Biphasic effects of cannabis and cannabinoid therapy on pain severity, anxiety, and sleep disturbance: a scoping review.

INTRODUCTION: Cannabinoids are being used by patients to help with chronic pain management and to address the 2 primary chronic pain comorbidities of anxiety and sleep disturbance. It is necessary to understand the biphasic effects of cannabinoids to improve treatment of this symptom triad. METHODS: A scoping review was conducted to identify whether biphasic effects of cannabinoids on pain severity, anxiolysis, and sleep disturbance have been reported. The search included the Embase, Biosis, and Medline databases of clinical literature published between 1970 and 2021. The inclusion criteria were (1) adults more than 18 years of age, (2) data or discussion of dose effects associated with U-shaped or linear dose responses, and (3) measurements of pain and/or anxiety and/or sleep disturbance. Data were extracted by 2 independent reviewers (with a third reviewer used as a tiebreaker) and subjected to a thematic analysis. RESULTS: After the database search and study eligibility assessment, 44 publications met the final criteria for review. Eighteen publications that specifically provided information on dose response were included in the final synthesis: 9 related to pain outcomes, 7 measuring anxiety, and 2 reporting sleep effects. CONCLUSIONS: This scoping review reports on biphasic effects of cannabinoids related to pain, sleep, and anxiety. Dose-response relationships are present, but we found gaps in the current literature with regard to biphasic effects of cannabinoids in humans. There is a lack of prospective research in humans exploring this specific relationship.

Associations Between Monthly Cannabis Use and Myocardial Infarction in Middle-Aged Adults: NHANES 2009 to 2018.

Mechanistic research suggests using Cannabis sativa L. (cannabis or marijuana) may increase the risk of cardiometabolic disease, but observational studies investigating associations between cannabis use and myocardial infarction (MI) have reported inconsistent results. Cross-sectional National Health and Nutrition Examination Survey data from five 2-year cycles between 2009 and 2018 and representing 9,769 middle-aged adults (35 to 59 years old) were analyzed. Multivariable logistic regression models accounting for sampling weights and adjusting for cardiovascular risk factors were used to assess associations between a history of monthly cannabis use before MI and a subsequent MI. A quarter of respondents (n = 2,220) reported a history of monthly use >1 year before an MI. A history of MI was reported by 2.1% of all respondents and 3.2.% of those who reported a history of monthly use. In fully adjusted multivariable models, and compared with never use, a history of monthly cannabis use preceding an MI was not associated with an MI (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.35 to 1.71). However, when stratified by recent use, the odds of MI were threefold greater (OR 2.98, 95% CI 1.08 to 8.60) when no use was reported within the past month than when use was reported within the past month. Duration of monthly use was also not significantly associated with MI, including monthly use >10 years (OR 0.78, 95% CI 0.30 to 2.01). In conclusion, in a representative sample of middle-aged US adults, a history of monthly cannabis use >1 year before an MI was not associated with a subsequent physician-diagnosed MI, except for threefold greater odds when cannabis was not used within the past month.

Trends in Cannabis Use, Blood Pressure, and Hypertension in Middle-Aged Adults: Findings From NHANES, 2009-2018.

BACKGROUND: Observational studies investigating associations between cannabis use and blood pressure (BP)/hypertension are inconsistent. METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) were analyzed for five 2-year cycles between 2009 and 2018 representing 9,783 middle-aged adults (35-59 years). Hypertension was defined as systolic BP (SBP) ≥130, diastolic BP (DBP) ≥80, or a BP medication. Sample-weighted multivariable logistic regression models were used to assess associations between cannabis use and BP and hypertension. RESULTS: One quarter of respondents (n = 2,228) reported a history of monthly cannabis use for more than 1 year, which was consistent over the study period (P for trend = 0.75). Approximately 48% (n = 4,831) met the definition of hypertension. While a significant positive trend was seen over time for mean SBP and DBP (P = <0.01 for both), no significant trend was seen in prevalent hypertension (P for trend = 0.23). In adjusted models, compared with never use, a history of monthly cannabis use for more than 1 year was not associated with increased BP (mean SBP: 124.5 mm Hg (95% confidence interval [CI], 122.4-126.6) vs. 122.6 (95% CI, 120.9-124.2); DBP: 74.7 mm Hg (95% CI, 73.1-76.2) vs. 74.1 (95% CI, 72.8-75.4)), or prevalent hypertension (odds ratio = 0.88 (95% CI, 0.62-1.24)). Results from analyses of duration of monthly use, and recency and frequency of recent use were similar. CONCLUSIONS: A history of monthly cannabis use for more than 1 year was not independently associated with either increased BP or prevalent hypertension in a nationally representative sample of middle-aged US adults.

Perceptions and Practices of Cannabis Use Among Emergency Department Patients.

BACKGROUND: Nationally, in states where cannabis has been legalized, increases in cannabis-related hospitalizations and emergency department (ED) visits have also been observed. OBJECTIVES: This study aims to: 1) Describe the sociodemographic characteristics of cannabis users presenting to two academic EDs in California; 2) Assess cannabis-related behaviors; 3) Assess perceptions of cannabis; 4) Identify and describe reasons for cannabis-related ED utilization. METHODS: This is a cross-sectional study of patients visiting one of two academic EDs between February 16, 2018 and November 21, 2020. Eligible participants completed a novel questionnaire developed by the authors. Basic descriptive statistics, Pearson correlation coefficients, and logistic regression were used for statistical analysis of responses. RESULTS: The questionnaire was completed by 2577 patients. A quarter were categorized as Current Users (n = 628, 24.4%). Current, Regular Users were evenly divided across gender, were relatively younger (18-34 years, 48.1%), and were largely non-Hispanic Caucasian. Over half of all respondents believed that the use of cannabis was less harmful than tobacco or alcohol use (n = 1537, 59.6%). One in five Current Users (n = 123, 19.8%) reported driving while using cannabis in the past month. A small proportion (n = 24, 3.9%) of Current Users reported ever visiting the ED for a cannabis-related chief complaint. CONCLUSIONS: Overall, many ED patients are currently using cannabis; few report utilizing the ED due to cannabis-related problems. Current, Irregular Users may represent the ideal target group for ED-based educational efforts aimed at improving knowledge of safe cannabis use.

Cannabinol and Sleep: Separating Fact from Fiction.

In recent years, marketers of cannabis (i.e., marijuana) products have claimed that cannabinol (CBN) has unique sleep-promoting effects. Despite a plausible mechanism, it is possible that such claims are merely rooted in cannabis lore. The aim of this narrative review was to answer the question: "Is there sufficient clinical evidence to support claims that CBN has sleep-promoting effects?" A systematic search of PubMed/MEDLINE was performed to evaluate the published evidence. The abstracts of 99 human studies were screened for relevance by the author and reviewed for compliance with the inclusion criteria. The characteristics and principal findings were extracted from eight full-text articles that met inclusion criteria for detailed review. Pre-clinical and clinical research investigating the effects of CBN is dated and limited, with the preponderance of human studies occurring in the 1970-1980s with small sample sizes lacking diversity in sociodemographic characteristics. Studies specifically assessing subjective effects associated with sleep, such as sedation or fatigue, are rare. Most importantly, published clinical trials investigating associations between CBN and validated sleep questionnaires and/or formal polysomnography were not identified in this review. In addition, evidence demonstrating that CBN itself elicits cannabis-like effects in humans is mixed, with the majority of available evidence demonstrating a lack of such an effect. Consequently, there is insufficient published evidence to support sleep-related claims. Randomized controlled trials are needed to substantiate claims made by manufacturers of cannabis products containing CBN. These studies should specifically evaluate its effects on sleep through polysomnography, or at minimum, through validated sleep questionnaires, and use dosages significantly higher than those found in currently available cannabis products marketed for sleep (typically ≤5 mg). Individuals seeking cannabis-derived sleep aids should be skeptical of manufacturers' claims of sleep-promoting effects.

Labeling of Cannabidiol Products: A Public Health Perspective.

Introduction: Interest in the therapeutic use of cannabidiol (CBD) has reached a fever-pitch in recent months, as CBD-containing products appear everywhere from online retailers to grocery stores and gas stations. The widespread availability of hemp-derived CBD products is confounding given that CBD is a U.S. Food and Drug Administration (FDA)-approved drug, and thus precluded from being added to food and beverages, or included in dietary supplements. The use by manufacturers of disease-related claims on marketing materials and product labels, along with the federal legalization of hemp in December 2018, has created political pressure on FDA to promulgate regulations. Conclusions: Accurate and informative labeling of hemp and hemp-derived CBD products is an important public health issue. FDA-regulated product labels are considered an essential tool for protecting consumers and enabling informed decision-making. Untruthful or unsubstantiated health-related claims, and unallowed Drug Claims, in marketing materials and on labels of CBD products may create harm by enticing consumers to forgo more evidence-based medical interventions. Furthermore, missing or inaccurate labeling of the amount of CBD, delta-9 tetrahydrocannabinol (THC), and potentially harmful contaminants such as pesticides, naturally-occurring yeast and mold or heavy metals may result in harm and/or lack of efficacy. Manufacturers of these products may reasonably be expected to understand and adhere to FDA regulations for labeling and marketing of food, dietary supplements and drugs, both over-the-counter (OTC) and prescription, even though FDA has interpreted federal law as excluding them from these categories. As manufacturers prepare for forthcoming regulations, a better understanding of the basic framework for FDA labeling and marketing regulations for food, dietary supplements and drugs is warranted.

Hold the Phone! Cell Phone-Related Injuries in Children, Teens, and Young Adults Are On the Rise.

We describe trends in cell phone-related injuries in patients 21 years of age and under presenting to United States Emergency Departments. We calculated age-adjusted rates of cell phone-related injury per 100 000 individuals using data from the National Electronic Injury Surveillance System (NEISS) database and United States Census Bureau. From 2002 to 2015, an estimated 38 063 patients 21 years old and younger sustained a cell phone-related injury. The overall rate of injuries for all ages increased from 17.1 injuries per 100 000 in 2002 to 138 injuries per 100 000 in 2015, an increase of over 700%. The incidence of cell phone-related injuries increased across all age groups, with children 2 years of age and under experiencing the highest single incidence rate of 159 injuries per 100 000 in 2014. These findings highlight an important and relatively under-reported pediatric safety issue. Anticipatory guidance and injury prevention plans should be updated accordingly.

Indications and administration practices amongst medical cannabis healthcare providers: a cross-sectional survey.

BACKGROUND: The medical use of cannabis has been legislatively restricted for decades in the US and abroad. In recent years, changing local and national policies have given rise to a community of healthcare providers who may be recommending the medical use of cannabis without the benefit of formal clinical practice guidelines or sufficient training and education. In addition, a citizen science movement has emerged whereby unlicensed and untrained individuals are acting as healthcare provider proxies, offering cannabis-specific clinical care to "patients". This study sought to characterize the clinical practice characteristics of these provider groups. METHODS: An anonymous, online survey was designed to describe levels of cannabis-specific education, practice characteristics, indications for medical use, dose, administration forms and adverse effects related to cannabis use. The questionnaire was disseminated via professional medical cannabis associations and by word-of-mouth. It was accessed between June 31-December 31, 2018. A self-selecting sample of respondents (n = 171) completed the survey. RESULTS: Formal education or training in the medical use of cannabis was significantly more common among licensed respondents than unlicensed respondents (95.5% vs 76.9% respectively, OR, 6.3, 95% CI, 1.2-32.3, p = 0.03). The vast majority (n = 74, 83.15%) of licensed respondents reported having recommended cannabis as an adjunct to an existing prescription drug. Almost two-thirds (n = 64, 71.9%) reported having recommended it as a substitute. When delta-9-tetrahydrocannabinol (THC) is the principal therapeutic constituent of interest, vaporization is the most common method of administration recommended (n = 94 responses, 71.4% of respondents). In contrast, when cannabidiol (CBD) is the principal therapeutic constituent of interest, oral administration (sublingual or oromucosal absorption) is the most common method (n = 70 responses, 71.4% of respondents). CONCLUSIONS: Individuals who recommend the medical use of cannabis appear to be self-generating a community standard of practice in the absence of formal clinical guidelines on dosing, interactions and other characteristics. Reducing barriers to clinical research on cannabis products is needed, not only to better understand their risks and benefits, but also to augment the evidence-base for informing clinical practice.

The Endocannabinoid System and its Modulation by Cannabidiol (CBD).

The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.

Randomized controlled trials investigating the relationship between dietary pattern and high-sensitivity C-reactive protein: a systematic review.

CONTEXT: Elevated serum concentration of high-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation, is associated with increased risk for coronary heart disease (CHD) and cardiovascular events (CVEs). Because elevations in hsCRP often occur in parallel with elevations in low-density lipoproteins (LDLs) and both biomarkers are reduced by hydroxymethylglutaryl-CoA reductase inhibitors (ie, statin drugs), efforts to determine nonpharmacological treatments to lower hsCRP remain limited. Dietary modifications in particular are rarely discussed as viable clinical interventions yet merit investigation. OBJECTIVE: This systematic review was performed to assess the relationship between dietary patterns and hsCRP among individuals enrolled in randomized controlled trials. DATA SOURCES: National Library of Medicine (ie, MEDLINE) and Google Scholar searches were performed using the search terms "C-reactive protein," "CRP," "dietary pattern," and/or "diet" to identify articles published between January 2000 and October 2017. DATA EXTRACTION: Data were extracted and analyzed according to PRISMA guidelines. Identified abstracts were reviewed and cross-referenced for relevance to dietary pattern. Full-text manuscripts were then abstracted for their principal findings. Fifty-six manuscripts met inclusion criteria for detailed review. RESULTS: Clinical trials of dietary interventions to reduce hsCRP are mixed in quality and findings. Several specific dietary patterns may reduce hsCRP, including low-fat, low-carbohydrate, Mediterranean, Portfolio, Paleolithic, and the Dietary Approaches to Stop Hypertension (DASH) diets. However, results were mixed for the majority of dietary patterns (eg, low-glycemic load diets). CONCLUSION: Information available to date suggests that a wide variety of dietary patterns may impact serum hsCRP, although studies are mixed in quality. The efficacy of dietary patterns for the treatment of elevated hsCRP as a strategy for primary prevention of CHD may be best elucidated in randomized clinical trials in healthy participants with elevated hsCRP but low or normal traditional risk factors, or by using more aggressive dietary modifications in high-risk patients. Given current incidence and prevalence of CHD risk factors, additional randomized controlled trials of this type are justified and needed.

Effects of a topical botanically-enriched salve on cutaneous oxygenation.

OBJECTIVE: There is a medical need to evaluate new treatments that may improve wound healing. This study aimed to determine if Original Healing Salve (OHS, Puremedy, Inc.) a topical, botanically-enriched salve (BES), changes distal leg tissue oxygenation in people with type 2 diabetes. METHOD: A randomised, controlled, crossover, double-blinded clinical trial comparing changes in cutaneous oxygen delivery (mean TcPO2) on multiple sites of the lower extremity following application of a botanically-enriched topical salve, as compared with application of the salve's base in patients with type 2 diabetes. Subjects were recruited from the general population as a convenience sample. RESULTS: A total of 16 participants were recruited. Analysis of the primary outcome demonstrated no statistically significant difference in TcPO2 at 30 minutes postapplication when comparing the BES to the base salve (BS) on the leg (-0.39±8.54mmHg; p=0.86). Analyses of secondary outcomes at 30 minutes postapplication indicated that mean TcPO2 was significantly higher than preapplication levels among subjects receiving both the BES (3.70±6.62mmHg; p=0.04) and BS on the leg (4.08±5.21mmHg; p=0.007). On the foot, mean TcPO2 at 30 minutes postapplication was higher in the BES compared with the BS, this difference was not significant (0.98±8.59mmHg; p=0.66). Mean TcPO2 was higher than preapplication levels among subjects receiving both the BES (1.21±7.70mmHg; p=0.54) and BS on the foot (2.19±7.27mmHg; p=0.25). These differences were non-significant. CONCLUSION: These findings support consideration of topical treatments containing botanical ingredients to increase cutaneous oxygen delivery in the lower extremity in patients with type 2 diabetes.

Prospective Safety Evaluation of a Cardiovascular Health Dietary Supplement in Adults with Prehypertension and Stage I Hypertension.

OBJECTIVE: To prospectively examine the long-term safety of a cardiovascular health dietary supplement by assessing a comprehensive set of safety measures. DESIGN: Single-arm, open-label study. LOCATION: National University of Natural Medicine, Portland, OR. SUBJECTS: Thirty adults with screening blood pressure readings consistent with prehypertension or stage I hypertension. INTERVENTION: One caplet per day of a dietary supplement for 6 months. The investigated herbal-mineral supplement contains several ingredients, most notably Rauwolfia serpentina. OUTCOME MEASURES: Primary measures included b-type natriuretic peptide (NT-proBNP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), estimated glomerular filtration rate (eGFR), electrolytes, and the Patient Health Questionnaire (PHQ-9). Exploratory measures included physical vital signs, cholesterol levels, high-sensitivity cardiac troponin-I, cystatin C, endothelin, interleukin (IL)-6, IL-17a, tumor necrosis factor-α, high-sensitivity C-reactive protein, blood counts, and the Patient Reported Outcome Measure Information System (PROMIS) Sleep Disturbance Short Form 8b. RESULTS: NT-proBNP, AST, ALT, eGFR, sodium, calcium, magnesium, PHQ-9 score, and the majority of exploratory measures did not change. However, serum potassium increased (p < 0.05), systolic blood pressure decreased (p < 0.0001), and diastolic blood pressure decreased (p < 0.0001). There were no serious adverse events, but 30% of participants withdrew citing potential side effects, most commonly nasal congestion or fatigue; most participants who reported nasal congestion also reported concomitant seasonal allergies. Adherence to the supplement was 90.9%. CONCLUSIONS: The findings of this study suggest that the investigated dietary supplement is safe for long-term use in adults with prehypertension and stage I hypertension. Additional results of this study, particularly the increase in serum potassium and decreases in systolic and diastolic blood pressure, are promising and suggest that future research on this dietary supplement, or its ingredients, should further explore effects on blood pressure and biologic mechanisms of action, which may involve potassium-sparing and diuretic effects.

Regulatory Status of Cannabidiol in the United States: A Perspective.

Cannabidiol (CBD) is 1 of > 100 cannabinoids found in Cannabis sativa L. (Cannabis spp. or Cannabis). Despite its complex and rapidly evolving regulatory status in the United States, projected retail sales of CBD products-hemp, Cannabis and pharmaceutical-are as high as $1.9 billion by 2020. CBD products can currently be purchased online, over the counter, and at Cannabis-specific dispensaries throughout most parts of the country, despite the fact that CBD is presently deemed a Schedule I controlled substance by the U.S. Drug Enforcement Administration and renounced as a dietary supplement ingredient by the U.S. Food and Drug Administration (FDA). These products are largely unregulated, and are being used predominantly to treat specific medical conditions. Recent FDA approval of Epidiolex (CBD) as a treatment for certain pediatric seizure disorders will prompt scheduling of CBD and likely alter FDA enforcement of the Federal Food, Drug, and Cosmetic Act (FD&C), which to date has mostly been in the form of warning letters. Persuasive legal arguments contend that CBD's legal status is based on its source. According to these arguments, there are three legal sources. CBD-derived from: (1) parts of the Cannabis plant that do not meet the definition of cannabis in the Controlled Substances Act (CSA); (2) imported "non-psychoactive hemp"; and (3) "Industrial hemp" cultivated as part of a state pilot program per the 2014 Farm Act. Although CBD's lawful status with respect to the CSA appears to be expanding, its future regulatory status with respect to the FD&C Act is difficult to predict.

A Cross-Sectional Study of Cannabidiol Users.

Introduction: Preclinical and clinical studies suggest that cannabidiol (CBD) found in Cannabis spp. has broad therapeutic value. CBD products can currently be purchased online, over the counter and at Cannabis-specific dispensaries throughout most of the country, despite the fact that CBD is generally deemed a Schedule I controlled substance by the U.S. Drug Enforcement Administration and renounced as a dietary supplement ingredient by the U.S. Food and Drug Administration. Consumer demand for CBD is high and growing, but few studies have examined the reasons for increasing CBD use. Materials and Methods: A self-selected convenience sample (n = 2409) was recruited via an online survey designed to characterize whom, how, and why individuals are currently using CBD. The anonymous questionnaire was accessed from October 25, 2017 to January 25, 2018. Participants were recruited through social media. Results: Almost 62% of CBD users reported using CBD to treat a medical condition. The top three medical conditions were pain, anxiety, and depression. Almost 36% of respondents reported that CBD treats their medical condition(s) "very well by itself," while only 4.3% reported "not very well." One out of every three users reported a nonserious adverse effect. The odds of using CBD to treat a medical condition were 1.44 (95% confidence interval, 1.16-1.79) times greater among nonregular users of Cannabis than among regular users. Conclusion: Consumers are using CBD as a specific therapy for multiple diverse medical conditions-particularly pain, anxiety, depression, and sleep disorders. These data provide a compelling rationale for further research to better understand the therapeutic potential of CBD.