Modulation of resistance artery tone by the trace amine ß-phenylethylamine: dual indirect sympathomimetic and α1-adrenoceptor blocking actions.

The trace amine ß-phenylethylamine (PEA) is normally present in the body at low nanomolar concentrations but can reach micromolar levels after ingestion of drugs that inhibit monoamine oxidase and primary amine oxidase. In vivo, PEA elicits a robust pressor response, but there is no consensus regarding the underlying mechanism, with both vasodilation and constriction reported in isolated blood vessels. Using functional and biochemical approaches, we found that at low micromolar concentrations PEA (1-30 µM) enhanced nerve-evoked vasoconstriction in the perfused rat mesenteric bed but at a higher concentration (100 µM) significantly inhibited these responses. The α2-adrenoceptor antagonist rauwolscine (1 µM) also enhanced nerve-mediated vasoconstriction, but in the presence of both rauwolscine (1 µM) and PEA (30 µM) together, nerve-evoked responses were initially potentiated and then showed time-dependent rundown. PEA (10 and 100 µM) significantly increased noradrenaline outflow from the mesenteric bed as determined by high-pressure liquid chromatography coupled with electrochemical detection. In isolated endothelium-denuded arterial segments, PEA (1 µM to 1 mM) caused concentration-dependent reversal of tone elicited by the α1-adrenoceptor agonists noradrenaline (EC50 51.69 ± 10.8 µM; n = 5), methoxamine (EC50 68.21 ± 1.70 µM; n = 5), and phenylephrine (EC50 67.74 ± 16.72 µM; n = 5) but was ineffective against tone induced by prostaglandin F2 α or U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2 α). In rat brain homogenates, PEA displaced binding of both [(3)H]prazosin (Ki ≈ 25 µM) and [(3)H]rauwolscine (Ki ≈ 1.2 µM), ligands for α1- and α2-adrenoceptors, respectively. These data provide the first demonstration that dual indirect sympathomimetic and α1-adrenoceptor blocking actions underlie the vascular effects of PEA in resistance arteries.

Naturalistic examination of the anxiolytic effects of medical cannabis and associated gender and age differences in a Canadian cohort.

BACKGROUND: The aim of the current study was to examine patterns of medical cannabis use in those using it to treat anxiety and to investigate if the anxiolytic effects of cannabis were impacted by gender and/or age. METHODS: Patient-reported data (n = 184 participants, 61% female, 34.7 ± 8.0 years) was collected through the Strainprint® app. Tracked sessions were included if the method of administration was inhalation, treatment was for anxiety and the product used was dried flower. The final analyzed dataset encompassed three of the most commonly utilized dried flower products in anxiety sessions. Independent sample t-tests were used. The core analysis examined within subject changes overtime (pre-medication to post-medication) and interactions between time with two candidate moderators [gender (male, female) and age (18-29, 30-39, and 40 + years old)] by using analysis of variance (ANOVA). For significant main effects of interactions, post hoc tests were conducted using a Bonferroni correction. A secondary analysis examined differences in proportion of emotives endorsed as a function of gender or age using chi-square test of independence. RESULTS: Cannabis consumption resulted in a significant decrease in anxiety scores among both males and females (average efficacy of 50%) and efficacy was similar across the three cultivars. However, gender differences in efficacy were identified in two of the cultivars. All age groups experienced significant reductions in their anxiety post cannabis consumption; however, the 40 + year old group had significantly less efficacy than the other groups. The overall optimal dosing for the entire cohort was 9-11 inhalations for males and 5-7 inhalations for females, with some variation in dosing across the different cultivars, genders and age groups. CONCLUSIONS: We found all three cultivars had significant anxiolytic effects and were well-tolerated. Some limitations of the study are the moderate sample size, self-reported diagnosis of anxiety, unknown comorbidities and experience with cannabis, whether other drugs or cannabis products were used, and restriction to solely inhaled administration. We suggest that the gender and age differences in optimal dosing could support both healthcare practitioners and patients initiate medical cannabis treatment for anxiety.

Evaluation of Patient Reported Safety and Efficacy of Cannabis From a Survey of Medical Cannabis Patients in Canada.

With the medical use of cannabis permitted in Canada since 2001, patients seek to use this botanical drug to treat a range of medical conditions. However, many healthcare practitioners express the need for further scientific evidence around the use of medical cannabis. This real-world evidence study aimed to address the paucity of scientific data by surveying newly registered medical cannabis patients, before beginning medical cannabis treatment, and at one follow up 6 weeks after beginning medical cannabis treatment. The goal was to collect data on efficacy, safety and cannabis product type information to capture the potential impact medical cannabis had on patient-reported quality of life (QOL) and several medical conditions over a 6-week period using validated questionnaires. The 214 participants were mainly male (58%) and 57% of the population was older than 50. The most frequently reported medical conditions were recurrent pain, post-traumatic stress disorder (PTSD), anxiety, sleep disorders [including restless leg syndrome (RLS)], and arthritis and other rheumatic disorders. Here we report that over 60% of our medical cannabis cohort self-reported improvements in their medical conditions. With the use of validated surveys, we found significant improvements in recurrent pain, PTSD, and sleep disorders after 6 weeks of medical cannabis treatment. Our findings from patients who reported arthritis and other rheumatic disorders are complex, showing improvements in pain and global activity sub-scores, but not overall changes in validated survey scores. We also report that patients who stated anxiety as their main medical condition did not experience significant changes in their anxiety after 6 weeks of cannabis treatment, though there were QOL improvements. While these results show that patients find cannabis treatment effective for a broad range of medical conditions, cannabis was not a remedy for all the conditions investigated. Thus, there is a need for future clinical research to support the findings we have reported. Additionally, while real-world evidence has not historically been utilized by regulatory bodies, we suggest changes in public policy surrounding cannabis should occur to reflect patient reported efficacy of cannabis from real-world studies due to the uniqueness of medical cannabis's path to legalization.

Activation of endothelial IKCa channels underlies NO-dependent myoendothelial feedback.

Agonist-induced vasoconstriction triggers a negative feedback response whereby movement of charged ions through gap junctions and/or release of endothelium-derived (NO) limit further reductions in diameter, a mechanism termed myoendothelial feedback. Recent studies indicate that electrical myoendothelial feedback can be accounted for by flux of inositol trisphosphate (IP3) through myoendothelial gap junctions resulting in localized increases in endothelial Ca(2+) to activate intermediate conductance calcium-activated potassium (IKCa) channels, the resultant hyperpolarization then conducting back to the smooth muscle to attenuate agonist-induced depolarization and tone. In the present study we tested the hypothesis that activation of IKCa channels underlies NO-mediated myoendothelial feedback. Functional experiments showed that block of IP3 receptors, IKCa channels, gap junctions and transient receptor potential canonical type-3 (TRPC3) channels caused endothelium-dependent potentiation of agonist-induced increase in tone which was not additive with that caused by inhibition of NO synthase supporting a role for these proteins in NO-mediated myoendothelial feedback. Localized densities of IKCa and TRPC3 channels occurred at the internal elastic lamina/endothelial-smooth muscle interface in rat basilar arteries, potential communication sites between the two cell layers. Smooth muscle depolarization to contractile agonists was accompanied by IKCa channel-mediated endothelial hyperpolarization providing the first demonstration of IKCa channel-mediated hyperpolarization of the endothelium in response to contractile agonists. Inhibition of IKCa channels, gap junctions, TRPC3 channels or NO synthase potentiated smooth muscle depolarization to agonists in a non-additive manner. Together these data indicate that rather being distinct pathways for the modulation of smooth muscle tone, NO and endothelial IKCa channels are involved in an integrated mechanism for the regulation of agonist-induced vasoconstriction.