Can we predict the treatment doses of THC and CBD and does it matter?

INTRODUCTION: Medical cannabis is an increasingly prevalent treatment for a wide variety of indications, yet there is still no uniformly accepted protocol for the titration of cannabinoid doses. We aimed to develop a model to predict the stable THC and CBD dosages after six months of treatment using available baseline patient characteristics. METHODS: In this prospective study, we included all consecutive adult patients (age 18 and above) who exclusively used a single method of cannabis delivery. Telephone interviews were conducted six months post-treatment initiation to assess changes in symptoms and side effects. We prospectively analyzed THC and CBD dosages with respect to demographic variables and patient characteristics in two main groups divided according to cannabis administration method - inhalation or sublingual oil. RESULTS: A total of 3,554 patients were included in the study (2,724 exclusively inhaled cannabis and 830 exclusively consumed cannabis as sublingual oil). The daily THC and CBD doses were significantly higher in the inhalation group than in the sublingual group (p<.001). None of the four models predicting THC and CBD doses in the two groups had satisfactory prediction ability (adjusted R-squared between 0.007 and 0.09). Male gender, unemployed status, tobacco smoking and a lack of concern about cannabis treatment were associated with a higher inhaled THC dose (p<.001). CONCLUSION: Models based on patient characteristics failed to accurately predict the final titration doses of CBD and THC for both inhalation and sublingual administration. Clinical guidelines should maintain a highly individual approach for cannabinoid dosing.

Herbal Cannabis Use Is Not Associated with Changes in Levels of Endocannabinoids and Metabolic Profile Alterations among Older Adults.

Activation of the endocannabinoid system has various cardiovascular and metabolic expressions, including increased lipogenesis, decreased blood pressure, increased heart rate, and changes in cholesterol levels. There is a scarcity of data on the metabolic effects of exogenous cannabis in older adults; therefore, we aimed to assess the effect of exogenous cannabis on endocannabinoid levels and the association with changes in 24 h ambulatory blood pressure and lipid levels. We conducted a prospective study of patients aged 60 years or more with hypertension treated with a new prescription of herbal cannabis. We assessed changes in endocannabinoids, blood pressure, and metabolic parameters prior to and following three months of cannabis use. Fifteen patients with a mean age of 69.47 ± 5.83 years (53.3% male) underwent complete evaluations. Changes in 2-arachidonoylglycerol, an endocannabinoid, were significantly positively correlated with changes in triglycerides. Changes in arachidonic acid levels were significantly positively correlated with changes in C-reactive protein and with changes in mean diastolic blood pressure. Exogenous consumption of cannabidiol was negatively correlated with endogenous levels of palmitoylethanolamide and oleoylethanolamide. On average, cannabis treatment for 3 months does not result in a significant change in the levels of endogenous cannabinoids and thus has a safe metabolic risk profile.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Estimation of Potassium Changes Following Potassium Supplements in Hypokalemic Critically Ill Adult Patients-A Patient Personalized Practical Treatment Formula.

Hypokalemia is common among critically ill patients. Parenteral correction of hyperkalemia depends on dosages and patient characteristics. Our aims were to assess changes in potassium levels following parenteral administration, and to derive a formula for predicting rises in serum potassium based on patient characteristics. We conducted a population-based retrospective cohort study of adults hospitalized in a general intensive care unit for 24 h or more between December 2006 and December 2017, with hypokalemia. The primary exposures were absolute cumulative intravenous doses of 20, 40, 60 or 80 mEq potassium supplement. Adjusted linear mixed models were used to estimate changes in serum potassium. Of 683 patients, 422 had mild and 261 moderate hypokalemia (serum potassium 3.0-3.5 mEq/L and 2.5-2.99 mEq, respectively). Following doses of 20-80 mEq potassium, serum potassium levels rose by a mean 0.27 (±0.4) mEq/L and 0.45 (±0.54) mEq/L in patients with mild and moderate hypokalemia, respectively. Changes were associated with creatinine level, and the use of mechanical ventilation and vasopressors. Among critically ill patients with mild to moderate hypokalemia, increases in serum potassium after intravenous potassium supplement are influenced by several clinical parameters. We generated a formula to predict the expected rise in serum potassium based on clinical parameters.

Medical Cannabis for Older Patients-Treatment Protocol and Initial Results.

Older adults may benefit from cannabis treatment for various symptoms such as chronic pain, sleep difficulties, and others, that are not adequately controlled with evidence-based therapies. However, currently, there is a dearth of evidence about the efficacy and safety of cannabis treatment for these patients. This article aims to present a pragmatic treatment protocol for medical cannabis in older adults. We followed consecutive patients above 65 years of age prospectively who were treated with medical cannabis from April 2017 to October 2018. The outcomes included treatment adherence, global assessment of efficacy and adverse events after six months of treatment. During the study period, 184 patients began cannabis treatment, 63.6% were female, and the mean age was 81.2 ± 7.5 years (median age-82). After six months of treatment, 58.1% were still using cannabis. Of these patients, 33.6% reported adverse events, the most common of which were dizziness (12.1%) and sleepiness and fatigue (11.2%). Of the respondents, 84.8% reported some degree of improvement in their general condition. Special caution is warranted in older adults due to polypharmacy, pharmacokinetic changes, nervous system impairment, and increased cardiovascular risk. Medical cannabis should still be considered carefully and individually for each patient after a risk-benefit analysis and followed by frequent monitoring for efficacy and adverse events.

Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy.

There has been a dramatic increase in the number of children diagnosed with autism spectrum disorders (ASD) worldwide. Recently anecdotal evidence of possible therapeutic effects of cannabis products has emerged. The aim of this study is to characterize the epidemiology of ASD patients receiving medical cannabis treatment and to describe its safety and efficacy. We analysed the data prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017. The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC. Symptoms inventory, patient global assessment and side effects at 6 months were primary outcomes of interest and were assessed by structured questionnaires. After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) have been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and 8 (8.6%) had no change in their condition. Twenty-three patients (25.2%) experienced at least one side effect; the most common was restlessness (6.6%). Cannabis in ASD patients appears to be well tolerated, safe and effective option to relieve symptoms associated with ASD.

Medical cannabis: aligning use to evidence-based medicine approach.

During the past decade we have been witnessing a rise in medical cannabis use, yet the evidence for the safety and efficacy of the various cannabinoid compounds is scarce. The State of Israel has always been at the forefront of clinical and translational research in support of Evidence Based Medicine. With respect to cannabis Israel has created a medical and regulatory environment that enables clinical studies with cannabis which may lead to improved Evidence Based use of these compounds. This opinion paper discusses selected studies into the safety and effects of cannabis derived products.

Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly.

INTRODUCTION: There is a substantial growth in the use of medical cannabis in recent years and with the aging of the population, medical cannabis is increasingly used by the elderly. We aimed to assess the characteristics of elderly people using medical cannabis and to evaluate the safety and efficacy of the treatment. METHODS: A prospective study that included all patients above 65 years of age who received medical cannabis from January 2015 to October 2017 in a specialized medical cannabis clinic and were willing to answer the initial questionnaire. Outcomes were pain intensity, quality of life and adverse events at six months. RESULTS: During the study period, 2736 patients above 65 years of age began cannabis treatment and answered the initial questionnaire. The mean age was 74.5 ±â€¯7.5 years. The most common indications for cannabis treatment were pain (66.6%) and cancer (60.8%). After six months of treatment, 93.7% of the respondents reported improvement in their condition and the reported pain level was reduced from a median of 8 on a scale of 0-10 to a median of 4. Most common adverse events were: dizziness (9.7%) and dry mouth (7.1%). After six months, 18.1% stopped using opioid analgesics or reduced their dose. CONCLUSION: Our study finds that the therapeutic use of cannabis is safe and efficacious in the elderly population. Cannabis use may decrease the use of other prescription medicines, including opioids. Gathering more evidence-based data, including data from double-blind randomized-controlled trials, in this special population is imperative.

Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer.

BACKGROUND: Cancer is a major public health problem as the leading cause of death. Palliative treatment aimed to alleviate pain and nausea in patients with advanced disease is a cornerstone of oncology. In 2007, the Israeli Ministry of Health began providing approvals for medical cannabis for the palliation of cancer symptoms. The aim of this study is to characterize the epidemiology of cancer patients receiving medical cannabis treatment and describe the safety and efficacy of this therapy. METHODS: We analyzed the data routinely collected as part of the treatment program of 2970 cancer patients treated with medical cannabis between 2015 and 2017. RESULTS: The average age was 59.5 ±â€¯16.3 years, 54.6% women and 26.7% of the patients reported previous experience with cannabis. The most frequent types of cancer were: breast (20.7%), lung (13.6%), pancreatic (8.1%) and colorectal (7.9%) with 51.2% being at stage 4. The main symptoms requiring therapy were: sleep problems (78.4%), pain (77.7%, median intensity 8/10), weakness (72.7%), nausea (64.6%) and lack of appetite (48.9%). After six months of follow up, 902 patients (24.9%) died and 682 (18.8%) stopped the treatment. Of the remaining, 1211 (60.6%) responded; 95.9% reported an improvement in their condition, 45 patients (3.7%) reported no change and four patients (0.3%) reported deterioration in their medical condition. CONCLUSIONS: Cannabis as a palliative treatment for cancer patients seems to be well tolerated, effective and safe option to help patients cope with the malignancy related symptoms.

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

BACKGROUND: Administration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be-discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields. MATERIAL AND METHODS: Using electrophysiological techniques, we identified 161 C- and 135 Aδ-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles. RESULTS: Seven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non-noxious mechanosensitivity of C-fibers or on responsiveness of Aδ-fibers to mechanical and chemical stimulation. DISCUSSION: This study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors' responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A's ability to act as a prophylactic.

Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy.

BACKGROUND: Ultraviolet B (UVB) rays are required by the skin for the production of vitamin D. The intensity of UVB at the Dead Sea area is the lowest in the world. Low vitamin D levels are often associated with musculoskeletal symptoms. OBJECTIVES: To assess the effectiveness of climatotherapy at the Dead Sea on the production of vitamin D in Norwegian patients suffering from various rheumatic diseases and to investigate possible associations between increased vitamin D serum levels, musculoskeletal symptoms and disease severity. METHODS: Sixty Norwegian patients who came to the Dead Sea area for 21 days of medical rehabilitation were divided into three groups according to their diagnosis: chronic pain syndromes, i.e., low back pain or fibromyalgia (Group 1, n=33); rheumatoid arthritis (Group 2, n=16); and osteoarthritis (Group 3, n=11). Serum 25-hydroxyvitamin D (25-OH-D) levels were determined at arrival and prior to departure. The treatment protocol included daily sun exposure (climatotherapy), bathing in the Dead Sea and mineral spring water (balneotherapy), mud applications and fitness classes. RESULTS: 25-OH-D serum levels increased significantly from 71.3 +/- 26.6 nM at arrival to 89.3 +/- 23.2 nM prior to departure (P < 0.001). Adjusted for the initial levels of pain (assessed by a visual analog scale) and disease severity, a direct correlation was observed between increased 25-OH-D serum levels and pain reduction (P = 0.012) and reduction of disease severity (P = 0.02). CONCLUSIONS: Climatotherapy at the Dead Sea induces significant changes in vitamin D. Increased 25-OH-D serum levels are associated with reduced musculoskeletal pain and disease severity.

The effects of natural antioxidants from tomato extract in treated but uncontrolled hypertensive patients.

PURPOSE: To evaluate the effect of adding tomato extract to the treatment regime of moderate hypertensives with uncontrolled blood pressure (BP) levels. METHODS: Fifty four subjects with moderate HT treated with one or two antihypertensive drugs were recruited and 50 entered two double blind cross-over treatment periods of 6 weeks each, with standardized tomato extract or identical placebo. Plasma concentrations of lycopene, nitrite and nitrate were measured and correlated with BP changes. RESULTS: There was a significant reduction of systolic BP after 6 weeks of tomato extract supplementation, from 145.8 +/- 8.7 to 132.2 +/- 8.6 mmHg (p < 0.001) and 140.4 +/- 13.3 to 128.7 +/- 10.4 mmHg (p < 0.001) in the two groups accordingly. Similarly, there was a decline in diastolic BP from 82.1 +/- 7.2 to 77.9 +/- 6.8 mmHg (p = 0.001) and from 80.1 +/- 7.9 to 74.2 +/- 8.5 mmHg (p = 0.001). There was no significant change in systolic and diastolic BP during the placebo period. Serum lycopene level increased from 0.11 +/- 0.09 at baseline, to 0.30 +/- 01.3 micromol/L after tomato extract therapy (p < 0.001). There was a significant correlation between systolic BP and lycopene levels (r = -0.49, p < 0.001). CONCLUSIONS: Tomato extract when added to patients treated with low doses of ACE inhibition, calcium channel blockers or their combination with low dose diuretics, had a clinically significant effect-reduction of BP by more than 10 mmHg systolic and more than 5 mmHg diastolic pressure. No side-effects to treatment were recorded and the compliance with treatment was high. The significant correlation between systolic blood pressure values and level of lycopene suggest the possibility of cause-effect relationships.

The prevalence of low hemoglobin values among new infantry recruits and nonlinear relationship between hemoglobin concentration and physical fitness.

There is limited information regarding the optimal hemoglobin level for physical activity and most studies followed relatively few participants. The object of this study was to assess iron storage levels in a population of healthy young males and their impact on physical fitness. Blood samples were drawn from 358 consenting infantry recruits for hemoglobin, iron, ferritin, transferrin, folic acid, and B(12) levels. A detailed medical and nutritional history was noted. Recruits performed a field fitness test including a 2,000-m run. Mean hemoglobin was 13.8 +/- 1.0 g/dl. Level of hemoglobin lower than 14 and 12 g/dl were found in 53.6% and 4.5% of the recruits, respectively. Mean ferritin was 57 +/- 34 ng/ml, with 15% of the recruits under 25 ng/ml. On multivariate analysis, after adjusting for pre-induction sports activity (P < 0.001), intermediate pre-induction hemoglobin level (12-14 g/dl) was associated with significantly faster 2,000-m running time (530 +/- 69 s, n = 176) than both the lower hemoglobin group (570 +/- 77 s, n = 16) and the higher hemoglobin group (552 +/- 86 s, n = 166, P < 0.05). The subjects in this study were non-athletic healthy young men. The high rate of abnormally low hemoglobin and ferritin values probably indicates a nutritional deficit in this population. The slower running results in the group with hemoglobin below 12 g/dl are in line with previous work, indicating the need for iron supplementation. The decrease in running ability with increased hemoglobin above 14 g/dl is surprising and will need further evaluation.