauma, and neurotransmitter deficits.

The literature suggests that impaired functioning of the endocannabinoid system in key brain regions responsible for emotional processing and stress response may underlie the manifestation of EUPD symptoms. The National Institute for Health and Care Excellence (NICE) 2009 guidelines state that “no drugs have established efficacy in treating or managing EUPD”, and yet, patients are commonly prescribed medication which includes antipsychotics, antidepressants, and mood stabilisers.

Here we present a case series of seven participants diagnosed with EUPD and treated with cannabis-based medicinal products (CBMPs). Participants were given an initial assessment and followed up one month after CBMPs prescription. Improvement in symptoms was assessed by the completion of ratified rating scales by the participant and psychiatrist.

Our results indicate that CBMPs were effective and well tolerated, as six participants reported a noticeable improvement in their symptoms and functioning. Although promising, further research is needed to ascertain the long-term tolerability, efficacy, and dosing strategy for CBMPs in EUPD.”

https://pubmed.ncbi.nlm.nih.gov/36358392/

“To our knowledge, this case series represents the first medical evidence of the use of CBMPs for the clinical management of patients with a diagnosis of EUPD, who are met with limited pharmacological options typically based on the off-label use of psychiatric medications.

Cannabinoids may represent a novel, efficacious, and safe treatment alternative for EUPD patients.

The neuro- and immune-modulatory effects of THC and CBD seem theoretically well-aligned with cellular and molecular deficits that are currently being investigated as key features underlying the pathogenesis of EUPD. Although preliminary, our results suggest that, when deployed in a rigorously controlled clinical environment, CBMPs can provide substantial improvement in symptoms associated with EUPD thus warranting the need for further research on this therapeutical strategy.”

https://www.mdpi.com/2076-3425/12/11/1467/htm

Supercritical Extract of Cannabis sativa Inhibits Lung Metastasis in Colorectal Cancer Cells by Increasing AMPK and MAPKs-Mediated Apoptosis and Cell Cycle Arrest

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“Colorectal cancer (CRC) is one of the diseases with the highest rates of prevalence and mortality despite therapeutic methods in the world. In particular, there are not enough methods to treat metastasis of CRC cells to distant organs. Cannabis sativa Linne (C. sativa) is a popular medicinal plant used by humans to treat many diseases. Recently, extracts of C. sativa have shown diverse pharmacological effects as a result of choosing different extraction methods. In this study, we performed experiments to confirm the inhibitory effect and related mechanisms of supercritical extract of C. sativa on metastatic CRC cells. The effect of SEC on the viability of CRC cell lines, CT26 and HCT116, was determined using CCK reagent. Flow cytometry was performed to confirm whether SEC can promote cell cycle arrest and apoptosis. Additionally, SEC reduced proliferation of CT26 and HCT116 cells without causing toxicity to normal colon cell line CCD-18Co cells. SEC treatment reduced colony formation in both CRC cell lines, promoted G0/G1 phase arrest and apoptosis in CT26 and HCT116 cells through AMPK activation and MAPKs such as ERK, JNK, and p38 inactivation. Moreover, oral administration of SEC decreased pulmonary metastasis of CT26 cells. Our research demonstrates the inhibitory effect of SEC on CRC cell proliferation and metastasis. Thus, SEC might have therapeutic potential for CRC treatment.”

https://pubmed.ncbi.nlm.nih.gov/36364815/

https://www.mdpi.com/2072-6643/14/21/4548/htm

Phytocannabinoid Compositions from Cannabis Act Synergistically with PARP1 Inhibitor against Ovarian Cancer Cells In Vitro and Affect the Wnt Signaling Pathway

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“Ovarian cancer (OC) is the single most lethal gynecologic malignancy. Cannabis sativa is used to treat various medical conditions, and is cytotoxic to a variety of cancer types. We sought to examine the effectiveness of different combinations of cannabis compounds against OC. Cytotoxic activity was determined by XTT assay on HTB75 and HTB161 cell lines. Apoptosis was determined by flow cytometry. Gene expression was determined by quantitative PCR and protein localization by confocal microscopy. The two most active fractions, F5 and F7, from a high Δ9-tetrahydrocannabinol (THC) cannabis strain extract, and their standard mix (SM), showed cytotoxic activity against OC cells and induced cell apoptosis. The most effective phytocannabinoid combination was THC+cannabichromene (CBC)+cannabigerol (CBG). These fractions acted in synergy with niraparib, a PARP inhibitor, and were ~50-fold more cytotoxic to OC cells than to normal keratinocytes. The F7 and/or niraparib treatments altered Wnt pathway-related gene expression, epithelial-mesenchymal transition (EMT) phenotype and β-catenin cellular localization. The niraparib+F7 treatment was also effective on an OC patient’s cells. Given the fact that combinations of cannabis compounds and niraparib act in synergy and alter the Wnt signaling pathway, these phytocannabinoids should be examined as effective OC treatments in further pre-clinical studies and clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36364346/

“We suggest that cannabis might be regarded as a complementary and effective anti-cancer treatment for OC. Given the favorable safety profile of phytocannabinoids, compared to standard pharmacotherapies, we propose that clinical trials with cannabis-based products are desperately needed for OC patients.”

https://www.mdpi.com/1420-3049/27/21/7523/htm

Design of a New 3D Gelatin-Alginate Scaffold Loaded with Cannabis sativa Oil

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“There is an increasing medical need for the development of new materials that could replace damaged organs, improve healing of critical wounds or provide the environment required for the formation of a new healthy tissue. The three-dimensional (3D) printing approach has emerged to overcome several of the major deficiencies of tissue engineering. The use of Cannabis sativa as a therapy for some diseases has spread throughout the world thanks to its benefits for patients. In this work, we developed a bioink made with gelatin and alginate that was able to be printed using an extrusion 3D bioprinter. The scaffolds obtained were lyophilized, characterized and the swelling was assessed. In addition, the scaffolds were loaded with Cannabis sativa oil extract. The presence of the extract provided antimicrobial and antioxidant activity to the 3D scaffolds. Altogether, our results suggest that the new biocompatible material printed with 3D technology and with the addition of Cannabis sativa oil could become an attractive alternative to common treatments of soft-tissue infections and wound repair.”

https://pubmed.ncbi.nlm.nih.gov/36365500/

“In summary, herein we show that the new biomaterial loaded with Cannabis sativa oil and printed with 3D technology could be a promising alternative to conventional treatments for wound healing.”

https://www.mdpi.com/2073-4360/14/21/4506/htm

The Characteristics of Clinical Trials on Cannabis and Cannabinoids: A Review of Trials for Therapeutic or Drug Development Purposes

SpringerLink

“Introduction: Patients and healthcare practitioners are increasingly interested in using cannabis and cannabinoids to address unmet clinical needs. Although we have clinical evidence on the medical use of cannabinoids, a significant portion of the data is not based on randomized clinical trials, which are considered the gold standard in clinical research. We have reviewed the registered clinical trials on cannabis and cannabinoids for therapeutic or drug development purposes to underline the past and current attempts to generate robust clinical evidence and identify existing knowledge gaps.

Methods: We reviewed four clinical trial registries (International Clinical Trials Registry Program [ICTRP], ClinicalTrials.gov, European Clinical Trial Registry [EUCTR], Australian New Zealand Clinical Trial Registry [ANZCTR]) to identify clinical trials on cannabinoids (phyto- or synthetic) or cannabis-based medications between January 1, 2000, and December 31, 2021. All interventional clinical trials on cannabinoids and other compounds interacting with the endocannabinoid system, regardless of the investigated medical condition, assessed health outcomes, or choice of comparator, were included, provided they had a therapeutic or drug development purpose. Data on the primary sponsor, type of sponsor, date of registration, recruitment status, number of participants, study design, the phase of the study, country, medical conditions, investigated cannabinoids, and the route of administration were extracted. The therapeutic area and class of cannabinoids were identified based on the details of each trial.

Results: We included 834 out of 2966 reviewed clinical trials. The number of registered clinical trials has constantly increased from 30 in 2013 to 103 in 2021. More than 40% of registered clinical trials in 2021 were phase II and phase III clinical trials. The mean number of trial enrollments for completed, ongoing, and terminated studies were 128, 156, and 542, respectively. Clinical research on Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and the oral routes of administration dominate the field. Approximately two-thirds of clinical trials were conducted in five therapeutic areas (i.e., ‘Chronic pain,’ ‘Mental, behavioral or neurodevelopmental disorders,’ ‘Nervous system diseases,’ ‘Endocrine, nutritional or metabolic diseases,’ and ‘Neoplasms’). Pharmaceutical companies sponsored 39% of all clinical trials. However, trial sponsorships vary noticeably in different jurisdictions, likely due to, in part, different regulatory frameworks.

Conclusion: Our review highlights the diversification of clinical trials on cannabinoid-based medications in the past 21 years. This review underlines the increased interest in conducting clinical studies on new cannabinoid administration methods such as topical applications and on the investigation of emerging phyto- and synthetic cannabinoids. Moreover, more clinical trials have been designed to explore the potential therapeutic benefits of cannabinoids in areas such as mental, behavioral, or neurodevelopmental disorders and skin diseases. There is a need for granular analyses of clinical trials on more commonly studied therapeutic areas such as chronic pain, nervous system diseases, and mental and behavioral disorders to generate more actionable information and insight for all stakeholders.”

https://pubmed.ncbi.nlm.nih.gov/36357543/

https://link.springer.com/article/10.1007/s40290-022-00447-7

Use of Medical Cannabis in Patients with Gilles de la Tourette’s Syndrome in a Real-World Setting

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“Objective: Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics and other comorbidities. Clinical recommendations for the use of medical cannabis are established, yet further guidance is needed. The aim of this study was to describe the experience of patients with TS with medical cannabis. 

Materials and Methods: TS patients were recruited from a registry of patients (“Tikun Olam” company). Questionnaires were answered before and after 6 months of treatment. Patients were divided into two groups: (A) patients who responded and (B) patients who did not respond to the follow-up questionnaire. In group A, an analysis was made to evaluate the presence and frequency of motor and vocal tics. The patients’ general mood, employment status, quality of life, and comorbidities were also included in the analysis. 

Results: Seventy patients were identified. The tetrahydrocannabinol and cannabidiol mean daily dose was 123 and 50.5 mg, respectively. In group A, a statistically significant improvement was identified in quality of life (p<0.005), employment status (p=0.027), and in the reduction of the number of medications (p<0.005). Sixty-seven percent and 89% of patients with obsessive-compulsive disorder and anxiety comorbidities, respectively, reported an improvement. No statistically significant improvement was identified in motor tics (p=0.375), vocal tics (p>0.999), tics frequency (p=0.062), or general mood (p=0.129). The most frequent adverse effects were dizziness (n=4) and increased appetite (n=3). 

Conclusion: Subjective reports from TS patients suggest that medical cannabis may improve their quality of life and comorbidities. More studies are needed to evaluate the efficacy and safety of medical cannabis.”

https://pubmed.ncbi.nlm.nih.gov/36342913/

https://www.liebertpub.com/doi/10.1089/can.2022.0112

Medical Cannabis Use and Inflammatory Cytokines and Chemokines Among Adult Chronic Pain Patients

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“Background: Utilizing cannabis as a therapeutic option for chronic pain (CP) has increased significantly. However, data regarding the potential immunomodulatory effects of cannabis in CP patients remain scarce. We aimed at exploring the relationship between cannabis use and inflammatory cytokines and chemokines among a cohort of CP patients. 

Methods: Adult patients with a CP diagnosis and medical authorization of cannabis were enrolled. Patients completed validated clinical questionnaires and self-reported the effectiveness of cannabis for symptom management. Patients’ blood and cannabis samples were analyzed for the presence of four major cannabinoids, two major cannabinoid metabolites, 29 different cytokines/chemokines, and cortisol. The multivariable linear regression model was used to identify cannabis and patient factors associated with immune markers. 

Results: Fifty-six patients (48±15 years; 64% females) were included, with dried cannabis (53%) being the most common type of cannabis consumed. Seventy percent of products were considered delta-9-tetrahydrocannabinol (Δ9-THC)-dominant. The majority of patients (96%) self-reported effective pain management, and 76% reported a significant decrease in analgesic medication usage (p≤0.001). Compared with males, female patients had higher plasma levels of cannabidiol (CBD), cannabidiolic acid, Δ9-THC, and 11-hydroxy-Δ9-tetrahydrocannabinol but lower concentrations of delta-9-tetrahydrocannabinolic acid and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH). Females had significantly lower eotaxin levels (p=0.04) in comparison to male patients. The regression analysis indicated that high cannabis doses were related to increased levels of interleukin (IL)-12p40 (p=0.02) and IL-6 (p=0.01), whereas female sex was associated with decreased eotaxin (p≤0.01) concentrations. Blood CBD levels were associated with lower vascular endothelial growth factor (p=0.04) concentrations, and THC-COOH was a factor related to decreased tumor necrosis factor alpha (p=0.02) and IL-12p70 (p=0.03). 

Conclusion: This study provides further support for the patient-perceived effectiveness of cannabis in managing CP symptoms and reducing analgesic medication consumption. The results suggest a potential sex difference in metabolizing cannabinoids, and the varying immune marker concentrations may support a possible immunomodulatory effect associated with patient sex and cannabis product type. These preliminary findings provide grounds for further validation using larger, well-designed studies with longer follow-up periods.”

https://pubmed.ncbi.nlm.nih.gov/36342776/

https://www.liebertpub.com/doi/10.1089/can.2022.0143

Endocannabinoids and related compounds as modulators of angiogenesis: Concepts and clinical significance

“Vasculogenesis (the process of differentiation of angioblasts toward endothelial cells and de novo formation of crude vascular networks) and angiogenesis (the process of harmonized sprouting and dispersal of new capillaries from previously existing ones) are two fundamentally complementary processes, obligatory for maintaining physiological functioning of vascular system. In clinical practice, however, the later one is of more importance as it guarantees correct embryonic nourishment, accelerates wound healing processes, prevents uncontrolled cell growth and tumorigenesis, contributes in supplying nutritional demand following occlusion of coronary vessels and is in direct relation with development of diabetic retinopathy. Hence, discovery of novel molecules capable of modulating angiogenic events are of great clinical importance. Recent studies have demonstrated multiple angio-regulatory activities for endocannabinoid system modulators and endocannabinoid-like molecules, as well as their metabolizing enzymes. Hence, in present article, we reviewed the regulatory roles of these molecules on angiogenesis and described molecular mechanisms underlying them.”

https://pubmed.ncbi.nlm.nih.gov/36317321/

https://onlinelibrary.wiley.com/doi/10.1002/cbf.3754

“Inhibition of tumor angiogenesis by cannabinoids”

https://pubmed.ncbi.nlm.nih.gov/12514108/

The role of Cannabis in treatment-resistant Fibromyalgia women

“Background: Fibromyalgia is a complex pain-focused syndrome. Previous studies showed that Cannabis is efficacious in promoting sleep, deepening and lengthening the sleep cycle, and good pain relief (compared to SSRIs and SNRIs).

Purpose: This study aimed to use the World Health Organization Quality of Life Bref questionnaire (WhoQoL-bref) to characterize the impact of Cannabis Treatment initiation on the quality of life in women suffering from treatment-resistant fibromyalgia.

Methods: a prospective cohort study involving 30 women aged 18-70 years old diagnosed with fibromyalgia, exhausted pharmacological fibromyalgia treatment, and started Cannabis treatment. Pregnant women were excluded. WhoQoL-bref was filled before Cannabis treatment initiation and one month following treatment.

Results: Women’s average age was 46 years(±5), with a poor general quality of life (1.47±0.63), poor general health (1.47±0.78), pain and discomfort, and dependence on medication (3.77±1.3 and 3.07±1.74 respectively) prior to Cannabis intervention. Cannabis treatment for 30 days showed a marked improvement in general quality of life (1.97 scores, p < 0.01), general health (1.83, p<0.01), physical health ( 1.5, p<0.01), and psychological domain (1.3, p<0.01). Financial resources and home environment were not influenced by cannabis treatment (p=0.07, p=0.31, respectively).

Conclusion: Results suggest a potentially significant role of Cannabis in treatment-resistant Fibromyalgia women. Early Cannabis treatment may result in a beneficial short-term effect on the quality of life through its influence on pain, sleep, physical and psychological domains. Further studies are still indicated to understand this potential and its long-term beneficial impact.”

https://pubmed.ncbi.nlm.nih.gov/36333278/

https://onlinelibrary.wiley.com/doi/10.1111/papr.13179

A 1:1 ratio of cannabidiol: tetrahydrocannabinol attenuates methamphetamine conditioned place preference in mice: A prospective study of antidopaminergic mechanism

Brain Research Bulletin

“A 1:1 ratio of cannabidiol to tetrahydrocannabinol (CT) was suggested to be safer for therapeutic purposes in many illnesses. However, CT effects on methamphetamine (METH) conditioned place preference (CPP) remained largely unexplored. This study aimed to examine the effects of CT on METH CPP mice evaluated by animal behaviors accompanied by local field potential (LFP) signals analysis. Male ICR mice were implanted with the LFP electrode in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Animals were next subjected to induce METH CPP by peritoneal injection with 1mg/kg METH and 0.9% NaCl on an alternate day for ten sessions and confined to the corresponding compartment for 30min meanwhile control mice were given normal saline all day for both compartments. On testing day, either 10mg/kg CT or 20mg/kg bupropion (BP), a dopamine reuptake inhibitor, and VTA GABAergic suppressor were orally administered before CPP testing. The results exposed that CPP scores elevation was observed in the METH+vehicle and METH+BP mice, but this was reversed by CT treatment. Although both METH+vehicle and METH+BP enhanced the VTA delta power, NAc gamma I power, NAc delta-gamma coupling, and VTA-NAc gamma I coherence, changes in opposite trends of all mentioned parameters were seen by CT application. These improvements were postulated to involve the antidopaminergic effects of CT via modulations of neural signaling in the VTA and NAc. Altogether, the evidence-based study may suggest the using CT in alternative drugs for METH-seeking and craving therapy.”

https://pubmed.ncbi.nlm.nih.gov/36336144/

“From the encouraging results, the CT would be developed and deployed as a novel drug for the treatment of METH dependence.”

https://www.sciencedirect.com/science/article/pii/S0361923022003112?via%3Dihub