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

Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress

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“Several animal studies have described the potential effect of cannabidiol (CBD) in alleviating the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic inflammatory disease of the urinary bladder. However, the effects of CBD, its mechanism of action, and modulation of downstream signaling pathways in urothelial cells, the main effector cells in IC/BPS, have not been fully elucidated yet. Here, we investigated the effect of CBD against inflammation and oxidative stress in an in vitro model of IC/BPS comprised of TNFα-stimulated human urothelial cells SV-HUC1. Our results show that CBD treatment of urothelial cells significantly decreased TNFα-upregulated mRNA and protein expression of IL1α, IL8, CXCL1, and CXCL10, as well as attenuated NFκB phosphorylation. In addition, CBD treatment also diminished TNFα-driven cellular reactive oxygen species generation (ROS), by increasing the expression of the redox-sensitive transcription factor Nrf2, the antioxidant enzymes superoxide dismutase 1 and 2, and hem oxygenase 1. CBD-mediated effects in urothelial cells may occur by the activation of the PPARγ receptor since inhibition of PPARγ resulted in significantly diminished anti-inflammatory and antioxidant effects of CBD. Our observations provide new insights into the therapeutic potential of CBD through modulation of PPARγ/Nrf2/NFκB signaling pathways, which could be further exploited in the treatment of IC/BPS.”

https://pubmed.ncbi.nlm.nih.gov/36902479/

https://www.mdpi.com/1422-0067/24/5/5055

The antinociceptive activity and mechanism of action of cannabigerol

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Biomedicine & Pharmacotherapy

“Cannabis has been used for centuries to treat pain.

The antinociceptive activity of tetrahydrocannabinol (THC) or cannabidiol (CBD) has been widely studied. However, the antinociceptive effects of other cannabis components, such as cannabichromene (CBC) and cannabigerol (CBG), have rarely been revealed. The antinociceptive mechanism of CBG is not yet clear, so we investigated the antinociceptive effect of CBG on different pain models, and explored the mechanism of action of CBG to exert antinociceptive effects.

In the current study, we compared the antinociceptive effects of CBC, CBD, and CBG on the carrageenan-induced inflammatory pain model in mice, and the results showed that CBG had a better antinociceptive effects through intraplantar administration. On this basis, we further investigated the antinociceptive effect of CBG on CIA-induced arthritis pain model and nerve pain model in mice, and found that CBG also relieved on both types of pain. Then, we explored the antinociceptive mechanism of CBG, which revealed that CBG can activate TRPV1 and desensitize it to block the transmission of pain signals. In addition, CBG can further activate CB2R, but not CB1R, to stimulate the release of β-endorphin, which greatly promotes the antinociceptive effect.

Finally, the safety test results showed that CBG had no irritating effect on the rabbits’ skin, and it did not induce significant biochemical and hematological changes in mice. Transdermal delivery results also indicated that CBG has certain transdermal properties. Overall, this study indicates that CBG is promising for developing a transdermal dosage for pain management.”

https://pubmed.ncbi.nlm.nih.gov/36916438/

“Cannabigerol can exert antinociceptive effects on multiple pain models.”

https://www.sciencedirect.com/science/article/pii/S0753332222015529?via%3Dihub

Cannabidiol prevents chemotherapy-induced neuropathic pain by modulating spinal TLR4 via endocannabinoid system activation

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Journal of Pharmacy and Pharmacology

“Objectives: This study aimed to investigate the effect of cannabidiol (CBD) on type 4 Toll-like receptors (TLR4), glial cells and pro-inflammatory cytokines during the neuropathic pain induced by the chemotherapy agent paclitaxel (PTX), as well as the involvement of the endocannabinoid system in this process.

Methods: Male C57BL6 mice were subjected to PTX-induced neuropathic pain. To evaluate the involvement of the TLR4, glial cells and cannabinoid CB2 receptor, specific inhibitors or antagonists were intrathecally administered. The western blotting and immunofluorescence assay was performed to evaluate the spinal expression of TLR4, microglia, astrocytes and cannabinoid CB2 receptor. The levels of spinal pro-inflammatory cytokines and endocannabinoids were determined by enzyme-linked immunosorbent assay and liquid chromatography-mass spectrometry analysis, respectively.

Key findings: CBD prevented PTX-induced neuropathic pain, and the cannabinoid CB2 receptor antagonist AM630 reversed this effect. In addition, CBD treatment inhibited the spinal expression of TLR4 and Iba1 in mice with neuropathic pain. CBD also increased spinal levels of endocannabinoids anandamide and 2-arachidonoylglycerol, and reduced levels of cytokines in mice with neuropathic pain.

Conclusions: CBD was efficient in preventing PTX-induced neuropathic pain, and this effect may involve inhibition of the TLR4 on microglia spinal with activation of the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/36946366/

https://academic.oup.com/jpp/advance-article-abstract/doi/10.1093/jpp/rgad023/7083482?redirectedFrom=fulltext&login=false

Comparing the effects of medical cannabis for chronic pain patients with and without co-morbid anxiety: A cohort study

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“Introduction: There is growing evidence on the efficacy of cannabis-based medicinal products (CBMPs) for chronic pain (CP). Due to the interaction between CP and anxiety, and the potential impact of CBMPs on both anxiety and CP, this article aimed to compare the outcomes of CP patients with and without co-morbid anxiety following CBMP treatment.

Methods: Participants were prospectively enrolled and categorized by baseline General Anxiety Disorder-7(GAD-7) scores, into ‘no anxiety'(GAD-7 < 5) and ‘anxiety'(GAD-7 ≥ 5) cohorts. Primary outcomes were changes in Brief Pain Inventory Short-Form, Short-form McGill Pain Questionnaire-2, Pain Visual Analogue Scale, Sleep Quality Scale (SQS), GAD-7 and EQ-5D-5L index values at 1, 3 and 6 months.

Results: 1254 patients (anxiety = 711; no anxiety = 543) met inclusion criteria. Significant improvements in all primary outcomes were observed at all timepoints (p < 0.050), except GAD-7 in the no anxiety group(p > 0.050). The anxiety cohort reported greater improvements in EQ-5D-5L index values, SQS and GAD-7(p < 0.050), but there were no consistent differences in pain outcomes.

Conclusion: A potential association between CBMPs and improvements in pain and health-related quality of life (HRQoL) in CP patients was identified. Those with co-morbid anxiety reported greater improvements in HRQoL.”

https://pubmed.ncbi.nlm.nih.gov/36803620/

“A potential association between initiation of CBMPs and improvements in pain and HRQoL, as well as reductions in opioid consumption and an acceptable AE profile in both cohorts was found, complimenting previous UKMCR studies. Moreover, CP patients with co-morbid anxiety may achieve better HRQoL outcomes and potentially pain outcomes due to CBMPs’ peripheral and central effects.”

https://www.tandfonline.com/doi/full/10.1080/14737175.2023.2181696

A Retrospective Medical Record Review of Adults with Non-Cancer Diagnoses Prescribed Medicinal Cannabis

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“Research describing patients using medicinal cannabis and its effectiveness is lacking. We aimed to describe adults with non-cancer diagnoses who are prescribed medicinal cannabis via a retrospective medical record review and assess its effectiveness and safety. From 157 Australian records, most were female (63.7%; mean age 63.0 years). Most patients had neurological (58.0%) or musculoskeletal (24.8%) conditions. Medicinal cannabis was perceived beneficial by 53.5% of patients.

Mixed-effects modelling and post hoc multiple comparisons analysis showed significant changes overtime for pain, bowel problems, fatigue, difficulty sleeping, mood, quality of life (all p < 0.0001), breathing problems (p = 0.0035), and appetite (p = 0.0465) Symptom Assessment Scale scores. For the conditions, neuropathic pain/peripheral neuropathy had the highest rate of perceived benefit (66.6%), followed by Parkinson’s disease (60.9%), multiple sclerosis (60.0%), migraine (43.8%), chronic pain syndrome (42.1%), and spondylosis (40.0%). For the indications, medicinal cannabis had the greatest perceived effect on sleep (80.0%), followed by pain (51.5%), and muscle spasm (50%). Oral oil preparations of balanced delta-9-tetrahydrocannabinol/cannabidiol (average post-titration dose of 16.9 mg and 34.8 mg per day, respectively) were mainly prescribed. Somnolence was the most frequently reported side effect (21%).

This study supports medicinal cannabis’ potential to safely treat non-cancer chronic conditions and indications.”

“Cannabis (Cannabaceae) has been used medicinally since 400 AD for its analgesic, appetite enhancement, and myorelaxant properties. Emerging evidence suggests that people with chronic conditions may benefit from using medicinal cannabis for treating chronic pain, multiple sclerosis-related spasticity, epilepsy, Parkinson’s disease, insomnia, and anxiety.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965412/

A Phase I Randomized, Double-blind, Placebo-controlled Study on Efficacy and Safety Profile of a Sublingually Administered Cannabidiol /Delta 9-tetrahydrocannabidiol (10: 1) Regimen in Diabetes Type 2 Patients

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“The current study aimed to evaluate the safety profile and efficacy of a cannabis-based sublingual spray, CBDEX10® (containing 100 µg cannabidiol and 10 µg Δ9-tetrahydrocannabinol per puff; CBD/Δ9-THC 10:1), in improving lipid profile and glycemic state of the diabetic patients.

Fifty diabetic patients were randomly allocated to the treatment (n = 25; receiving two puffs of CBDEX10® twice daily) or the control groups (n = 25; receiving two puffs of placebo). The primary endpoint of the study was to evaluate the efficacy of the CBDEX10® adjunctive therapy in improving the lipid profile and glycemic state of diabetic patients; the secondary endpoint was to assess the safety profile and tolerability of the spray.

A statistically significant decline in total cholesterol [estimated treatment difference (ETD) = −19.73 mg/dL; P < 0.05], triglyceride (ETD = −27.84 mg/dL; P < 0.01), LDL-C (ETD = −5.37 mg/dL; P < 0.01), FBS (ETD = −12 mg/dL; P < 0.01), Hb A1C (ETD = −0.21 mg/dL; P < 0.01) and insulin secretion (ETD = -5.21 mIU/L; P < 0.01) was observable in the patients treated with CBDEX10® at the end of the 8-week treatment period. Regarding safety, the mentioned adjunctive regimen was well, and there were no serious or severe adverse effects.

Overall, CBDEX1® sublingual spray could be a new therapeutic agent for lipid and glycemic control in diabetic patients.”

“Based on these observations, the combination of CBD/Δ9-THC regimen could be a new therapeutic regimen for controlling the lipid profile and glycemic state of DM patients.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10024807/

Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease

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“Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer’s disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a novel nanoformulation containing melatonin, insulin, and THC in aged APPswe/PS1ΔE9 (APP/PS1) mice, a transgenic model of AD.

Transgenic mice at the age of 12 months were intranasally administered with a new nanoformulation containing melatonin, insulin, and THC at doses of 0.04, 0.008, and 0.02 mg/kg, respectively, once daily for 3 months. The spatial memory of the mice was assessed using the radial arm water maze (RAWM) test before and after drug treatment. Brain tissues were collected at the end of the treatment period for the assessment of Aβ load, tauopathy state, and markers of mitochondrial function.

The RAWM test revealed that the treatment with the melatonin-insulin-THC (MIT) nasal spray improved the spatial learning memory of APP/PS1 mice significantly. Results of protein analyses of brain homogenates indicated that MIT treatment significantly decreased the tau phosphorylation implicated in tau toxicity (p < 0.05) and the expression of CKMT1 associated with mitochondrial dysfunction. Moreover, MIT significantly decreased the expression of two mitochondrial fusion-related proteins, Mfn2 and Opa1 (p < 0.01 for both), while increasing the expression of a mitophagy regulator, Parkin, suggesting a compensatory enhancement of mitophagy due to MIT-promoted mitochondrial fusion.

In conclusion, this study was the first to demonstrate the ability of an MIT nanoformulation to improve spatial memory in AD mice through its multi-targeting effects on Aβ production, tau phosphorylation, and mitochondrial dynamics. Thus, MIT may be a safe and effective therapeutic for AD.”

https://pubmed.ncbi.nlm.nih.gov/36830601/

“The results of the present study provide the first evidence that MIT nanoformulation containing melatonin, insulin, and THC has potential as a multi-targeting treatment for AD.”

https://www.mdpi.com/2218-273X/13/2/232

Medical Cannabis for Chronic Nonmalignant Pain Management

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SpringerLink

“Purpose of review: Cannabis has been used since ancient times for medical and recreational research. This review article will document the validity of how medical cannabis can be utilized for chronic nonmalignant pain management.

Recent findings: Current cannabis research has shown that medical cannabis is indicated for symptom management for many conditions not limited to cancer, chronic pain, headaches, migraines, and psychological disorders (anxiety and post-traumatic stress disorder). Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are active ingredients in cannabis that modulate a patient’s symptoms. These compounds work to decrease nociception and symptom frequency via the endocannabinoid system. Research regarding pain management is limited within the USA as the Drug Enforcement Agency (DEA) classifies it as a schedule one drug. Few studies have found a limited relationship between chronic pain and medical cannabis use. A total of 77 articles were selected after a thorough screening process using PubMed and Google Scholar. This paper demonstrates that medical cannabis use provides adequate pain management. Patients suffering from chronic nonmalignant pain may benefit from medical cannabis due to its convenience and efficacy.”

https://pubmed.ncbi.nlm.nih.gov/36897501/

“Patients often seek medical consultations most commonly because of having intolerable chronic pain. Medications such as NSAIDs or opioids are being used to relieve such pain. However, long-term use of these medications can also cause adverse effects on health. Several studies have been done regarding cannabis as an alternative for chronic pain. Some patients were reported to get relief from cannabis consumption through various routes, and the use of it has been legalized, too, in some states in the USA and countries like Germany. Italy, the Netherlands, UK, Australia, Uruguay, Brazil, Colombia, Chile, Thailand, and Jamaica. Compared with opioids, studies show that cannabis use has lesser adverse effects, and it could even lessen opioid dependence.”

https://link.springer.com/article/10.1007/s11916-023-01101-w

Cannabinoids modulate the microbiota-gut-brain axis in HIV/SIV infection by reducing neuroinflammation and dysbiosis while concurrently elevating endocannabinoid and indole-3-propionate levels

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“Background: Although the advent of combination anti-retroviral therapy (cART) has transformed HIV into a manageable chronic disease, an estimated 30-50% of people living with HIV (PLWH) exhibit cognitive and motor deficits collectively known as HIV-associated neurocognitive disorders (HAND). A key driver of HAND neuropathology is chronic neuroinflammation, where proinflammatory mediators produced by activated microglia and macrophages are thought to inflict neuronal injury and loss. Moreover, the dysregulation of the microbiota-gut-brain axis (MGBA) in PLWH, consequent to gastrointestinal dysfunction and dysbiosis, can lead to neuroinflammation and persistent cognitive impairment, which underscores the need for new interventions.

Methods: We performed RNA-seq and microRNA profiling in basal ganglia (BG), metabolomics (plasma) and shotgun metagenomic sequencing (colon contents) in uninfected and SIV-infected rhesus macaques (RMs) administered vehicle (VEH/SIV) or delta-9-tetrahydrocannabinol (THC) (THC/SIV).

Results: Long-term, low-dose THC reduced neuroinflammation and dysbiosis and significantly increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid and indole-3-propionate levels in chronically SIV-infected RMs. Chronic THC potently blocked the upregulation of genes associated with type-I interferon responses (NLRC5, CCL2, CXCL10, IRF1, IRF7, STAT2, BST2), excitotoxicity (SLC7A11), and enhanced protein expression of WFS1 (endoplasmic reticulum stress) and CRYM (oxidative stress) in BG. Additionally, THC successfully countered miR-142-3p-mediated suppression of WFS1 protein expression via a cannabinoid receptor-1-mediated mechanism in HCN2 neuronal cells. Most importantly, THC significantly increased the relative abundance of Firmicutes and Clostridia including indole-3-propionate (C. botulinum, C. paraputrificum, and C. cadaveris) and butyrate (C. butyricum, Faecalibacterium prausnitzii and Butyricicoccus pullicaecorum) producers in colonic contents.

Conclusion: This study demonstrates the potential of long-term, low-dose THC to positively modulate the MGBA by reducing neuroinflammation, enhancing endocannabinoid levels and promoting the growth of gut bacterial species that produce neuroprotective metabolites, like indole-3-propionate. The findings from this study may benefit not only PLWH on cART, but also those with no access to cART and more importantly, those who fail to suppress the virus under cART.”

https://pubmed.ncbi.nlm.nih.gov/36890518/