cannabidiol and Hypotension

To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects.. A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods.. Patients attended as outpatients, but took the CME at home.. Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1).. Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events.. Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME.. Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings.

Topics: Administration, Oral; Analgesics, Non-Narcotic; Cannabidiol; Cannabis; Cross-Over Studies; Double-Blind Method; Dronabinol; Humans; Hypotension; Muscle Spasticity; Nervous System Diseases; Pain; Phytotherapy; Placebos; Plant Preparations; Severity of Illness Index; Spasm; Urination Disorders

Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model.. To assess the safety and potential neuroprotective effects of high-dose CBD.. Anesthetized newborn piglets underwent global HI by ventilation with 8% O2 until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure ≤20 mm Hg). Piglets were randomized to intravenous treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for analysis.. CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant negative correlation between the plasma concentration of CBD and hypotension during drug infusion was observed (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathology score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T.. High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets.

Topics: Animals; Animals, Newborn; Arterial Pressure; Brain; Cannabidiol; Disease Models, Animal; Hypotension; Hypoxia-Ischemia, Brain; Infusions, Intravenous; Neuroprotective Agents; Risk Assessment; S100 Calcium Binding Protein beta Subunit; Sus scrofa; Time Factors; Troponin T

Intravenous injection of the endocannabinoid anandamide induces complex cardiovascular changes via cannabinoid CB(1), CB(2) and vanilloid TRPV1 receptors. Recently, evidence has been accumulating that in vitro, but not in vivo, anandamide relaxes blood vessels, via an as yet unidentified, non-CB(1) vascular cannabinoid receptor, sensitive to O-1918 (1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene). We here examined whether the anandamide-induced hypotension in urethane-anaesthetized rats was also mediated via a non-CB(1) vascular cannabinoid receptor.. Effects of two antagonists (O-1918 and cannabidiol) of the non-CB(1) vascular cannabinoid receptor on anandamide-induced changes in mean, systolic and diastolic blood pressure (MBP, SBP, DBP), mesenteric (MBF) and renal (RBF) blood flow and heart rate (HR) in urethane-anaesthetized rats was examined.. In anaesthetized rats, anandamide (1.5-3 micromol.kg(-1)) and its stable analogue methanandamide (0.5 micromol.kg(-1)) caused a delayed and prolonged decrease in MBP, SBP, DBP, MBF and RBF by about 10-30% of the respective basal values without changing HR. In pithed rats, anandamide (3 micromol.kg(-1)) decreased blood pressure by about 15-20% of the basal value without affecting HR, MBF and RBF. All vascular changes were reduced by about 30-70% by cannabidiol and O-1918 (3 micromol.kg(-1), each).. Non-CB(1) cannabinoid vascular receptors, sensitive to O-1918, contribute to the hypotensive effect of anandamide in anaesthetized rats. Activation of these receptors may be therapeutically important as the endocannabinoid system could be activated as a compensatory mechanism in various forms of hypertension.

Topics: Anesthesia; Animals; Anisoles; Arachidonic Acids; Blood Pressure; Cannabidiol; Cannabinoid Receptor Antagonists; Cyclohexanes; Endocannabinoids; Hypotension; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Renal Circulation; Splanchnic Circulation

The results of vasorespiratory studies in rats anaesthetised with pentobarbital show that (+/-) cannabidiol, a cannabinoid that lacks psychotropic actions and is inactive at cannabinoid (CB) receptors, does not affect respiration or blood pressure when injected (1-2000 microg; 3.2-6360 nmol i.a.). Cannabidiol in doses up to 2 mg (6360 nmol) i.a. or i.v. did not affect the fall in mean blood pressure or the increase in ventilation (respiratory minute volume) caused by capsaicin and high doses of anandamide, responses that are mediated by activation of vanilloid VR1 (TRPV1) receptors in this species. Similar results were obtained with (-) cannabidiol (30-100 microg i.a.; 95-318 nmol). It has previously been shown using human embryonic kidney (HEK) cells over-expressing vanilloid human VR1 (hVR1) receptors that cannabidiol is a full agonist at vanilloid VR1 receptors in vitro. However, in the intact rat cannabidiol lacked vanilloid VR1 receptor agonist effects. We conclude that there are substantial functional differences between human and rat vanilloid VR1 receptors with respect to the actions of cannabidiol as an agonist at vanilloid VR1 receptors. Studies in vivo show that cannabidiol lacks any significant effect on mean blood pressure or respiratory minute volume when injected i.a. or i.v., and that this cannabinoid does not modulate the vanilloid VR1 receptor-mediated cardiovascular and ventilatory changes reflexly evoked by capsaicin or anandamide in rats anaesthetised with pentobarbital.

Topics: Anesthesia; Animals; Arachidonic Acids; Blood Pressure; Cannabidiol; Capsaicin; Dose-Response Relationship, Drug; Endocannabinoids; Hyperventilation; Hypotension; Male; Polyunsaturated Alkamides; Pulmonary Ventilation; Rats; Rats, Wistar; Receptors, Drug