The therapeutic use of cannabis and cannabis-based medicines raises safety concerns for patients, clinicians, policy-makers, insurers, researchers and regulators. Although the efficacy of ...cannabinoids is being increasingly demonstrated in randomized controlled trials, most safety information comes from studies of recreational use.
We performed a systematic review of safety studies of medical cannabinoids published over the past 40 years to create an evidence base for cannabis-related adverse events and to facilitate future cannabis research initiatives. We critically evaluated the quality of published studies with a view to identifying ways to improve future studies.
A total of 321 articles were eligible for evaluation. After excluding those that focused on recreational cannabis use, we included 31 studies (23 randomized controlled trials and 8 observational studies) of medical cannabis use in our analysis. In the 23 randomized controlled trials, the median duration of cannabinoid exposure was 2 weeks (range 8 hours to 12 months). A total of 4779 adverse events were reported among participants assigned to the intervention. Most (4615 96.6%) were not serious. Of the 164 serious adverse events, the most common was relapse of multiple sclerosis (21 events 12.8%), vomiting (16 events 9.8%) and urinary tract infection (15 events 9.1%). The rate of nonserious adverse events was higher among participants assigned to medical cannabinoids than among controls (rate ratio RR 1.86, 95% confidence interval CI 1.57-2.21); the rates of serious adverse events did not differ significantly between these 2 groups (RR 1.04, 95% CI 0.78-1.39). Dizziness was the most commonly reported nonserious adverse event (714 events 15.5%) among people exposed to cannabinoids.
Short-term use of existing medical cannabinoids appeared to increase the risk of nonserious adverse events. The risks associated with long-term use were poorly characterized in published clinical trials and observational studies. High-quality trials of long-term exposure are required to further characterize safety issues related to the use of medical cannabinoids.
Cannabis is widely used as a self-management strategy by patients with a wide range of symptoms and diseases including chronic non-cancer pain. The safety of cannabis use for medical purposes has not ...been systematically evaluated. We conducted a prospective cohort study to describe safety issues among individuals with chronic non-cancer pain. A standardized herbal cannabis product (12.5% tetrahydrocannabinol) was dispensed to eligible individuals for a 1-year period; controls were individuals with chronic pain from the same clinics who were not cannabis users. The primary outcome consisted of serious adverse events and non-serious adverse events. Secondary safety outcomes included pulmonary and neurocognitive function and standard hematology, biochemistry, renal, liver, and endocrine function. Secondary efficacy parameters included pain and other symptoms, mood, and quality of life. Two hundred and fifteen individuals with chronic pain were recruited to the cannabis group (141 current users and 58 ex-users) and 216 controls (chronic pain but no current cannabis use) from 7 clinics across Canada. The median daily cannabis dose was 2.5 g/d. There was no difference in risk of serious adverse events (adjusted incidence rate ratio = 1.08, 95% confidence interval = .57–2.04) between groups. Medical cannabis users were at increased risk of non-serious adverse events (adjusted incidence rate ratio = 1.73, 95% confidence interval = 1.41–2.13); most were mild to moderate. There were no differences in secondary safety assessments. Quality-controlled herbal cannabis, when used by patients with experience of cannabis use as part of a monitored treatment program over 1 year, appears to have a reasonable safety profile. Longer-term monitoring for functional outcomes is needed.
The study was registered with www.controlled-trials.com (ISRCTN19449752).
This study evaluated the safety of cannabis use by patients with chronic pain over 1 year. The study found that there was a higher rate of adverse events among cannabis users compared with controls but not for serious adverse events at an average dose of 2.5 g herbal cannabis per day.
•Medical cannabis used for chronic pain over one year appears to have a reasonable safety profile.•The detailed listing of adverse events to medical cannabis will enhance clinical decision-making.•The average daily dose of dried herbal cannabis used by patients with chronic pain was 2.5g/day.•Medical cannabis use over one year was associated with improvements in pain, function, quality of life and cognitive function.
Chronic neuropathic pain affects 1%-2% of the adult population and is often refractory to standard pharmacologic treatment. Patients with chronic pain have reported using smoked cannabis to relieve ...pain, improve sleep and improve mood.
Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events.
We recruited 23 participants (mean age 45.4 standard deviation 12.3 years, 12 women 52%), of whom 21 completed the trial. The average daily pain intensity, measured on the 11-point numeric rating scale, was lower on the prespecified primary contrast of 9.4% v. 0% tetrahydrocannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% confidence interval CI 0.02-1.4). Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief. Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p = 0.001; faster, p < 0.001; more drowsy, p = 0.003) and improved quality of sleep (less wakefulness, p = 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough.
A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated. Further long-term safety and efficacy studies are indicated. (International Standard Randomised Controlled Trial Register no. ISRCTN68314063).
Children who did not have a history of allergies but who had recurrent wheezing with colds were given high-dose inhaled fluticasone or placebo by their parents at the first signs of an upper ...respiratory tract infection. Practitioners prescribed fewer treatments with oral corticosteroids for children treated with inhaled fluticasone than for those given placebo, but those treated with fluticasone had smaller gains in height and weight. This preemptive use of inhaled corticosteroids cannot be recommended.
Practitioners prescribed fewer treatments with oral corticosteroids for children treated with inhaled fluticasone than for those given placebo, but those treated with fluticasone had smaller gains in height and weight. This preemptive use of inhaled corticosteroids cannot be recommended.
Upper respiratory tract infections account for more than 80% of wheezing episodes in children.
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With more than 30 acute care visits per 1000 population, preschool-age children have a rate of acute care visits for asthma that is higher by a factor of three than that for school-age children and adults.
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Most children wheeze only when they have upper respiratory tract infections, are usually nonatopic, and outgrow symptoms by 6 years of age.
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Yet, since preschool-age children have 6 to 10 upper respiratory tract infections each year,
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recurrent virus-induced wheezing is associated with considerable distress and use of . . .
Loneliness and social isolation have negative consequences on physical and mental health in both adult and pediatric populations. Children with neurodevelopmental disabilities (NDD) are often ...excluded and experience more loneliness than their typically developing peers. This scoping review aims to identify the type of studies conducted in children with NDD to determine the effects of loneliness and/or social isolation. Three electronic databases (Ovid MEDLINE, EMBASE, PsychINFO) were searched from inception until 5 February 2019. Two independent reviewers screened the citations for inclusion and extracted data from the included articles. Quantitative (i.e., frequency analysis) and qualitative analyses (i.e., content analysis) were completed. From our search, 5768 citations were screened, 29 were read in full, and 12 were included. Ten were case-control comparisons with cross-sectional assessment of various outcomes, which limited inference. Autism spectrum disorder, attention-deficit/hyperactivity disorder, and learning disorder were the most commonly studied NDD. This review showed that loneliness among children with NDD was associated with negative consequences on mental health, behaviour, and psychosocial/emotional development, with a likely long-term impact in adulthood. Lack of research in this area suggests that loneliness is not yet considered a problem in children with NDD. More studies are warranted using prospective designs and a larger sample size with a focus on the dynamic aspect of loneliness development.
Post-stroke autonomic nervous dysfunction measured with heart rate variability (HRV) is correlated with the traditional risk factors and poor outcome. This study aimed to investigate the association ...between HRV and infarct locations, etiology subtypes, and neurological functional outcomes in patients with acute ischemic stroke (AIS).
In this prospective observational study, 186 consecutive patients were assigned to four major stroke severity categories based on the National Institutes of Health Stroke Scale score (NIHSS) and the modified Rankin Scale score (mRS): mild (NIHSS 0-4) stroke, moderate (NIHSS 5-14) stroke, 'favorable' (mRS 0-2) group, and 'unfavorable' (mRS 3-5) group. HRV time domain parameters were applied to evaluate the autonomic function of patients within 1 week after admission. All patients were classified into different etiology subtypes based on the TOAST (modified Trial of ORG 10172 in Acute Stroke Treatment) classification. The association of HRV with stroke location, etiology subtypes, neurological outcome was explored for all participants. Univariate and multivariate analyses were applied to explore the prediction value of HRV.
160 participants had large artery atherosclerotic infarction (LAA), 61 had right internal carotid artery system infarction (R-ICA), and 61 had vertebrobasilar artery system infarction (VB). Root-mean-square of differences (RMSSD) of adjacent RR intervals and the proportion calculated by dividing the interbeat interval differences >50 ms (pNN50) in patients of VB group was significantly lower than those of patients in R-ICA group (P < 0.01). HRV parameters in the LAA group was significantly lower than non-LAA group (P < 0.01). At discharge, significant lower HRV presented in the unfavorable group and moderate group (P < 0.05). After logistic univariate and multivariate analysis, lower SDNN (OR = 1.019; 95% CI = 1.003-1.035; p= 0.021) was independently associated with unfavorable mRS and higher NIHSS at discharge (OR = 1.013; 95%CI = 1.003-1.024; p= 0.015). Only SDNN showed predictive value for mRS≥3 (OR = 1.012; 95%CI = 1.002-1.022; p= 0.016) at 1 year.
HRV measured after admission is related to the AIS infarction basin, TOAST subtypes, and neurological outcomes at discharge suggesting a possible role for HRV in evaluating AIS and identifying high-risk patients.
Electroencephalogram (EEG) alpha-band oscillations may reflect executive and processing function in patients with cerebral small vessel disease (CSVD). We aimed to assess such association and its ...relationship with CSVD severity, and to identify specific alpha-band parameters and the cut-off values for cognitive screening. We analysed the dispersion of amplitude-frequency characteristics of EEG alpha-band and different alpha-band parameters (PFα , ΔPFα , PPα , NCL) in different brain locations. We also assessed patients' executive and processing functions using verbal fluency test (VFT) and color trails test (CTT), and CSVD severity using total burden and Fazekas scores. 129 patients were recruited in the study. After adjusting for age, gender and education, PFα(F3), PFα(F4) and NCL were significantly associated with VFT-composite performance (
0.05). CTT-1 time and error were associated with PFα(F3), PFα(F4), ΔPFα(O1;F3) and CSVD severity (
0.05), whereas CTT-2 time was only associated with CSVD severity. Moreover, the correlations between alpha-band oscillations and cognitive function were higher in low than in high disease-severity group (ρ: -0.58 vs. -0.38,
0.05). The AUC of selected alpha-band parameters were higher than 0.8 for VFT and CTT. Specific alpha-band parameters in the frontal lobe were identified to correspond to executive and processing function. Assessing EEG alpha-band oscillations may assist in screening cognitive impairment.
Background
Type 1 diabetes (T1D) is a chronic source of metabolic and neuropsychological stress, which may eventually lead to autonomic neuropathy and other complications related to micro‐ and ...macro‐vasculopathies. We aimed to investigate the relationship between T1D chronic stress and autonomic response to acute stress testing that was expected being affected by chronic stress.
Methods
Twenty youths with confirmed diagnosis of T1D were assessed. Chronic stress assessment included hemoglobin A1c (HbA1c) ≥7.5%, psychological stress assessed by perceived stress scale (PSS), hypoglycemic events, and proinflammatory cytokines. The acute stress testing used standardized stress video games. Autonomic response to acute stress was assessed by the amplitude and direction of changes in heart rate variability. Analyses determined correlations between changes in parasympathetic nervous system during stress testing and chronic diabetes stressors.
Results
A strong correlation was found between the amplitude of high frequency (HF) changes and HbA1c values (ρ = 0.74, P < .001). Youths with HbA1c ≥7.5% showed a larger amplitude of HF changes during acute stress (49% vs 16%, P < .001) and a higher PSS score (22.5 vs 19.0, P = .003), compared to those with HbA1c <7.5%. Additionally, among youths with HbA1c ≥7.5%, those with positive changes in HF had a lower level of IL‐8 than those with negative changes (5.40 vs 7.85 pg/mL, P = .009).
Conclusions
Study findings support the need for better understanding the health effects of stress‐related autonomic dysfunction in youth with T1D.
The bacterial Rcs phosphorelay is a stress-induced defense mechanism that controls the expression of numerous genes, including those for capsular polysaccharides, motility, and virulence factors. It ...is a complex multicomponent system that includes the histidine kinase (RcsC) and the response regulator (RcsB) and also auxiliary proteins such as RcsF. RcsF is an outer membrane lipoprotein that transmits signals from the cell surface to RcsC. The physiological signals that activate RcsF and how RcsF interacts with RcsC remain unknown. Here, we report the three-dimensional structure of RcsF. The fold of the protein is characterized by the presence of a central 4-stranded β sheet, which is conserved in several other proteins, including the copper-binding domain of the amyloid precursor protein. RcsF, which contains four conserved cysteine residues, presents two nonconsecutive disulfides between Cys74 and Cys118 and between Cys109 and Cys124, respectively. These two disulfides are not functionally equivalent; the Cys109–Cys124 disulfide is particularly important for the assembly of an active RcsF. Moreover, we show that formation of the nonconsecutive disulfides of RcsF depends on the periplasmic disulfide isomerase DsbC. We trapped RcsF in a mixed disulfide complex with DsbC, and we show that deletion of dsbC prevents the activation of the Rcs phosphorelay by signals that function through RcsF. The three-dimensional structure of RcsF provides the structural basis to understand how this protein triggers the Rcs signaling cascade.
OBJECTIVES:Biliary atresia (BA) is a leading cause of liver failure and liver transplantation in pediatrics. BA manifests by 3 weeks of life with jaundice and pale stools. Delayed diagnosis and ...surgical intervention with Kasai portoenterostomy after 3 months of age is significantly associated with poor prognosis for native liver survival. A national Taiwan infant stool color card (SCC) screening program has entirely eliminated late Kasai portoenterostomy >90 days of age and improved native liver survival. A recent large-scale prospective cohort study in British Columbia, Canada, indicated that distribution of SCC on the maternity ward was feasible, led to high utilization rate, and was cost-effective. The aim of the present study was to assess the generalizability of this screening strategy in another Canadian jurisdiction with a different sociodemographic profile.
METHODS:An SCC was distributed to families of newborns discharged at St Maryʼs Hospital Center, Montreal, Quebec. Families were instructed to monitor their infantʼs stool color for 21 days and then complete and mail the SCC to the study center. Phone surveys to families who did not return cards were used to estimate total card utilization rate.
RESULTS:Two thousand two hundred forty-six infants were eligible for inclusion; 99.9% were enrolled. Mail SCC return rate was 63.3%. No cases of BA were identified. All of the 118 families who completed the phone survey reported that they had utilized the SCC. Conservative and optimistic estimates for total card utilization rates were 82% and 100%, respectively.
CONCLUSIONS:The high enrollment and utilization rates in this screening study strongly support the feasibility of implementing a Canadian SCC screening program to improve outcomes of children with BA.
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