Article

Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts

Authors:

Weizmann Institute of Science

Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femora from rats given a mixture of CBD and THC for 8 weeks were markedly increased by CBD. This effect is not shared by Δ(9) -tetrahydrocannabinol (THC, the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks post fracture followed by attenuation of the CBD effect at 8 weeks. Using μCT, the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier Transform Infrared Spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Examining the role of cannabinoids on osteoporosis: a review

Article

Full-text available

Nov 2022

PurposePrior research studies have shown that the endocannabinoid system, influenced by CBD and THC, plays a role in bone remodeling. As both the research on cannabis and use of cannabis continue to grow, novel medicinal uses of both its constituents as well as the whole plant are being discovered. This review examines the role of cannabinoids on osteoporosis, more specifically, the endocannabinoid system and its role in bone remodeling and the involvement of the cannabinoid receptors 1 and 2 in bone health, as well as the effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and synthetic cannabinoids on bone.MethodsA comprehensive literature search of online databases including PUBMED was utilized.ResultsA total of 29 studies investigating the effects of cannabis and/or its constituents as well as the activation or inactivation of cannabinoid receptors 1 and 2 were included and discussed.Conclusion While many of the mechanisms are still not yet fully understood, both preclinical and clinical studies show that the effects of cannabis mediated through the endocannabinoid system may prove to be an effective treatment option for individuals with osteoporosis.

A COMPARATIVE QUALITATIVE STUDY OF THE TYPES OF TRADITIONAL TREATMENT OF FRACTURES BY TRADITIONAL HEALTH PRACTITIONERS IN KWAZULU-NATAL, SOUTH AFRICA AND THE NORTH ISLAND OF NEW ZEALAND: A SURVEY-BASED STUDY

Article

Full-text available

Nov 2020

Abstract Background: Traditional methods for the treatment of fractures world-wide include the physical manipulation (resetting) of bones and traditional herbal remedies in various dosage forms. Although traditional bone-setting is no longer widely practiced in most developed countries, traditional remedies (plant or animal derived) are still used to treat fractures. Traditional health practitioners administer a variety of traditional medicines for bone strengthening, pain relieving, inflammation reduction and speedy recovery of fractures. An objective of this study was to determine the types of treatment administered for fractures according to Zulu medicine practices in KwaZulu-Natal, South Africa and Māori medicine practices in the North Island of New Zealand. Methods: Traditional health practitioners who routinely practice in urban, semi-urban and rural areas of three districts in KwaZulu-Natal, South Africa and in the North Island of New Zealand were surveyed between October 2018 and September 2019. A mixed method study was conducted by a survey, and a moderator with a single focus group of three traditional health practitioners, resulting in qualitative research based on their traditional treatment/management of fractures in South Africa and New Zealand. Results: In both South Africa and New Zealand, traditional health practitioners included in this study practiced in a similar way, mainly as traditional Zulu herbalists or Izinyanga in South Africa (22/26. 84.6%) and as Tohunga-Rongoā or traditional Māori practitioners who are experts in medicine and healing (12/12, 100%) in New Zealand. Although the respondents were mainly herbalists in KwaZulu-Natal, South Africa, four practiced as diviners (Izangoma). Most of the respondents were male (20/38, 52.6%) practitioners who practiced as traditional health practitioners for 11-20 years (13/26, 50%) in SA and the same length of time in New Zealand (5/12, 41.7%). It was interesting to note that traditional health practitioners interviewed in this study in both New Zealand and South Africa, no longer practiced the manipulation of bones or traditional bone-setting. Rather they used traditional mixtures with presumed fracture-healing activity. The formulae for preparing 74 traditional medicines were documented. Conclusion: Traditional health practitioners surveyed in this study identified 47 traditional medicines from South Africa and 27 traditional medicines from New Zealand with presumed fracture-healing activity. Traditional medicine preparations of Umhlabelo (Talinum caffrum) and Umahlanganisa (Drimia delagoensis) in South Africa, and Harakeke (Phormium tenax) and Tutu (Coriaria arborea) in New Zealand were most prescribed by traditional health practitioners to treat fractures. Further investigation is warranted on the phytochemical compositions of the two most commonly used herbal mixtures identified above, each in South Africa and New Zealand. The use of support structures for fractures to limit mobility, prevent further injury and promote healing by Izinyanga (Zulu traditional herbalists) should be encouraged. Keywords: Traditional medicine, traditional health practitioner, traditional Zulu medicine, traditional Māori medicine, broken bones, fractures, conventional medicine.

Article

Full-text available

Jan 2020

Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research

Article

Full-text available

Jul 2020

Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.

Cannabinoid Use in Musculoskeletal Illness: a Review of the Current Evidence

Article

Full-text available

Aug 2020

Purpose of review: The use of cannabinoids has increased since legalization of recreational and medical use in the USA. It is likely that many orthopaedic patients consume cannabinoid products during the traumatic or perioperative period. The purpose of this study was to investigate the pre-clinical data evaluating the mechanism of action of cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (Δ9-THC) and to evaluate the current clinical data on the use of cannabinoids in musculoskeletal illness. Recent findings: Recent pre-clinical studies have demonstrated that cannabinoid use and the endocannabinoid system (ECS) has an important role in bone healing and bone homeostasis. There is data that suggests that the use of cannabidiol (CBD) may increase bone healing, whereas the use of Δ9-Tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in marijuana, likely inhibits bone metabolism and repair. The clinical implications and consumption of marijuana by orthopaedic patients have not been thoroughly evaluated. Studies have demonstrated concern for negative cardiovascular and psychiatric effects caused by marijuana use, but have not yet elucidated outcomes in the orthopaedic literature. With the recent increase in advertising of CBD products and legalization of marijuana, it is likely that many orthopaedic patients are consuming cannabinoid products. The clinical implications and consumption of these products are unclear. We need more robust and well-designed clinical studies prior to making further recommendations to our patients on the consumption of these products.

Serum Markers of Bone Turnover Following Controlled Administration of Two Medical Cannabis Products in Healthy Adults

Article

Nov 2022

Introduction: Cannabidiol (CBD) has been shown to maintain bone integrity in pre-clinical models, but little is known about the effects of delta-9-tetrahydrocannabinol (THC) on bone turnover. In this study we explored the effects of two oral medical cannabis products on normal bone homeostasis through evaluation of markers of bone resorption (carboxyl-terminal collagen crosslinks, CTx) and bone formation (procollagen type 1 N-terminal propeptide, P1NP; alkaline phosphatase, ALP). Methods: This study is an analysis of secondary data from two Phase 1 double-blind, placebo-controlled trials of Spectrum Yellow (0.9 mg THC, 20 mg CBD/mL of oil) and Spectrum Red (2.5 mg THC, 0.3 mg CBD/softgel). Healthy participants (n=38 men, 45 women) were randomized to receive 5-20 mg THC (CBD levels varied as a function of administered product) or placebo daily (BID) for 7 days. Bone markers were assessed at baseline, upon completion of product administration (day 8), and after a 5-day washout (day 13). Results: All bone markers were significantly higher in men at baseline (p≤0.008). For CTx, there was a significant day×group interaction (F=3.23, p=0.04); CTx levels were significantly lower in participants treated with Spectrum Red (b=-164.28; 95% confidence interval [CI], -328 to -0.29; p=0.04) and marginally lower in participants treated with Spectrum Yellow (b=-157.31; 95% CI, -323 to 8.68; p=0.06) versus placebo on day 8. For P1NP and ALP, there were no significant differences between treatments across study days. Bone marker values outside the reference range (RR) were observed; CTx > RR (n=71) was predominantly (85.9%) observed in male participants, whereas P1NP > RR (n=100) was more evenly distributed between sexes (53.0% in men). These were not considered clinically significant and did not differ between treatment groups. Conclusions: These are the first interventional human data on the effect of cannabinoids on biomarkers of bone turnover. Short-term treatment with CBD- or THC-dominant medical cannabis products resulted in attenuation of a marker of bone resorption. Although the attenuation was not clinically significant, this finding may be indicative of protective properties of cannabinoids in bone. Further research over longer dosing durations in individuals exhibiting bone-specific conditions (e.g., osteoporosis) is warranted. ClinicalTrials.gov IDs: ACTRN12619001723178 and ACTRN12619001450101.

Cannabinoids for Pain Modulation in Orthopedic Surgery

Article

Jul 2022

Cannabinoid compounds are being increasingly used as an analgesic adjuvant in the orthopedic population, but little data exist to either support or oppose this practice pattern. A review of all contemporary (2000-2020) studies on the use of cannabinoids in orthopedics is presented. Physicians and patients are optimistic that cannabinoids can decrease pain scores and perhaps opioid use; however, their application in orthopedics is not well characterized. In addition to the social stigma regarding the use of cannabis, there is limited high-quality evidence of the efficacy of cannabinoids in treating orthopedic-related pain. As cannabis becomes more accessible, well-designed trials are needed to better understand cannabinoids and guide orthopedic practice. [Orthopedics. 202x;xx(x):xx-xx.].

A Natural Language Processing Pipeline to Study Disparities in Cannabis Use and Documentation Among Children and Young Adults A Survey of 21 Years of Electronic Health Records

Preprint

Full-text available

Oct 2022

The legalizations of medical and recreational cannabis have generated a great deal of interest in studying the health impacts of cannabis products. Despite increases in cannabis use, its documentation during clinical visits is not yet mainstream. This lack of information hampers efforts to study cannabis effects on health outcomes. A clear and in-depth understanding of current trends in cannabis use documentation is necessary to develop proper guidelines to screen and document cannabis use. Here we have developed and used a hierarchical natural language processing pipeline (AUROC=0.94) to evaluate the trends and disparities in cannabis documentation on more than 23 million notes from a large cohort of 370,087 patients seen in a high-volume multi-site pediatric and young adult clinic over a period of 21 years. Our findings show a very low but growing rate of cannabis use documentation (<2%) in electronic health records with significant demographic and socioeconomic disparities in both documentation and use, which requires further attention.

Plant-based Bone Grafting: The Future of Bone Healing

Preprint

Jan 2023

Objectives Bone fractures are very common diseases, which can be caused by impact injuries or physiological disorders. Thus, the present review aimed to study the use of medicinal plants in the healing mechanism of bone fractures. Evidence acquisition Through research in the PubMed, Google Academic, and Scielo databases, this article reviews 11 ethnopharmacological studies and 34 preclinical studies on the biological actions of different plants in bone fracture healing mechanism. Results Indian tribes have highlighted in the plants ethnopharmacological study for various diseases, including bone fractures. However, despite the large citations of traditional use, technical-scientific studies are still scarce in the literature. Chenopodium ambrosioides, Piper sarmentosum, quadrangular Cissus, Ricinus communis and Radix salvia miltiorrhiza plants were the most studied in the literature regarding their osteogenic, angiogenic, anti-inflammatory and remodeling effects, acting on bone receptors, stimulating bone metabolism, increasing minerals uptake, and assisting in free radicals breakdown. Conclusion Thus, the medicinal plants use is promising in the field of bone regeneration, as well as being alternative when conventional therapies are unfeasible, increasing herbal medicines demand and popularity.

Dietary Hempseed Decreases Femur Maximum Load in a Young Female C57BL/6 Mouse Model but Does Not Influence Bone Mineral Density or Micro-Architecture

Article

Full-text available

Oct 2022

Numerous seed and seed extract diets have been investigated as a means of combating age-related bone loss, with many findings suggesting that the seeds/extracts confer positive effects on bone. Recently, there has been rising interest in the use of dietary hempseed in human and animal diets due to a perceived health benefit from the seed. Despite this, there has been a lack of research investigating the physiologic effects of dietary hempseed on bone. Previous studies have suggested that hempseed may enhance bone strength. However, a complete understanding of the effects of hempseed on bone mineralization, bone micro-architecture, and bone biomechanical properties is lacking. Using a young and developing female C57BL/6 mouse model, we aimed to fill these gaps in knowledge. From five to twenty-nine weeks of age, the mice were raised on either a control (0%), 50 g/kg (5%), or 150 g/kg (15%) hempseed diet (n = 8 per group). It was found that the diet did not influence the bone mineral density or micro-architecture of either the right femur or L5 vertebrae. Furthermore, it did not influence the stiffness, yield load, post-yield displacement, or work-to-fracture of the right femur. Interestingly, it reduced the maximum load of the right femur in the 15% hempseed group compared to the control group. This finding suggests that a hempseed-enriched diet provides no benefit to bone in young, developing C57BL/6 mice and may even reduce bone strength.

Cannabidiol in Dentistry: A Scoping Review

Article

Full-text available

Oct 2022

Cannabidiol (CBD) has been gaining increased attention in contemporary society but seems to have been little explored in dentistry. This scoping review mapped the scientific and technological scenarios related to the use of CBD in dentistry. Peer-reviewed publications were searched in five international databases, patents were searched in five technological platforms. In total, 11 articles and 13 patents involving CBD in dentistry-related applications were included. The countries contributing to most articles were Brazil (27.3%) and USA (18.2%). The studies involved experiments on animals (63.6%) and/or using bacteria or cells (36.4%), and no clinical study was found. Three different applications of CBD were observed: periodontal therapy (45.4%), aid for bone regeneration (27.3%), and general use in oral therapies (27.3%). Patent inventors were based in China (53.8%) or USA (46.2%). The patent claims were mainly compositions for oral care, tooth whitening, injury repair, antifungal, anti-inflammatory, and analgesic effects. A total of 76.9% of the patents were filed in association with a company. In general, research suggests that CBD has promising biological properties for applications in dentistry, whereas patents indicate that the current interest of industry relies on compositions for oral care. There appears to be extensive room available for research and technological applications of CBD in dentistry.

Assessment of spent hemp biomass as a potential ingredient in ruminant diet: Nutritional quality and effect on performance, meat and carcass quality, and hematological parameters in finishing lambs

Article

Aug 2022

Spent hemp biomass (SHB), a byproduct of cannabinoids extraction from the production of industrial hemp has not been approved by FDA-CVM since its effects on animal health, performance, and product quality are unknown. Our objective was to investigate the effects of feeding two levels of SHB and a four-week withdrawal period on performance, carcass characteristic, meat quality and hematological parameters in finishing lambs. A total of 35 weaned, Polypay male lambs kept in single pens were randomly assigned to five feeding treatments (n=7) and fed diets containing either no SHB (CON) or SHB at 10% (LH1) or 20% (HH1) for 4 weeks with 4 weeks of clearing period from SHB, or SHB at 10 (LH2) or 20% (HH2) for 8 weeks. Chemical analysis revealed SHB to have nutritive quality similar to alfalfa with no mycotoxin, terpenes, or organic residuals as a result of the extraction process. Feed intake of lambs was negatively affected by 20% SHB in Period 1 but not in Period 2 where feed intake was the greatest in HH1 and LH2. In contrast, none of the performance data, including liveweight gains, were different across the groups and periods. In Period 1, blood glucose, cholesterol, calcium, paraoxonase, and tocopherol were decreased by the level of SHB fed, while bilirubin and alkaline phosphatase (ALP) were increased. In Period 2, concentration in blood of urea, magnesium, bilirubin, ALP, and ferric reducing ability of the plasma (FRAP) were higher in LH2 and HH2 as compared to CON, while β-hydroxybutyrate was lower in HH2. Blood parameters related to liver health, kidney function, immune status, and inflammation were unaffected by feeding SHB. Most carcass and meat quality parameters did not differ across feeding groups either. Except carcass purge loss and meat cook loss were larger in lambs that were fed 20% SHB. Although lower feed intake of lambs that were fed 20% SHB initially in period 1 suggested SHB was not palatable to the lambs, increased feed intake at lower level of inclusion at 10% in Period 2 may point to a positive long-term effect of feeding SHB.

Using the BMD Approach to Derive Acceptable Daily Intakes of Cannabidiol (CBD) and Tetrahydrocannabinol (THC) Relevant to Electronic Cigarette Liquids

Article

Full-text available

Jul 2022
FRONT BIOSCI

Background: In the past 60 years, Cannabis sativa L. has been an object of increasing interest because of the psychotropic effects of some of its constituents. These effects mainly arise from the cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). C. sativa species also synthesize and accumulate the non-psychotropic compound cannabidiol (CBD). Due to their therapeutic potential, both cannabinoids are an object of medical research and drug development. More recently, CBD has received increasing interest as an ingredient in electronic cigarette liquids (e-liquids). This trend may have been reinforced by health and disease-related claims, often based on clinical studies, which are used to advertise CBD. CBD liquids may be based on full-spectrum hemp extracts, CBD isolates, or synthetic CBD, all of which may contain some residual levels of Δ9-THC from either natural content (in the extracts) or from possible degradation of CBD to Δ9-THC, which may occur during storage. There is uncertainty about safety regarding the consumption of CBD (and Δ9-THC) in e-liquids. The aim of this publication was to present an approach for a toxicological risk assessment of CBD and Δ9-THC relevant to e-liquids by using the benchmark dose (BMD) approach. Materials and methods: Before an analysis to estimate a reference dose (RfD) for both cannabinoids, a systematic review of dose-response data was conducted. The data obtained were analyzed using the BMD approach to derive a benchmark dose lower confidence limit (BMDL). The BMDL was used as a point of departure to estimate the RfD. Results: No adequate human data suitable for dose-response modeling were identified. Based on animal data, the RfD values for the most sensitive endpoints were selected. For CBD, an RfD for acute exposure of 1 mg/kg body weight (bw) was estimated. For Δ9-THC, an acute RfD was found to be 0.006 mg/kg bw. Additionally, the RfD for chronic exposure to CBD was estimated to be 4 mg/kg bw per day. The respective endpoints for CBD were a reduction in norepinephrine turnover and a reduction in uterus weight. The endpoint for Δ9-THC was a change in blood pressure. Conclusions: Because of the limited availability and quality of dose-response data, it cannot be excluded that the estimated RfD values might be afflicted with considerable uncertainties. Therefore, it is recommended to conduct further research on dose-response data, preferably from human studies.

Systematic Review In-vitro and in-vivo supportive research on medicinal properties of Cannabis sativa: A comprehensive review

Article

Full-text available

Mar 2022

Cannabis sativa is an herbaceous plant which is mainly used as a remedy for neurological, digestive and immunological ailments in traditional medicine. Even though Cannabis is the most illicit plant around the world, its medicinal properties are beneficial in number of ways. Numerous beneficial effects of C. sativa have been demonstrated in multiple in-vitro and in-vivo studies from different parts of the world. The aim of this paper was to systematically review the literature and provide a summary on potential medicinal benefits of C. sativa. This systematic review was conducted by using the data bases; Science direct and PubMed for studies published from 1st of January 2015 to 31st of October 2020. In order to obtain further data, a manual search was also carried out from the reference lists of included articles. After removing the duplicate articles 77 total number of articles included in this present review. The beneficial health effects of C. sativa were anti-inflammatory, analgesic, anti-microbial, anti-parasitic, anti-oxidant and anti-cancer properties. In addition, it revealed that C. sativa lower blood glucose, serum cholesterol and blood pressure levels. Apart from that, the use of Cannabis in other diseases such as irritable bowel disease, renal diseases, neurofibromatosis, and leucorrhea was also identified. The wide range of medicinal effects may be due to main active ingredients of Tetrahydro cannabinol, Cannabidiol, Cannabinol and Tetrahydro cannabivarin. Available in-vitro and invivo evidence suggested that C. sativa has many favorable health effects and further randomized controlled clinical trials will be needed to determine these effects thoroughly

Components of the Endocannabinoid System and Effects of Cannabinoids Against Bone Diseases: A Mini-Review

Article

Full-text available

Jan 2022

Background: The endocannabinoid system (ECS) is involved in multiple physiological processes, including appetite regulation, pain perception, motor function development, and immune response regulation. Cannabinoids have been approved for the clinical treatment of nausea and vomiting caused by cytostatic therapy or cancer chemotherapy, loss of appetite in HIV/AIDS-associated cachexia, refractory spasms induced by multiple sclerosis, chronic pain, and urinary incontinence. Methods: Check out the research on ECS and bone diseases in the past 20 years. Results: Many studies have demonstrated that endocannabinoids (eCBs) and cannabinoid receptors (CBRs) are expressed in bone and synovial tissues, playing important roles in bone metabolism. Preclinical studies using cannabis-based therapies in animal models have shown that cannabinoids (CBs) can alleviate the development of osteoarthritis (OA), prevent osteoporosis (OP), reduce cancer-induced osteolytic destruction, and improve fracture healing, highlighting the therapeutic potential of CBs for human bone diseases. Conclusions: The present review summarizes various components of the ECS in bone diseases and their potential as a therapeutic target.

Association of cannabinoid receptor modulation with normal and abnormal skeletal remodelling: A systematic review and meta-analysis of in vitro, in vivo and human studies

Article

Nov 2021
PHARMACOL RES

To address the inconsistent findings from studies that used different models to explore the role of classical cannabinoid type 1 (CB1) and 2 (CB2) receptors in skeletal remodelling, we searched Medline, Web of Science and Embase for relevant studies from inception to June 23, 2020. We identified 38 in vitro, 34 in vivo and 9 human studies. A meta-analysis of in vitro studies showed that exposure to the inverse-agonists AM251 (mean difference [MD]:-26.75, 95% confidence interval [CI]:-45.36,-8.14, p=0.005), AM630 (standard[std.] MD:-3.11, CI:-5.26,-0.97, p=0.004; SR144528, std.MD:-4.88, CI -7.58,-2.18, p=0.0004) and CBD (std.MD:-1.39, CI -2.64,-0.14, p=0.03) is associated with reduced osteoclastogenesis, whereas the endocannabinoid 2-AG (std.MD:2.00, CI:0.11-3.89, p=0.04) and CB2-selective agonist HU308 (MD:19.38, CI:11.75-27.01, p<0.00001) were inhibitory. HU308 also enhanced osteoblast differentiation (std.MD:2.22, CI:0.95-3.50, p=0.0006) and activity (std.MD:2.97, CI:1.22-4.71, p=0.0008). In models of bone loss, CB1/2 deficiency enhanced peak bone volume (std.MD:3.70, CI:1.77-5.63, p=0.0002) and bone formation (std.MD:-0.54, CI:-0.90,-0.17, p=0.004) in female mice. In male rats, CB1/2 deficiency (std.MD:2.31, CI:0.30-4.33, p=0.02) and AM251 or CBD treatments (std.MD:2.19, CI:0.46-3.93, p=0.01) enhanced bone volume. CB1/2 deficiency (std.MD:9.78, CI:4.96-14.61, p<0.0001) and AM251 or AM630 treatments (std.MD:28.19, CI:19.13-37.25, p<0.0001) were associated with osteoprotection. The CB2-selective agonists JWH133 and 4Q3C enhanced bone volume in arthritic rodents (std.MD:14.45, CI:2.08-26.81, p=0.02). In human, CB2 SNPs (AA:rs2501431, MD:-0.28, CI:-0.55,-0.01, p=0.04; CC:rs2501432, MD:-0.29, CI:-0.56,-0.02, p=0.03) were associated with reduced bone mineral density, however the association of Marijuana use remains unclear. Thus, CB1/2 modulation is associated with altered bone metabolism, however findings are confounded by low study number and heterogenicity of models. Data availability The datasets used and analysed in the present study are available from the public sources described

333 Assessment of Spent Hemp Biomass as a Potential Feedstuff in Ruminant Diets

Article

Oct 2021

The 2018 Farm Bill removed hemp (Cannabis sativa) from the Controlled Substances Act, classifying it as an agricultural product. The process of cannabidiol extraction from hemp yields large quantities of spent hemp biomass (SHB) that may potentially be included in animal diets. However, the use of SHB in animal diets has not been approved by FDA yet since its effect on animal health, production and product quality is still unknown. Thus, a feeding study was carried out to investigate the effects of varying levels of SHB and a four-week withdrawal period on feed intake and liveweight gains of weaned lambs. A total of 35 weaned, male Polypay lambs kept in single pens were randomly assigned to five feeding treatments (n=7) and fed diets containing either no SHB (CON) or SHB at 10% (LH1) or 20% (HH1) for 4 weeks with 4 weeks withdrawal from SHB, or SHB at 10 (LH2) or 20% (HH2) for 8 weeks. The nutritive analysis of the SHB indicated a high-quality feed, with 20% (DM) crude protein and 27% NDF. Dry matter (DM) intake of lambs was negatively affected by 20% SHB during the first period. In the second period, DM intake was larger in lambs fed 10% SHB vs. CON, with the largest feed intake observed in HH1 lambs. In contrast, none of the performance data, including liveweight gains, were different across the groups and periods. Feeding 20% SHB decreased plasma cholesterol, NEFA, BHBA, Ca, and Cl and increased urea and Mg, while 10% SHB increased glucose, cholesterol, and NEFA. Our findings indicated that 10% SHB can be included in ruminant diets without causing any detrimental effect on performance with a possible positive effect on feed intake. The long-term feeding of 20% SHB strongly affects the metabolism.

The effects of cannabis and cannabinoids on the endocrine system

Article

Full-text available

Jun 2022
REV ENDOCR METAB DIS

With the increase in cannabis use due to policy changes and areas of decriminalization, it is important to recognize the potential impact of these substances on endocrine processes. Cannabinoids have many effects by activating the endocannabinoid system. This system plays a role in the normal functioning of nearly every organ and consists of the body’s natural endocannabinoids, the cannabinoid receptors, and the enzymes and processes that regulate endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) are known to act through cannabinoid type 1 and 2 receptors, and have been shown to mimic endocannabinoid signaling and affect receptor expression. This review summarizes the known impacts of cannabis on thyroid, adrenal, and gonadal function in addition to glucose control, lipids, and bone metabolism, including: reduced female fertility, increased risk of adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunting of stress response with chronic use, increased risk of prediabetes but lower risk of diabetes, suggested improvement of high density lipoproteins and triglycerides, and modest increase in fracture risk. The known properties of endocannabinoids, animal data, population data, and the possible benefits and concerns of cannabinoid use on hormonal function are discussed. The interconnectivity of the endocrine and endocannabinoid systems suggests opportunities for future therapeutic modalities which are an area of active investigation.

L’usage du cannabidiol dans le sport : une bonne idée ?

Article

Jul 2021
SCI SPORT

Résumé Objectifs Dans cet article, nous souhaitons faire le point sur les différentes propriétés du cannabidiol (CBD) potentiellement intéressantes pour le sportif. Actualités Le CBD est, avec le Δ9-tetrahydrocannabinol, l’un des phytocannabinoïdes les plus abondants du Cannabis Sativa L. Avec la levée de l’interdiction en 2018 du CBD par l’Agence mondiale anti-dopage, il est probable que les sportifs se tournent davantage vers les produits au CBD dérivés du Cannabis Sativa L. Perspectives et projets Des études précliniques sur le CBD ont montré des effets anxiolytiques, analgésiques, anti-inflammatoires, neuroprotecteurs mais également sur le sommeil. Ces propriétés pourraient être intéressantes dans la gestion des blessures, des commotions, de l’anxiété et des troubles du sommeil. Si le CBD paraît être une molécule sûre, les effets secondaires indésirables existent bel et bien et notamment pour les produits non réglementés. Conclusion Le manque de preuves scientifiques et le trop peu d’études cliniques appliquées aux sportifs ne permettent pas, pour le moment, de recommander l’utilisation du CBD aux athlètes.

The impact of E-cigarette vaping and vapour constituents on bone health

Article

Full-text available

May 2021
J Inflamm

Background In contrast to cigarettes, electronic cigarette use (E-cigarettes) has grown substantially over the last decade. This is due to their promotion as both a safer alternative to cigarettes and as an aide to stop smoking. Critically, upon E-cigarette use, the user may be exposed to high doses of nicotine in addition to other compounds including flavouring chemicals, metal particulates and carbonyl compounds, particularly in highly vascularised tissues such as bone. However, there has been limited investigation into the impact of E-cigarette usage on bone physiology, particularly over extended time periods and there are no clinical recommendations regarding E-cigarette usage in relation to orthopaedic surgery. This literature review draws together data from studies that have investigated the impact of E-cigarette vapour and its major constituents on bone, detailing the models utilised and the relevant mechanistic and functional results. Main body Currently there is a lack of studies both in vivo and in vitro that have utilised E-cigarette vapour, necessary to account for changes in chemical composition of E-cigarette liquids upon vaping. There is however evidence that human bone and bone cells express nicotine receptors and exposure of both osteoblasts and osteoclasts to nicotine, in high concentrations may reduce their viability and impair function. Similarly, it appears that aldehydes and flavouring chemicals may also negatively impact osteoblast viability and their ability to form bone. However, such functional findings are predominantly the result of studies utilising bone cell lines such as MG-63 or Saos-2 cells, with limited use of human osteoblasts or osteoclasts. Additionally, there is limited consideration for a possible impact on mesenchymal stem cells, which can also play an import role in bone repair. Conclusion Understanding the function and mechanism of action of the various components of E-cigarette vapour in mediating human bone cell function, in addition to long term studies to determine the potential harm of chronic E-cigarette use on human bone will be important to inform users of potential risks, particularly regarding bone healing following orthopaedic surgery and injury.

The Effects of Cannabis: Implications for the Surgical Patient

Article

Full-text available

Mar 2021

Cannabis use is increasingly prevalent. Cannabinoid receptors regulate pro-inflammatory cytokines, and compounds in marijuana exert diverse physiologic effects. As more patients use cannabis, clinicians should recognize implications of perioperative cannabis use. Although the role of cannabis use in perioperative pain control has been explored, little is known about its effect on perioperative wound healing or on hematologic, pulmonary, and cardiovascular physiology. Methods: We searched PubMed for English-language articles related to cannabis (ie, marijuana, cannabidiol oil, and tetrahydrocannabinol) and wound healing, cardiovascular, pulmonary, or hematologic outcomes, and surgery. Titles and abstracts were reviewed, and relevant articles were analyzed. Human, animal, and pathology studies were included. Editorials, case reports, and review articles were excluded. Results: In total, 2549 wound healing articles were identified; 5 human studies and 8 animal/pathology studies were included. Results were conflicting. An estimated 2900 articles related to cardiovascular effects were identified, of which 2 human studies were included, which showed tetrahydrocannabinol and marijuana caused tachycardia. A total of 142 studies regarding pulmonary effects were identified. Three human studies were included, which found no difference in respiratory complications. In total, 114 studies regarding hematologic effects were identified. The 3 included human studies found conflicting venous thromboembolism risks. The overall study quality was poor. Information about dose/duration, administration route, and follow-up was reported with variable completeness. Conclusions: Surgeons should consider effects of cannabis in the perioperative setting. Little is known about its perioperative effects on wound healing, or on cardiovascular, pulmonary, and hematologic physiology. Further research should elucidate the effects of administration route, dose, and timing of cannabis use among surgical patients.

Do E-cigarettes and vaping have a lower risk of osteoporosis, nonunion, and infection than tobacco smoking?

Article

Full-text available

Mar 2021

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Article

Full-text available

Jul 2020
INT J MOL SCI

As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

Cannabidiol: A Brief Review of Its Therapeutic and Pharmacologic Efficacy in the Management of Joint Disease

Article

Mar 2020

Cannabis use in the management of musculoskeletal diseases has gained advocacy since several states have legalized its recreational use. Cannabidiol (CBD), a commercially available, non-neurotropic marijuana constituent, has shown promise in arthritic animal models by attenuating pro-inflammatory immune responses. Additional research has demonstrated the benefit of CBD in decreasing the endogenous pain response in mice subjected to acute arthritic conditions, and further studies have highlighted improved fracture healing following CBD use in murine mid-femoral fractures. However, there is a lack of high-quality, novel research investigating the use of CBD in human musculoskeletal diseases aside from anecdotal accounts and retrospective reviews, perhaps due to legal ramifications limiting the enrollment of patients. The purpose of this review article is to highlight the extent of current research on CBD and its biochemical and pharmacologic efficacy in the treatment of joint disease, as well as the evidence for use of CBD and cannabis in patients undergoing joint arthroplasty. Based on available literature relying on retrospective data and case reports, it is challenging to propose a recommendation for CBD use in perioperative pain management. Additionally, a number of CBD products currently available as supplements with different methods of administration, and it is important to remember that these products are non-pharmaceuticals. However, given the increased social relevance of CBD and cannabis-based medicines, future, prospective controlled studies evaluating their efficacy are needed.

Cannabidiol in sport: Ergogenic or else?

Article

Mar 2020

In the sports domain, cannabis is prohibited by the World Anti-Doping Agency (WADA) across all sports in competition since 2004. The few studies on physical exercise and cannabis focused on the main compound i.e. Δ9-tetrahydrocannabinol. Cannabidiol (CBD) is another well-known phytocannabinoid present in dried or heated preparations of cannabis. Unlike Δ9-tetrahydrocannabinol, CBD is non-intoxicating but exhibits pharmacological properties that are interesting for medical use. The worldwide regulatory status of CBD is complex and this compound is still a controlled substance in many countries. Interestingly, however, the World Anti-Doping Agency removed CBD from the list of prohibited substances – in or out of competition - since 2018. This recent decision by the WADA leaves the door open for CBD use by athletes. In the present opinion article we wish to expose the different CBD properties discovered in preclinical studies that could be further tested in the sport domain to ascertain its utility. Preclinical studies suggest that CBD could be useful to athletes due to its anti-inflammatory, analgesic, anxiolytic, neuroprotective properties and its influence on the sleep-wake cycle. Unfortunately, almost no clinical data are available on CBD in the context of exercise, which makes its use in this context still premature.

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

Article

Full-text available

Aug 2019

Cannabidiol (CBD), as the only phytocannabinoid that has no psychoactive effect, has both antioxidant and anti-inflammatory effects, and thus might be suggested as a cytoprotective compound against UV-induced metabolic changes in skin cells. Therefore, the aim of this study was to investigate the level of protective CBD activity by evaluating the proteomic profile of 2D and 3D cultured skin fibroblasts models following exposure to UVA and UVB radiation. The CBD cytoprotective effect against UV-induced damage in 2D and 3D cultured fibroblasts were different. The main alterations focus on the range of cell reaction and involved different proteins associated with various molecular functions. In the 2D cultured cells, following UV radiation, the major changes were associated with proteins involved in antioxidant response and inflammation, while, in the 3D cultured fibroblasts, CBD action against UV induced changes were mainly associated with the activation of signalling pathways. Therefore, the knowledge of the CBD action in a multilayer skin cells model allowed for the prediction of changes in cell-cell interactions and skin cell metabolism. Knowledge about the lower protective effect of CBD in 3D cultured fibroblasts should be taken into account during the design of UV light protection.

New UHPLC Method for Cannabidiol Determination in Hard Capsules

Article

Full-text available

May 2019

Objectives : The aim of the study was to propose a new UHPLC method for the determination of cannabidiol (CBD) from supplements and drugs available on the Romanian market. Materials and methods : The HPLC assay of CBD was achieved by using a Phenomenex Gemini NX-C18 column. The mobile phase consisted of 70% acetonitrile and 30% water. Elution was performed in isocratic mode and the detection was done at 208 nm. The method was tested on hard capsules containing 150 mg of CBD. Results and discussions : The retention time of CBD was 2.8 minutes. Regression analysis showed good linearity over the 1-100 ug/ml concentration range. The lowest limit of quantification was established at 1 µg/ml. The method was developed by using reconstituted capsules. The substance proved low stability in solution at room temperature and stability at temperatures between 2-8°C. The recovery of reconstituted samples was 96.77%. The commercial capsules had a very low content of 15-20% from declared content. Conclusions : The proposed method can be used for CBD determination in different pharmaceutical formulations – hard and soft capsules with coconut oil as excipient.

Dental pulp stem cells-derived cannabidiol-pretreated micro-spheroids showed robust osteogenic potential via upregulation of WNT6

Preprint

Full-text available

Feb 2023

Dental pulp stem cells (DPSC)-derived 3D-aggregates/spheroids have shown robust soft/hard tissue regeneration potential. However, difficulties to control the cell number, size, and shape of DPSC-aggregates/spheroids cause cell necrosis and difficulties in homogenous seeding of aggregates/spheroids in the 3D-printed microporous bone grafts. Moreover, inducing the osteogenic potential of these aggregates/spheroids is still a challenge. This study developed cannabidiol (CBD)-pretreated, self-assembled, and injectable DPSC-derived osteogenic micro-spheroids (70 μm) that robustly promoted in situ bone regeneration. We developed micro-spheroids by seeding 250 cells/microwell in agarose gel microwells of 200 µm diameter developed using prefabricated mold and cultured with CBD for 14 days to induce osteogenic potential. In vitro study results showed that CBD did not affect the viability of DPSC but promoted osteogenic differentiation during 2D culture. In micro-spheroids, 3D cytoskeleton visualization showed better integrity and robustly higher expression of osteogenic markers and promoted in situ bone regeneration compared with DPSC. CBD-pretreated micro-spheroids showed robustly higher bone-regenerative capacity via upregulation of WNT6. Taken together, our approach of developing organoid-like injectable osteogenic micro-spheroids can be used as the effective carrier of the effect of in vitro drug treatment during in situ bone tissue engineering which eliminates the direct in vivo drug application-related adverse effects.

Evaluation of the efficacy of a cannabidiol and cannabidiolic acid rich hemp extract for pain in dogs following a tibial plateau leveling osteotomy

Article

Full-text available

Jan 2023

Objective To determine the impact of a cannabidiol (CBD) and cannabidiolic acid (CBDA) rich hemp product on acute post-operative pain in dogs following a tibial plateau leveling osteotomy (TPLO), and to evaluate for changes in early bone healing, serum chemistry profiles, and complete blood counts. Methods In this randomized, placebo controlled, blinded clinical trial, 44 client-owned dogs were assigned to receive either a CBD/CBDA product dosed at 2–2.5 mg/kg PO every 12 h or a placebo for 4 weeks following a TPLO. Variables evaluated before (week 0), and at 2 and 4 weeks post-operatively included standardized veterinary assessments for pain score, weight-bearing, and lameness, the Canine Brief Pain Inventory (pain interference score–PIS, pain severity score–PSS), and serum biochemistry. Complete blood counts were performed at weeks 0 and 4. Additionally, orthogonal radiographs evaluating the degree of healing were taken at week 4. A mixed model analysis, analyzing changes of variables of interest from enrollment baseline to all other time points was utilized, with a p -value ≤ 0.05 considered significant. Results Of the 44 enrolled patients, 3 were lost to follow up and excluded from analysis. No significant differences were noted between placebo ( n = 19) and CBD/CBDA ( n = 22) groups at any point in pain score, degree of lameness, degree of weight-bearing, PIS, PSS, or radiographic healing of the osteotomy. A significant finding of elevation of ALP above normal reference range in the treatment group was identified ( p = 0.02) and eosinophil count was affected by treatment ( p = 0.01), increasing from baseline in placebo and decreasing in treatment groups. Finally, a significant difference ( p = 0.03) was noted at 2 weeks post-operatively where 4 patients in the placebo group and no treatment patients received trazodone to facilitate activity restrictions. Clinical significance Use of a CBD/CBDA rich hemp product dosed at 2–2.5 mg/kg PO every 12 h did not have a significant impact on pain or delay early bone healing. A statistically significant increase in ALP, decrease in eosinophils, and reduced use of trazodone was identified in the treatment group.

Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs

Article

Full-text available

Sep 2022

Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong ( r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.

Buccally Absorbed Cannabidiol Shows Significantly Superior Pain Control and Improved Satisfaction Immediately After Arthroscopic Rotator Cuff Repair: A Placebo-Controlled, Double-Blinded, Randomized Trial

Article

Jul 2022
AM J SPORT MED

Background Despite the widespread use and sales of cannabidiol (CBD) products in the United States, there is a paucity of literature to evaluate its effectiveness, safety, or ideal route of administration for postoperative pain. Purpose To evaluate the potential analgesic effects of buccally absorbed CBD in patients who have undergone arthroscopic rotator cuff repair (ARCR). Study Design Randomized controlled trial; Level of evidence, 1. Methods This was a US Food and Drug Administration–sanctioned, multicenter, placebo-controlled, randomized, double-blinded trial conducted in patients undergoing ARCR. Patients aged from 18 to 75 years undergoing ARCR were prospectively enrolled and randomized to the control and experimental groups. The experimental group received an oral, buccally absorbed tablet containing 25 mg of CBD 3 times a day if <80 kg, or 50 mg of CBD 3 times a day if >80 kg, for 14 days postoperatively, while the control group received an identical placebo. Patients were followed up on days 1, 2, 7, and 14, and visual analog scale (VAS) for pain scores, opioid consumption, and satisfaction with pain control were recorded. Additionally, liver function tests were conducted on days 7 and 14 to assess safety, and nausea was monitored. P < .05 was considered to be statistically significant. Results Overall, 100 patients were recruited, with 1 patient being excluded, for a total of 99 patients. There were no significant differences in patient demographics between the 2 groups. On day 1, the VAS pain score was significantly lower in the CBD group than in the control group (4.4 ± 3.1 vs 5.7 ± 3.2, respectively; P = .04), although this difference was no longer present on day 2 (4.7 ± 2.8 vs 5.3 ± 2.6, respectively; P = .32). On both days 1 and 2, patient satisfaction with pain control was significantly higher in the CBD group than in the control group (day 1: 7.0 ± 3.0 vs 5.6 ± 3.7, respectively [ P = .04]; day 2: 7.3 ± 2.5 vs 6.0 ± 3.3, respectively [ P = .03]). The quantity of opioids consumed was low in both groups, and there were no statistically significant differences in opioid consumption ( P > .05). On days 7 and 14, there were no statistically significant differences in VAS scores, opioid consumption, or patient satisfaction with pain control between the CBD and control groups ( P > .05 for all). There were no significant differences in liver function test results postoperatively ( P > .05). Conclusion Buccally absorbed CBD demonstrated an acceptable safety profile and showed significant promise in the reduction of pain in the immediate perioperative period after ARCR compared with the control. Further studies are currently ongoing to confirm dosing and effectiveness in other orthopaedic conditions. Registration NCT04672252 (ClinicalTrials.gov identifier).

Cannabinoids in the Orthopedic Setting: A Literature Review

Article

Mar 2022

Public interest in the analgesic potential of cannabinoids has grown, but there is no consensus regarding orthopedic applications. Available evidence was identified for cannabinoid use in arthritis, neuropathic pain, fibromyalgia, multiple sclerosis, and postoperative pain. Extracted information included the risks of preoperative use, associations with opioid dependence, and surgical complications. There is limited evidence for therapeutic benefit of cannabinoids in rheumatoid arthritis and fibromyalgia. Cannabinoids are not indicated for postoperative pain. Preoperative unregulated use has been linked with postoperative opioid dependence. Cannabinoids may be considered a second- or third-line treatment for analgesia for some orthopedic pathologies. [Orthopedics. 202x;xx(x):xx-xx.].

Marijuana in Orthopaedics: Effects on Bone Health, Wound-Healing, Surgical Complications, and Pain Management

Article

Feb 2022

»: Marijuana use is on the rise in the United States, and there is a paucity of information on the effects of cannabis and its chemical constituents on bone health, wound-healing, surgical complications, and pain management. »: Current evidence suggests that cannabidiol (CBD) may enhance bone health and metabolism, while Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component in marijuana, has an inhibitory effect. »: Marijuana users are at higher risk for delayed bone-healing, demonstrate lower bone mineral density, are at increased risk for fracture, and may experience postoperative complications such as increased opioid use and hyperemesis.

Cannabinoid receptors: A potential target for osteoporosis pain Cannabinoid receptors: A potential target for osteoporosis pain

Article

Full-text available

Jun 2021

Osteoporosis, a systemic bone metabolic disorder which is characterized by explicit decline in bone density. Besides, microstructural alterations of the bone are very common in old people with osteoporosis. In menopausal women, prevalent management strategies for osteoporosis involve opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) which relieve the pain temporarily but they have several side effects like tolerance, addiction, safety, etc. Recent advancement in studies indicates cannabinoid receptors are the new target in osteoporosis pain. Cannabinoid receptors (type 1 and type 2) play a remarkable role in the stimulation of bone formation and in the inhibition of bone resorption. The deficiency of this anti-resorptive agent accelerates age-dependent bone loss due to marked elevation in bone resorption and reduced bone formation. GRP55 and transient receptor potential vanilloid type 1 (TRPV1) are two other receptors that are co-expressed in bone cells, which show involvement in bone homeostasis. Recent studies suggest that GPR55 cannabidiol antagonist increases the activity of osteoblast and decreases the function of osteoclast. The opposing effects of TRPV1 vs. Cannabinoid receptor (CBR1 and CBR2) in regulating human osteoblast activity is also a significant aspect of this concern. Both TRPV1 and GRP55 exert opposite action when compared to CBR1 and CBR2. So multi-targeting is more convenient rather than single targeting. The involvement of a nervous system in osteoporosis, especially in the pain signalling mechanism of glial cells is also an important feature to be further studied. This review is all about targeting the cannabinoid receptors in the treatment of osteoporosis pain and its recent development.

Effects of Marijuana Use in Patients with Orthopaedic Trauma

Article

Dec 2021

: The use of cannabis and cannabis-related products has increased dramatically in the last 2 decades. As states continue to legalize cannabis products, it is important for surgeons to understand the effects they may have on patients who have sustained orthopaedic trauma. ➢: Cannabinoids have been shown to decrease the severity of certain symptoms related to traumatic brain injury as well as posttraumatic stress disorder. ➢: Cannabinoids can modulate the body's endocannabinoid system, which can play an important role in bone homeostasis. Activation of cannabinoid receptors has been shown to be bone-protective in adults. ➢: Venous thromboembolism is a major concern for trauma patients. Cannabis use has been linked to overall increased rates of venous thromboembolism events. ➢: Literature regarding human-based cannabis studies is sparse; however, the growing field is opening new opportunities for research of this topic.

Development and Characterization of Cannabidiol-loaded Alginate Copper Hydrogel for Repairing Open Bone Defects in vitro

Article

Jan 2022
COLLOID SURFACE B

The clinical treatment of open bone defects caused by accidental bone trauma, bone tumors, bone diseases and bone infections is challenging. In this study, we designed and fabricated a multifunctional alginate-based hydrogel that contains cannabidiol (CBD), [email protected]/CBD hydrogel, for repairing open bone defects. The results of physicochemical characterization showed that the [email protected]/CBD hydrogel was successfully prepared and showed a suitable swelling ratio, high thermal stability, and stable mechanical properties. In vitro evaluation of antibacterial activity indicated that more than 90% of S. aureus and E. coli were inhibited compared to the control group. The ALP activity assay showed that the ALP expression level of MC3T3-E1cells in [email protected]/CBD hydrogel was approximately 2-fold higher than that in the control group on day 7 and 14. Additionally, compared to the control group, the level of mineralized deposits in [email protected]/CBD hydrogel was also improved by about 2 times on day 14. The PCR results indicated the mRNA expression levels of osteogenic markers (ALP, Col1α1, OCN, and RUNX2 genes) and angiogenic markers (EGFL6 and VEGF genes) in [email protected]/CBD hydrogel were significantly upregulated compared to that in the control group, and the mRNA expression levels of critical inflammatory cytokines (TNF-α and IL-1β) in the [email protected]/CBD hydrogel were significantly down-regulated compared to that in [email protected] hydrogel. Taken together, these results demonstrated that the [email protected]/CBD hydrogel showed significantly anti-bacterial, anti-inflammation, angiogenic and osteogenic activities in vitro studies. Thus, [email protected]/CBD hydrogels may be a promising candidate in repairing open bone defects.

Benefits, toxicity and current market of cannabidiol in edibles

Article

Full-text available

Jan 2022

The commercialization of products with cannabidiol (CBD) has undergone a significant increase. These products can be presented in different forms such as baked goods, gummies or beverages (such as kombucha, beer or teas, among others) using wide concentrations ranges. The use of CBD in edibles favors its consumption, for medicinal users, during the work week, avoid its possible social stigma and facilitates its transport. These products can be purchased on store shelves and online. There is a large number of specialized studies, in which the possible advantages of CBD consumption are described in the preclinical and clinical trials. it is also necessary to recognize the existence of other works revealing that the excessive consumption of CBD could have some repercussions on health. in this review, it is analyzed the composition and properties of Cannabis sativa L., the health benefits of cannabinoids (focusing on CBD), its consumption, its possible toxicological effects, a brief exposition of the extraction process, and a collection of different products that contain CBD in its composition.

Effect of Dietary Hemp Seed Cake on Systemic, Tissue and Organ Health of Commercial Laying Hens

Article

Full-text available

Dec 2021
Int J Poultry Sci

Marijuana Use Results in Increased Time to Union in Surgically Treated Pediatric Fracture Patients

Article

Aug 2021
J ORTHOP TRAUMA

Objective: To identify the impact of marijuana use on fracture healing in surgically treated pediatric patients. Design: Retrospective review. Setting: Level 1 trauma center, single center study. Patients/participants: Surgically treated pediatric patients 10 to 18 years of age with extremity fractures from 2010-2020. Conservatively treated patients and patients with nonunions were excluded from the study. 339 patients were included in the study, 21 of which were confirmed marijuana users by toxicology screening. Intervention: Surgical treatment of extremity fractures by any type of fixation. Main outcome measurements: Time to union was the primary outcome and was defined as radiographic evidence of bridging callus on all sides of the fracture and absence of the prior fracture line. Analysis of covariance, logistic regression analysis, and Fisher's Exact Tests were utilized to establish the relationship between all collected variables and time to radiographic union. Results: The average time to union for marijuana users (159.1 +/- 69.5 days, 95% confidence interval) was significantly longer than for non-users (80.3 +/- 7.8 days), p < .001. The odds of having a time to union of greater than 4 months and greater than 6 months were 4.17 (p = .00192) and 6.19 (p = .000159), respectively, for marijuana users compared to non-users. Conclusion: Marijuana users demonstrated longer time to union in surgically treated pediatric fracture patients. Level of evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Cannabinoid receptors: A potential target for osteoporosis pain

Article

Full-text available

Jul 2021

Biomechanical Effects of Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD), the Major Constituents of Cannabis, in a Sprague Dawley Rat Achilles Tendon Surgical Repair Model: A Pilot Study

Article

Jun 2021

Background: The use of cannabis is common among athletes and the US population at large. Cannabinoids are currently being evaluated as alternatives to opioid medications for chronic pain management. However, the effects of recreational and/or medical use of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on musculoskeletal injury and healing remain largely unknown. Hypothesis/purpose: The purpose of this study was to evaluate the biomechanical effects of CBD and THC on tendon-to-tendon healing in a rat Achilles tendon repair model. The hypothesis was that rats administered CBD would demonstrate decreased tensile load to failure of surgically repaired Achilles tendons compared with the THC and control groups. Study design: Controlled laboratory study. Methods: A total of 33 Sprague Dawley rats underwent Achilles tendon surgical transection and repair and were randomized to receive subcutaneous injection of THC, CBD, or vehicle once daily starting on the day of surgery and for 5 total days. After sacrifice, biomechanical tensile load-displacement testing was performed to determine Achilles tendon load to failure and stiffness. Data were analyzed by 1-way analysis of variance. Results: The THC group demonstrated the highest median load to failure, 18.7 N (95% CI, 15.3-19.2 N); the CBD group had the second highest at 16.9 N (95% CI, 15.1-19.8 N), and the control group had the lowest at 14.4 N (95% CI, 12.1-18.3 N). Stiffness was highest in the THC group at 4.1 N/mm (95% CI, 2.7-5.1 N/mm) compared with 3.6 N/mm (95% CI, 2.9-4.1 N/mm) for the CBD group and 3.6 N/mm (95% CI, 2.8-4.3 N/mm) for the control group. No statistically significant differences for strength and stiffness were observed between the groups. Conclusion: In this pilot study using an animal tendon-to-tendon repair model, neither THC nor CBD resulted in altered biomechanical characteristics compared to control. Clinical relevance: Cannabinoids do not appear to adversely affect Achilles tendon healing.

Well Being

Chapter

May 2021

The concept of well-being is a common topic in both human and veterinary medicine with a wide-ranging and highly debated definition (Zainuddin and Russell-Bennett 2017; Charlemagne-Badal et al. 2015). In its broadest sense, “well-being” encompasses all aspects of an individual’s life and experiences. It can be viewed as a multi-dimensional coordination of “an intersecting triumvirate of emotional, physical, and cognitive self” (Charlemagne-Badal et al. 2015; Gillett-Swan and Sargeant 2015).

Knowledge and Opinion on Cannabinoids Among Orthopaedic Traumatologists

Article

Full-text available

Apr 2021

Introduction: Cannabinoids are an increasingly popular therapy among orthopaedic patients for musculoskeletal conditions. A paucity of evidence to support their use in orthopaedics exists, likely because of the incongruence of federal and state legalization and the stigma surrounding cannabis. The purpose of this study is to elucidate sentiments and knowledge base of the orthopaedic trauma community with regard to cannabinoid-containing compounds. Methods: A 21-question online survey was distributed to the members of the Orthopaedic Trauma Association with a response window of 3 months. Results: We evaluated 251 responses. Most (88%) of the respondents did not believe that they were knowledgeable about the mechanism of action of cannabis/cannabidiol (CBD) but did feel that cannabis or CBD products play a role in managing postoperative pain (73%). Most respondents did not believe that they would be stigmatized if they suggested CBD (83%) or cannabis (67%) to patients. Despite this, fewer respondents have suggested CBD (38%) or cannabis (29%) to their patients. Conclusions: Sentiment toward cannabinoids among orthopaedic traumatologists is remarkably favorable; however, in-depth understanding is admittedly poor and routine use is uncommon. More clinical research for cannabinoids is needed to help orthopaedic traumatologists provide guidance for patients seeking advice for this recently popular therapeutic.

Evaluation of Cannabinoids on the Odonto/Osteogenesis in Human Dental Pulp Cells In Vitro

Article

Dec 2020

Introduction: Cannabinoids possess anti-inflammatory, analgesic and osteogenic effects in different cell types and tissues. The null hypothesis is delta-9-tetrahydrocannabinol (THC) might induce dental tissue repair and regeneration. The aim of this study was to investigate the effect of THC on human dental pulp cell (HDPC) viability and biomineralization, as well as the molecular mechanism of THC-induced odonto/osteogenic differentiation of HDPCs. Methods: The toxicity of THC on HDPCs was determined by MTT assay. The odonto/osteogenic differentiation marker genes of HDPCs were assessed by RT-PCR with or without THC treatment. HDPCs biomineralization was examined by collagen synthesis and calcium nodule deposition. The molecular mechanism of THC on HDPCs was investigated by examining the MAPK signaling pathway via blocking CB1 or CB2 receptors. Results: We found that THC had no inhibition of HDPC vitality in the testing concentration (0-100 μM). THC showed biphasic effects on HDPCs proliferation. At low dose (<5 μM), THC considerably increased HDPC cell division. HDPC proliferation reduced with higher THC concentrations (>5 μM). The expression of odonto/osteogenic marker genes were upregulated in the presence of cannabinoids. These were confirmed by increased collagen synthesis and mineralized calcium nodule formation in cannabinoids group. The effect of THC-induced odonto/osteogenesis occured via MAPK signaling. Conclusion: THC was biocompatible to HDPCs by promoting their mitogenic division in a biphasic pattern depending on the concentration. THC induced HDPCs odonto/osteogenic differentiation through activation of MAPK mediated by CB1 and CB2 receptors. Cannabinoids may play an important role in HDPCs regeneration process, and potentially be used as a pulp-capping agent.

Pharmacology of Endocannabinoids and Their Receptors

Chapter

Oct 2020

The identification of cannabinoid (CB) receptors has contributed to the state-of-the-art on the endocannabinoid system and its elements. Endocannabinoids (eCBs) are the endogenous agonists, derived from the conjugation of arachidonic acid with either ethanolamine (i.e. anandamide) or glycerol (i.e. 2-arachidonoylglycerol) acting as a lipid signaling mediator via two types of cannabinoid receptors (i.e. CB1 and CB2). Introduction of selective CB antagonists, inhibitors of eCB transport and metabolism, cannabinoid receptor-deficient mice and highlights on amidohydrolase have greatly facilitated the subsequent investigation of the eCB system. Moreover, modulation of the eCB system holds a promising therapeutic potential in the management of a myriad of pathophysiological conditions such as anxiety or mood disorders, neuropathic pain, multiple sclerosis, neurodegenerative diseases, osteoporosis, obesity and cancer among others. This chapter is comprehensively focused on the signal transduction and metabolic pathways, physiological roles, pharmacology and therapeutic potential of the endocannabinoids, with particular emphasis on cannabinoid addiction.

The Cannabinoids Effect on Bone Formation and Bone Healing

Article

Full-text available

Oct 2020
Curr Osteoporos Rep

Purpose of review: Here, we overview the latest findings from studies investigating the skeletal endocannabinoid (EC) system and its involvement in bone formation and resorption. Recent findings: The endocannabinoid system consists of endogenous ligands, receptors, and enzymes. The main cannabinoids found in the cannabis plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoid receptors CB1 and CB2 are expressed in bone and regulate bone homeostasis in rodents and humans. CBD treatment was shown to enhance fracture healing in rats. Recent studies in mice indicate that strain, age, and sex differences dictate the skeletal outcome of the EC activation. CBD treatment was shown to enhance bone healing, but needs validation in clinical trials. While research shows that EC activity protects against bone loss, studies on CB1 and CB2 agonists in bone regeneration models are lacking. Whether modulating the EC system would affect bone repair remains therefore an open question worth investigating.

Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK

Article

Jul 2020

In this study, we report the potential of cannabidiol, one of the major cannabis constituents, for enhancing osteoblastic differentiation in U2OS and MG‐63 cells. Cannabidiol increased the expression of Angiopoietin1 and the enzyme activity of alkaline phosphatase in U2OS and MG‐63. Invasion and migration assay results indicated that the cell mobility was activated by cannabidiol in U2OS and MG‐63. Western blotting analysis showed that the expression of tight junction related proteins such as Claudin1, Claudin4, Occuludin1, and ZO1 was increased by cannabidiol in U2OS and MG‐63. Alizarin Red S staining analysis showed that calcium deposition and mineralization was enhanced by cannabidiol in U2OS and MG‐63. Western blotting analysis indicated that the expression of osteoblast differentiation related proteins such as distal‐less homeobox 5, bone sialoprotein, osteocalcin, type I collagen, Runt‐related transcription factor 2 (RUNX2), osterix (OSX), and alkaline phosphatase was time dependently upregulated by cannabidiol in U2OS and MG‐63. Mechanistically, cannabidiol‐regulated osteoblastic differentiation in U2OS and MG‐63 by strengthen the protein‐protein interaction among RUNX2, OSX, or the phosphorylated p38 mitogen‐activated protein kinase (MAPK). In conclusion, cannabidiol increased Angiopoietin1 expression and p38 MAPK activation for osteoblastic differentiation in U2OS and MG‐63 suggesting that cannabidiol might provide a novel therapeutic option for the bone regeneration.

Characteristics of Marijuana Use Among Orthopedic Patients

Article

Dec 2019

Marijuana use among orthopedic patients has not been extensively studied. The purpose of this study was to investigate the prevalence of marijuana use among orthopedic surgery patients. Additionally, the authors sought to better characterize how and why their patients use marijuana. Patients presenting at 3 institutions in 2 states for orthopedic surgery were asked to complete a voluntary survey. In addition to basic demographic information, the survey contained questions regarding the frequency of, methods of, and reasons for marijuana use. Patients who had used marijuana in the past year were categorized as marijuana users. A total of 275 patients completed surveys, of whom 94 (34%) endorsed marijuana use in the past year. A majority of marijuana users (55%) endorsed using marijuana either daily or weekly. Smoking was the most common means of marijuana use (90%), followed by edible products (35%) and vaporizing (24%). Pain management (54%) and recreation (52%) were the most commonly cited reasons for using marijuana. Eighty-six percent of marijuana users indicated that they would stop using marijuana if told by their physician that marijuana use would adversely affect their surgery. Marijuana use is common among orthopedic patients. Many patients believe marijuana is beneficial for managing pain and other medical conditions, although most would be willing to stop using marijuana if told it would negatively impact their surgery. Further study into the effects of marijuana use on musculoskeletal health is warranted because marijuana use may be a risk factor easily modified to improve surgical outcomes. [Orthopedics. 202x; xx(x): xx-xx.].

The Effects of Marijuana Use on Lumbar Spinal Fusion

Article

Nov 2019

Study design: A retrospective cohort study. Objective: The purpose of this study was to evaluate marijuana usage and its effect on outcomes following transforaminal lumbar interbody fusion (TLIF). Summary of background data: As marijuana becomes legalized throughout the United States, its medicinal and recreational usage is becoming more mainstream. Clinicians currently have little guidance regarding both short-term and long-term effects of marijuana usage on surgical interventions. While the rate of lumbar spinal fusion in the United States continues to grow, the effect of marijuana usage on fusion remains uncertain. Methods: 102 patients who underwent TLIF performed by the same surgeon were followed for 12 months. Patients were self-reported for marijuana usage (n = 36). Patient reported outcome measures included preoperative Oswestry Disability Index (ODI), 6-month ODI and 12-month ODI, as well as length of stay (LOS), complications, return to operating room (OR), revision surgery, and confirmed fusion. Continuous variables were compared using the independent two-sample t test or analysis of variance (ANOVA), whereas categorical variables were analyzed using the chi-square or Fischer exact tests. Adjusted analysis was performed using a multivariate logistic regression model. Results: Marijuana usage was associated with a younger population (p < 0.001), but showed no difference regarding sex or BMI compared to the non-usage group. There was no statistically significant difference in complications, return to OR, or revision surgery between groups. When controlling for factors such as age and pre-operative ODI, multivariate analysis demonstrated that marijuana usage did not limit post-operative ODI reduction. The marijuana usage group demonstrated shorter LOS (2.42 vs. 3.00 days, p = 0.020). Fusion rates at 12 months were similar between groups (96% vs. 92.3%, p = 0.678). ODI was similar between groups at all time points. Conclusions: Perioperative outcomes were similar in patients who underwent TLIF regardless of marijuana usage. Level of evidence: 3.

Bones and Joints: The Effects of Cannabinoids on the Skeleton

Article

Full-text available

Aug 2019
J CLIN ENDOCR METAB

This paper reviews the endocannabinoid system and focuses on the role of endocannabinoids in bone metabolism and their potential use in the management of conditions associated with bone loss. Context: The endocannabinoid system uses tissue-specific lipid ligands and G protein-coupled transmembrane receptors to regulate neurological, metabolic, and immune responses. Recent studies demonstrate that the endocannabinoid system influences bone metabolism. With the increasing use of endocannabinoid mimetics, e.g. tetrahydrocannabinol (THC) and cannabidiol (CBD), endocannabinoids' involvement in bone growth and remodeling has become clinically relevant. Evidence acquisition: This literature review is based upon a search of Pubmed and Google Scholar databases, as of June 2019, for all English-language publications relating to cannabinoids and bone. We evaluated retrieved articles for relevance, experimental design, data acquisition, statistical analysis, and conclusions. Evidence synthesis: Preclinical studies establish a role for endocannabinoids in bone metabolism. These studies yield complex and often contradictory results attributed to differences in the specific experimental model examined. Studies using human cells or subjects are limited. Conclusions: In vitro and animal models document that endocannabinoids participate in bone biology. The relevance of these observations to humans is not clear. The increasing chronic use of medical and recreational cannabis underscores the need to better understand the role of endocannabinoids in human bone metabolism. Moreover, it is important to evaluate the role of endocannabinoids as a therapeutic target to prevent and treat disorders associated with bone loss.

Evaluation of composition and mineral structure of callus tissue in rat femoral fracture

Article

Full-text available

Feb 2014
J BIOMED OPT

Callus formation is a critical step for successful fracture healing. Little is known about the molecular composition and mineral structure of the newly formed tissue in the callus. The aim was to evaluate the feasibility of small angle x-ray scattering (SAXS) to assess mineral structure of callus and cortical bone and if it could provide complementary information with the compositional analyses from Fourier transform infrared (FTIR) microspectroscopy. Femurs of 12 male Sprague-Dawley rats at 9 weeks of age were fractured and fixed with an intramedullary 1.1 mm K-wire. Fractures were treated with the combinations of bone morphogenetic protein-7 and/or zoledronate. Rats were sacrificed after 6 weeks and both femurs were prepared for FTIR and SAXS analysis. Significant differences were found in the molecular composition and mineral structure between the fracture callus, fracture cortex, and control cortex. The degree of mineralization, collagen maturity, and degree of orientation of the mineral plates were lower in the callus tissue than in the cortices. The results indicate the feasibility of SAXS in the investigation of mineral structure of bone fracture callus and provide complementary information with the composition analyzed with FTIR. Moreover, this study contributes to the limited FTIR and SAXS data in the field.

Bone Quality in Diabetes

Article

Full-text available

Jun 2013

Diabetes is associated with increased risk of fracture, although type 2 diabetes is characterized by normal bone mineral density (BMD). The fracture risk of type 1 diabetes increases beyond an explained by a decrease of BMD. Thus, diabetes may be associated with a reduction of bone strength that is not reflected in the measurement of BMD. Based on the present definition, both bone density and quality, which encompass the structural and material properties of bone, are important factors in the determination of bone strength. Diabetes reduces bone quality rather than BMD. Collagen cross-linking plays an important role in bone strength. Collagen cross-links can be divided into lysyl hydroxylase and lysyl oxidase-mediated enzymatic immature divalent cross-links, mature trivalent cross-links, and glycation- or oxidation-induced non-enzymatic cross-links (Advanced Glycation End-products: AGEs) such as pentosidine. These types of cross-links differ in the mechanism of formation and in function. Not only hyperglycemia, but also oxidative stress induces the reduction in enzymatic beneficial cross-links and the accumulation of disadvantageous AGEs in bone. In this review, we describe the mechanism of low bone quality in diabetes.

A randomised controlled trial of cannabis based medicinal extract in central neuropathic pain due to multiple sclerosis

Article

Full-text available

Mar 2005
J PAIN

Impaired Collagen Biosynthesis and Cross‐linking in Aorta of Patients With Bicuspid Aortic Valve

Article

Full-text available

Dec 2013

Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysm. In the present study, collagen homeostasis in nondilated and dilated aorta segments from patients with BAV was studied, with normal and dilated aortas from tricuspid aortic valve (TAV) patients as reference. Ascending aortas from 56 patients were used for biochemical and morphological analyses of collagen. mRNA expression was analyzed in 109 patients. Collagen turnover rates were similar in nondilated and dilated aortas of BAV patients, showing that aneurysmal formation in BAV is, in contrast to TAV, not associated with an increased collagen turnover. However, BAV in general was associated with an increased aortic collagen turnover compared with nondilated aortas of TAV patients. Importantly, the ratio of hydroxylysyl pyridinoline (HP) to lysyl pyridinoline (LP), 2 distinct forms of collagen cross-linking, was lower in dilated aortas from patients with BAV, which suggests that BAV is associated with a defect in the posttranslational collagen modification. This suggests a deficiency at the level of lysyl hydroxylase (PLOD1), which was confirmed by mRNA and protein analyses that showed reduced PLOD1 expression but normal lysyl oxidase expression in dilated aortas from patients with BAV. This suggests that impaired collagen cross-linking in BAV patients may be attributed to changes in the expression and/or activity of PLOD1. Our results demonstrate an impaired biosynthesis and posttranslational modification of collagen in aortas of patients with BAV, which may explain the increased aortic aneurysm formation in BAV patients.

Procollagen Lysyl Hydroxylase 2 Is Essential for Hypoxia-Induced Breast Cancer Metastasis

Article

Full-text available

Feb 2013
MOL CANCER RES

Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies to treat cancer patients. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, HIF-1 activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the extracellular matrix. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We demonstrate that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs.

The Material Bone: Structure-Mechanical Function Relations

Article

Full-text available

Nov 2003
Annu Rev Mater Sci

▪ Abstract The term bone refers to a family of materials, all of which are built up of mineralized collagen fibrils. They have highly complex structures, described in terms of up to 7 hierarchical levels of organization. These materials have evolved to fulfill a variety of mechanical functions, for which the structures are presumably fine-tuned. Matching structure to function is a challenge. Here we review the structure-mechanical relations at each of the hierarchical levels of organization, highlighting wherever possible both underlying strategies and gaps in our knowledge. The insights gained from the study of these fascinating materials are not only important biologically, but may well provide novel ideas that can be applied to the design of synthetic materials.

Safety and Side Effects of Cannabidiol, a Cannabis sativa Constituent

Article

Full-text available

Sep 2011

Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.

Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): Clinical, molecular and biochemical delineation

Article

Full-text available

Jun 2011
ORPHANET J RARE DIS

The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.

Cannabidiol reverses the reduction in social interaction produced by low dose Δ9-tetrahydrocannabinol in rats

Article

Full-text available

May 2009

While Delta(9)-tetrahydrocannabinol (THC) is the main psychoactive constituent of the cannabis plant, a non-psychoactive constituent is cannabidiol (CBD). CBD has been implicated as a potential treatment of a number of disorders including schizophrenia and epilepsy and has been included with THC in a 1:1 combination for the treatment of conditions such as neuropathic pain. This study investigated the effect of THC and CBD, alone or in combination, on some objective behaviours of rats in the open field. Pairs of rats were injected with CBD or vehicle followed by THC or vehicle and behaviour in the open field was assessed for 10 min. In vehicle pretreated rats THC (1 mg/kg) significantly reduced social interaction between rat pairs. Treatment with CBD had no significant effect alone, but pretreatment with CBD (20 mg/kg) reversed the THC-induced decreases in social interaction. A higher dose of THC (10 mg/kg) produced no significant effect on social interaction. However, the combination of high dose CBD and high dose THC significantly reduced social interaction between rat pairs, as well as producing a significant decrease in locomotor activity. This data suggests that CBD can reverse social withdrawal induced by low dose THC, but the combination of high dose THC and CBD impairs social interaction, possibly by decreasing locomotor activity.

Novel human pathological mutations. Gene symbol: PLOD1. Disease: Ehlers-Danlos syndrome type VIA, kyphoscoliotic type.

Article

Full-text available

May 2009
HUM GENET

Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: Indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17

Article

Full-text available

Mar 1999

Bruck syndrome is characterized by the presence of osteoporosis, joint contractures, fragile bones, and short stature. We report that lysine residues within the telopeptides of collagen type I in bone are underhydroxylated, leading to aberrant crosslinking, but that the lysine residues in the triple helix are normally modified. In contrast to bone, cartilage and ligament show unaltered telopeptide hydroxylation as evidenced by normal patterns of crosslinking. The results provide compelling evidence that collagen crosslinking is regulated primarily by tissue-specific enzymes that hydroxylate only telopeptide lysine residues and not those destined for the helical portion of the molecule. This new family of enzymes appears to provide the primary regulation for controlling the different pathways of collagen crosslinking and explains why crosslink patterns are tissue specific and not related to a genetic collagen type. A genome screen identified only a single region on chromosome 17p12 where all affected sibs shared a cluster of haplotypes identical by descent; this might be the BS (Bruck syndrome) locus and consequently the region where bone telopeptidyl lysyl hydroxylase is located. Further knowledge of this enzyme has important implications for conditions where aberrant expression of telopeptide lysyl hydroxylase occurs, such as fibrosis and scar formation.

Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor

Article

Full-text available

May 2002

The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

Article

Full-text available

Jul 2004
Br Med J

To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis. Randomised double blind placebo controlled crossover trial. Outpatient clinic, University Hospital of Aarhus, Denmark. 24 patients aged between 23 and 55 years with multiple sclerosis and central pain. Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period. Median spontaneous pain intensity (numerical rating scale) in the last week of treatment. Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change. Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.

A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol

Article

Full-text available

Feb 2006
MED HYPOTHESES

This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.

Peripheral cannabinoid receptor, CB2, regulates bone mass

Article

Full-text available

Feb 2006

The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2–/– phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-κB ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries. • bone remodeling • HU-308 • osteoblast • osteoclast

Involvement of Neuronal Cannabinoid Receptor CB1 in Regulation of Bone Mass and Bone Remodeling

Article

Full-text available

Oct 2006

The CB1 cannabinoid receptor has been implicated in the regulation of bone remodeling and bone mass. A high bone mass (HBM) phenotype was reported in CB1-null mice generated on a CD1 background (CD1(CB1-/-) mice). By contrast, our preliminary studies in cb1-/- mice, backcrossed to C57BL/6J mice (C57(CB1-/-) mice), revealed low bone mass (LBM). We therefore analyzed CB1 expression in bone and compared the skeletons of sexually mature C57(CB1-/-) and CD1(CB1-/-) mice in the same experimental setting. CB1 mRNA is weakly expressed in osteoclasts and immunoreactive CB1 is present in sympathetic neurons, close to osteoblasts. In addition to their LBM, male and female C57(CB1-/-) mice exhibit decreased bone formation rate and increased osteoclast number. The skeletal phenotype of the CD1(CB1-/-) mice shows a gender disparity. Female mice have normal trabecular bone with a slight cortical expansion, whereas male CD1(CB1-/-) animals display an HBM phenotype. We were surprised to find that bone formation and resorption are within normal limits. These findings, at least the consistent set of data obtained in the C57(CB1-/-) line, suggest an important role for CB1 signaling in the regulation of bone remodeling and bone mass. Because sympathetic CB1 signaling inhibits norepinephrine (NE) release in peripheral tissues, part of the endocannabinoid activity in bone may be attributed to the regulation of NE release from sympathetic nerve fibers. Several phenotypic discrepancies have been reported between C57(CB1-/-) and CD1(CB1-/-) mice that could result from genetic differences between the background strains. Unraveling these differences can provide useful information on the physiologic functional milieu of CB1 in bone.

The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling

Article

Full-text available

Feb 2008
FASEB J

We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the beta-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic beta2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.

Cannabidiol – Recent Advances

Article

Full-text available

Sep 2007
CHEM BIODIVERS

The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.

Inhibition of fracture healing

Article

Full-text available

Jan 2008
J BONE JOINT SURG BR

This paper reviews the current literature concerning the main clinical factors which can impair the healing of fractures and makes recommendations on avoiding or minimising these in order to optimise the outcome for patients. The clinical implications are described.

Cannabinoids in health and disease

Article

Full-text available

Feb 2007

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.

A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae) (vol 91, pg 966, 2004)

Article

Sep 2005

Healing of Bone Fracture: General Concepts

Chapter

Feb 2012

The skeleton is frequently exposed to accidental and iatrogenic insults. Bone, similar to several other tissues, portrays a marked potential for regeneration and repair. Generally, healing proceeds until a complete restoration of the osseous function and anatomy is achieved. Cellular and molecular participants are similar in healing processes of bone and other tissues of mesenchymal origin. Skeletal injury initiates a multifaceted healing process since additional non-osseous tissues are involved. In view of potential complications in the healing process, a methodological approach to expected cellular and molecular therapeutic targets is required. The study of such targets in skeletal morphogenesis reveals that the phases of bone healing display striking similarities to osseous growth and development [1–5].

Bone Reaction to Implants

Chapter

Feb 2012

David Kohavi

Endosseous insertion of an artificial orthopedic or dental material induces an extensive tissue reaction at the implant–bone interface. Formation of a bone–implant attachment has been regularly reported. Bone repair in these instances is portrayed in several patterns. Healing depends on systemic and local conditions, inter alia, bone status, surgical technique, implant surface, biomechanical properties, and forces used. Osseointegration is defined as a direct structural bonding between bone tissue and implant surface. Clinically, such implant attachment produces a firm, asymptomatic fixation maintained in bone under functional loading. In other instances, healing is completed by fibro-integration, namely, implants are surrounded by fibrous connective tissue, showing an evident clinical mobility when loaded [1–6].

Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia

Article

Nov 2013
AM J PHYSIOL-LUNG C

Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood, although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung, and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was up-regulated in the lungs of mouse pups exposed to 85% O2, an experimental animal model of BPD. Transforming growth factor (TGF)-β increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-β signaling in the experimental animal model of BPD, TGF-β was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD.

Towards a better Cannabis drug.

Article

Sep 2013
BRIT J PHARMACOL

Unlabelled: This commentary discusses the importance of a new study entitled 'Cannabidiol attenuates deficits of visuo-spatial associative memory induced by Δ(9) -tetrahydrocannabinol' by Wright et al. from the Scripps Institute in La Jolla, California. The results in this study show that the non-psychoactive cannabis constituent cannabidiol opposes some, but not all, forms of behavioural and memory disruption caused by Δ(9) -tetrahydrocannabinol in male rhesus monkeys. Linked article: This article is a commentary on the research paper by Wright et al., pp 1365-1373 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12199.

Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ 9 tetrahydrocannabinol

Article

Mar 2013
BRIT J PHARMACOL

Background and purpose: Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ(9) tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship. Experimental approach: In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg(-1) , i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg(-1) CBD. Key results: CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task. Conclusions and implications: This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects. Linked article: This article is commented on by Mechoulam and Parker, pp 1363-1364 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12400.

Fourier Transform Infrared Spectroscopic Imaging Parameters Describing Acid Phosphate Substitution in Biologic Hydroxyapatite

Article

Feb 2013
CALCIFIED TISSUE INT

Acid phosphate substitution into mineralized tissues is an important determinant of their mechanical properties and their response to treatment. This study identifies and validates Fourier transform infrared spectroscopic imaging (FTIRI) spectral parameters that provide information on the acid phosphate (HPO(4)) substitution into hydroxyapatite in developing mineralized tissues. Curve fitting and Fourier self-deconvolution were used to identify subband positions in model compounds (with and without HPO(4)). The intensity of subbands at 1127 and 1110 cm(-1) correlated with the acid phosphate content in these models. Peak height ratios of these subbands to the ν(3) vibration at 1096 cm(-1) found in stoichiometric apatite were evaluated in the model compounds and mixtures thereof. FTIRI spectra of bones and teeth at different developmental ages were analyzed using these spectral parameters. Factor analysis (a chemometric technique) was also conducted on the tissue samples and resulted in factor loadings with spectral features corresponding to the HPO(4) vibrations described above. Images of both factor correlation coefficients and the peak height ratios 1127/1096 and 1112/1096 cm(-1) demonstrated higher acid phosphate content in younger vs. more mature regions in the same specimen. Maps of the distribution of acid phosphate content will be useful for characterizing the extent of new bone formation, the areas of potential decreased strength, and the effects of therapies such as those used in metabolic bone diseases (osteoporosis, chronic kidney disease) on mineral composition. Because of the wider range of values obtained with the 1127/1096 cm(-1) parameter compared to the 1110/1096 cm(-1) parameter and the smaller scatter in the slope, it is suggested that this ratio should be the parameter of choice.

Blurred Boundaries: The Therapeutics and Politics of Medical Marijuana

Article

Feb 2012
MAYO CLIN PROC

J Michael Bostwick

For 5 millennia, Cannabis sativa has been used throughout the world medically, recreationally, and spiritually. From the mid-19th century to the 1930s, American physicians prescribed it for a plethora of indications, until the federal government started imposing restrictions on its use, culminating in 1970 with the US Congress classifying it as a Schedule I substance, illegal, and without medical value. Simultaneous with this prohibition, marijuana became the United States' most widely used illicit recreational drug, a substance generally regarded as pleasurable and relaxing without the addictive dangers of opioids or stimulants. Meanwhile, cannabis never lost its cachet in alternative medicine circles, going mainstream in 1995 when California became the first of 16 states to date to legalize its medical use, despite the federal ban. Little about cannabis is straightforward. Its main active ingredient, δ-9-tetrahydrocannabinol, was not isolated until 1964, and not until the 1990s were the far-reaching modulatory activities of the endocannabinoid system in the human body appreciated. This system's elucidation raises the possibility of many promising pharmaceutical applications, even as draconian federal restrictions that hamstring research show no signs of softening. Recreational use continues unabated, despite growing evidence of marijuana's addictive potential, particularly in the young, and its propensity for inducing and exacerbating psychotic illness in the susceptible. Public approval drives medical marijuana legalization efforts without the scientific data normally required to justify a new medication's introduction. This article explores each of these controversies, with the intent of educating physicians to decide for themselves whether marijuana is panacea, scourge, or both. PubMed searches were conducted using the following keywords: medical marijuana, medical cannabis, endocannabinoid system, CB1 receptors, CB2 receptors, THC, cannabidiol, nabilone, dronabinol, nabiximols, rimonabant, marijuana legislation, marijuana abuse, marijuana dependence, and marijuana and schizophrenia. Bibliographies were hand searched for additional references relevant to clarifying the relationships between medical and recreational marijuana use and abuse.

The relationship between adipose tissue and bone metabolism

Article

Mar 2012

The authors have set out to evaluate the literature relevant to the dynamic regulation of adipogenesis and osteogenesis. A detailed search of the past and recent literature was conducted on Pubmed using a combination of keywords including: adipogenesis, bone marrow, hematopoiesis, mesenchymal stromal/stem cell, and osteogenesis. Throughout one's lifespan, the bone marrow microenvironment provides a unique niche for mesenchymal stromal/stem cells (BMSCs) and hematopoietic stem cells (HSCs). The marrow changes as a function of biological age and pathophysiology. Historically, clinical biochemistry has observed these changes from an HSC and hematological perspective. Nevertheless, these changes also reflect the balance between BMSC adipogenic and osteogenic processes which can display an inverse or reciprocal relationship. Multiple hormonal factors and nuclear hormone receptor ligands and drugs are responsible for BMSC lineage selection. Data from a number of laboratories now implicates endocrine feedback loops between extramedullary adipose depots and the central nervous system. This concise review provides a perspective on the mechanisms regulating BMSC differentiation in the context of biological aging, obesity, and osteoporosis.

Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts

Abstract

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