The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence

“Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether “low-dose” CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ9 -tetrahydrocannabinol content greater than 2.0%.

Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300-400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti-addiction effects in drug-dependent individuals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., <300 mg/day) oral doses of CBD.”

https://pubmed.ncbi.nlm.nih.gov/36259271/

https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.13425

The inverse association of state cannabis vaping prevalence with the e-cigarette or vaping product-use associated lung injury

Lopiccolo & Chang in PLoS ONE – BU Linguistics

“The e-cigarette or vaping product-use-associated lung injury (EVALI) epidemic was primarily associated with the use of e-cigarettes containing tetrahydrocannabinol (THC)- the principal psychoactive substance in cannabis, and vitamin-E-acetate- an additive sometimes used in informally sourced THC-containing e-liquids. EVALI case burden varied across states, but it is unclear whether this was associated with state-level cannabis vaping prevalence. We, therefore, used linear regression models to assess the cross-sectional association between state-level cannabis vaping prevalence (obtained from the 2019 behavioral Risk Factor Surveillance System) and EVALI case burden (obtained from the Centers for Disease Control and Prevention) adjusted for state cannabis policies. Cannabis vaping prevalence ranged from 1.14%(95%CI, 0.61%-2.12%) in Wyoming to 3.11%(95%CI, 2.16%-4.44%) in New Hampshire. EVALI cases per million population ranged from 1.90(0.38-3.42) in Oklahoma to 59.10(19.70-96.53) in North Dakota.

There was no significant positive association but an inverse association between state cannabis vaping prevalence and EVALI case burden (Coefficient, -18.6; 95%CI, -37.5-0.4; p-value, 0.05).

Thus, state-level cannabis vaping prevalence was not positively associated with EVALI prevalence, suggesting that there may not be a simple direct link between state cannabis vaping prevalence and EVALI cases, but rather the relationship is likely more nuanced and possibly reflective of access to informal sources of THC-containing e-cigarettes.”

https://pubmed.ncbi.nlm.nih.gov/36251673/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0276187

Anti-cancer effects of selective cannabinoid agonists in pancreatic and breast cancer cells

“Objective: Cancer ranks first among the causes of morbidity and mortality all over the world, and it is expected to continue to be the main cause of death in the coming years. Therefore, new molecular targets and therapeutic strategies are urgently needed. In many cases, some reports show increased levels of endocannabinoids and their receptors in cancer, a condition often associated with tumour aggressiveness. Recent studies have suggested that cannabinoid-1/2 receptors contribute to tumour growth in a variety of cancers, including pancreatic, colon, prostate, and breast cancer. Understanding how cannabinoids can regulate key cellular processes involved in tumorigenesis, such as: cell proliferation and cell death, is crucial to improving existing and new therapeutic approaches for the cancer patients. The present study was aimed to characterize the in-vitro effect of L-759633 (a selective CB2 receptor agonist), ACPA (a selective CB1 receptor agonist) and ACEA (a selective CB1 receptor agonist) on the cell proliferation, clonogenicity, and apoptosis in pancreatic (PANC1) and breast (MDA-MB-231) cancer cells.

Methods: The viability and/or proliferation of cells were detected by MTS assay. A clonogenic survival assay was used to detect the ability of a single cell to grow into a colony. Apoptosis was determined with Annexin V staining (Annexin V-FITC/PI test) and by analyzing the expression of Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2).

Results: We found that selective CB1/2 agonists suppressed cell proliferation, clonogenicity and induced proapoptotic function in human PANC1 pancreatic and MDA-MB-231 breast cancer cells. Based on our findings, these agonists led to the inhibition of both cell viability and clonogenic growth in a dose dependent manner. CB1/2 agonists were observed to induce intrinsic apoptotic pathway by upregulating Bax, while downregulating Bcl-2 expression levels.

Conclusion: Our data suggests that CB1/2 agonists have the therapeutic potential through the inhibition of survival of human PANC1 pancreatic and MDA-MB-231 breast cancer cells and also might be linked with further cellular mechanisms for the prevention.”

https://pubmed.ncbi.nlm.nih.gov/36254639/

http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=7812&category_id=179&option=com_virtuemart&vmcchk=1&Itemid=1

“Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts”

https://pubmed.ncbi.nlm.nih.gov/36144796/

Medical cannabis for the treatment of comorbid symptoms in children with autism spectrum disorder: An interim analysis of biochemical safety

Frontiers - Crunchbase Company Profile & Funding

“Background: Autistic Spectrum Disorder (ASD) is a common neurodevelopmental disorder and no effective treatment for the core symptoms is currently available. The present study is part of a larger clinical trial assessing the effects of cannabis oil on autism co-morbidities. 

Objectives: The aim of the present study was to assess the safety of a CBD-rich oil treatment in children and adolescents with ASD. 

Methods: Data from 59 children and young adults (ages 5-25 years) from a single-arm, ongoing, prospective, open-label, one center, phase III study was analyzed. Participants received the Nitzan Spectrum® Oil, with cannabis extracts infused in medium chain triglyceride (MCT) oil with a cannabidiol:THC ratio of 20:1, for 6 months. Blood analysis was performed before treatment initiation, and after 3 months. Complete blood count, glucose, urea, creatinine, electrolytes, liver enzymes (AST, ALT, gamma glutamyl transferase), bilirubin, lipid profile, TSH, FT4, thyroid antibodies, prolactin, and testosterone measurements were performed at baseline, prior to starting treatment and at study midpoint, after 3 months of treatment. 

Results: 59 children (85% male and 15% female) were followed for 18 ± 8 weeks (mean ±SD). The mean total daily dose was 7.88 ± 4.24 mg/kg body weight. No clinically significant differences were found in any of the analytes between baseline and 3 months follow up. Lactate dehydrogenase was significantly higher before treatment (505.36 ± 95.1 IU/l) as compared to its level after 3 months of treatment (470.55 ± 84.22 IU/L) (p = 0.003). FT4 was significantly higher after 3 months of treatment (15.54 ± 1.9) as compared to its level before treatment (15.07 ± 1.88) (p = 0.03), as was TSH [(2.34 ± 1.17) and (2.05 ± 1.02)] before and after 3 months of treatment, respectively (p = 0.01). However, all these values were within normal range. A comparison of the group with additional medications (n = 14) to those who received solely medical cannabis (n = 45) showed no difference in biochemical analysis, including liver enzymes, which remained stable, except for change in potassium level which was significantly higher in the group that did not receive additional medications (0.04 ± 0.37) compared to the group receiving concomitant drug therapy (-0.2 ± 0.33) (p = 0.04). A comparison of patients who received a high dose of the cannabis oil (upper quartile-16 patients), with those receiving a low dose (lower quartile-14 patients) showed no significant difference between the two groups, except for the mean change of total protein, which was significantly higher among patients receiving high dose of CBD (0.19 ± 2.74) compared to those receiving a low dose of CBD (1.71 ± 2.46 (p = 0.01), and mean change in number of platelets, that was significantly lower among patients who received high dose of CBD (13.46 ± 31.38) as compared to those who received low dose of CBD (29.64 ± 26.2) (p = 0.0007). However, both of these changes lack clinical significance. 

Conclusion: CBD-rich cannabis oil (CBD: THC 20:1), appears to have a good safety profile. Long-term monitoring with a larger number of participants is warranted.”

https://pubmed.ncbi.nlm.nih.gov/36249785/

https://www.frontiersin.org/articles/10.3389/fphar.2022.977484/full

Cannabinoids for behavioral symptoms in severe dementia: Safety and feasibility in a long-term pilot observational study in nineteen patients

Frontiers - Crunchbase Company Profile & Funding


“Context: The management of behavioral symptoms and rigidity in patients with dementia constitutes a significant challenge. Short-term studies suggest an interest in the use of medical cannabis, but long-term data are lacking.

Objectives: The objective of this study was to investigate the feasibility and long-term safety of administering tetrahydrocannabinol/cannabidiol (THC/CBD) treatment as an additional drug to a poly medicated population with severe dementia, evaluate clinical improvements, and collect information on the pharmacokinetics of cannabinoids and possible drug-drug interactions.

Methods: A prospective observational study of patients with severe dementia living in a long-term care home to whom the physicians had prescribed a medical cannabis treatment. Data were collected over 2 years. We assessed the changes in medical cannabis dosages, safety parameters, variations in neuropsychiatric problems, agitation, rigidity, the most invalidating daily activity, and disabling behavior trouble scores. We evaluated the pharmacokinetics of cannabinoids by measuring plasma levels and analyzing the enzymatic activity.

Results: We assessed 19 patients (81.4 years-17 women and two men) receiving an average of 12.4 mg THC/24.8 mg CBD per day for up to 13 months, with no reported problems related to the treatment and limited adverse drug reactions. Clinical scores showed a marked improvement that was stable over time, deprescription of other medications, and care facilitated. The pharmacokinetic evaluation showed an expected slight reduction in the enzymatic activity of CYP1A2 and CYP2C19.

Conclusion: A long-term THC/CBD (1:2) medication can be administered safely and with overall positive clinical improvement to poly medicated older adults with severe dementia and associated problems. The results must be confirmed in a randomized trial.”

https://pubmed.ncbi.nlm.nih.gov/36247984/

“To our knowledge, this is the first study of this kind, with the administration of medical cannabis for an extended period in a highly vulnerable poly medicated demented population conducted within a “natural” setting. The natural cannabis oil has a THC: CBD proportion of 1:2, where CBD possibly reduces the THC psychoactive properties and other side effects previously reported with synthetic THC formulations. The dosages used in this study were significantly higher than the ones reported in other studies, even if the safety limits proposed for other pathologies were respected. Despite the particularity of the population, in which we could expect adverse events or complications, the side effects were limited. Also, the pharmacological profile was favorable and did not provide evidence of critical drug–drug interactions. The interest in medical cannabis is rising. Based on the results of this study, this new approach might represent a valid, feasible, and safe alternative for patients with dementia.”

https://www.frontiersin.org/articles/10.3389/fnagi.2022.957665/full

Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages

Frontiers - Crunchbase Company Profile & Funding

“Cannabis (Cannabis sativa) is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (-)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood. Here we report that CBD modulates type I interferon responses in human macrophages. Transcriptomics analysis shows that CBD treatment significantly attenuates cGAS-STING-mediated activation of type I Interferon response genes (ISGs) in monocytic THP-1 cells. We further showed that CBD treatment effectively attenuates 2’3-cGAMP stimulation of ISGs in both THP-1 cells and primary human macrophages. Interestingly, CBD significantly upregulates expression of autophagy receptor p62/SQSTM1. p62 is critical for autophagy-mediated degradation of stimulated STING. We observed that CBD treated THP-1 cells have elevated autophagy activity. Upon 2’3′-cGAMP stimulation, CBD treated cells have rapid downregulation of phosphorylated-STING, leading to attenuated expression of ISGs. The CBD attenuation of ISGs is reduced in autophagy deficient THP-1 cells, suggesting that the effects of CBD on ISGs is partially mediated by autophagy induction. Lastly, CBD decreases ISGs expression upon HIV infection in THP-1 cells and human primary macrophages, leading to increased HIV RNA expression 24 hours after infection. However, long term culture with CBD in infected primary macrophages reduced HIV viral spread, suggesting potential dichotomous roles of CBD in HIV replication. Our study highlights the immune modulatory effects of CBD and the needs for additional studies on its effect on viral infection and inflammation.”

https://pubmed.ncbi.nlm.nih.gov/36248834/

https://www.frontiersin.org/articles/10.3389/fimmu.2022.926696/full

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

Frontiers - Crunchbase Company Profile & Funding

“Neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor (CB2R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aim to assess the alterations in brain CB2R levels and evaluate novel CB2R imaging tracers in the arcAß mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for amyloid-ß deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB2R antibody was performed on brain slices from 17-month-old arcAß mice. Autoradiography using the CB2R imaging probes [18F]RoSMA-18-d6, [11C]RSR-056, and [11C]RS-028 and mRNA analysis were performed in brain tissue from arcAß and non-transgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB2R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAß mice compared to NTL mice. CB2R immunofluorescence was higher in glial cells inside 6E10-positive amyloid-ß deposits than peri-plaque glial cells, which showed low background immunofluorescence in the hippocampus and cortex of 17-month-old arcAß mice. Ex vivo autoradiography showed that the specific binding of [18F]RoSMA-18-d6 and [11C]RSR-056 was comparable in arcAß and NTL mice at 6, 17, and 24 months of age. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAß and NTL mice at 6, 17, or 24 months of age. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB2R expression levels in a mouse model of AD-related cerebral amyloidosis, emphasizing CB2R as a suitable target for imaging neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/36248003/

https://www.frontiersin.org/articles/10.3389/fnagi.2022.1018610/full

Design and function of targeted endocannabinoid nanoparticles

Scientific Reports

“Nanoparticles and nano-delivery systems are constantly being refined and developed for biomedical applications such as imaging, gene therapy, and targeted delivery of drugs. Nanoparticles deliver beneficial effects by both release of their cargo and by liberation of their constitutive structural components. The N-acylethanolamines linoleoyl ethanolamide (LEA) and oleoyl ethanolamide (OEA) both exhibit endocannabinoid-like activity. Here, we report on their ability to form nanoparticles that when conjugated with tissue-specific molecules, are capable of localizing to specific areas of the body and reducing inflammation. The facilitation of pharmacological effects by endocannabinoids at targeted sites provides a novel biocompatible drug delivery system and a therapeutic approach to the treatment, patient management and quality of life, in conditions such as arthritis, epilepsy, and cancer.”

https://pubmed.ncbi.nlm.nih.gov/36241847/

https://www.nature.com/articles/s41598-022-21715-1

Endocannabinoid signaling in microglia

“Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention.

Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases.

Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an anti-inflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds.

This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs.

Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.”

https://pubmed.ncbi.nlm.nih.gov/36222019/

https://onlinelibrary.wiley.com/doi/10.1002/glia.24281

Tonic Endocannabinoid Levels Modulate Retinal Signaling

ijerph-logo

“The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.”

https://pubmed.ncbi.nlm.nih.gov/36231760/

https://www.mdpi.com/1660-4601/19/19/12460/htm