Sex and gender: modifiers of health, disease, and medicine.

Worldwide medicinal use of cannabis is rapidly escalating, despite limited evidence of its efficacy from preclinical and clinical studies. Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel NaV1.1. The duration and severity of thermally induced seizures and the frequency of spontaneous seizures were substantially decreased. Treatment with lower doses of CBD also improved autistic-like social interaction deficits in DS mice. Phenotypic rescue was associated with restoration of the excitability of inhibitory interneurons in the hippocampal dentate gyrus, an important area for seizure propagation. Reduced excitability of dentate granule neurons in response to strong depolarizing stimuli was also observed. The beneficial effects of CBD on inhibitory neurotransmission were mimicked and occluded by an antagonist of GPR55, suggesting that therapeutic effects of CBD are mediated through this lipid-activated G protein-coupled receptor. Our results provide critical preclinical evidence supporting treatment of epilepsy and autistic-like behaviors linked to DS with CBD. We also introduce antagonism of GPR55 as a potential therapeutic approach by illustrating its beneficial effects in DS mice. Our study provides essential preclinical evidence needed to build a sound scientific basis for increased medicinal use of CBD.

https://www.pnas.org/content/pnas/114/42/11229.full.pdf

Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.

"Constant Stress Has Become the New Normal": Stress and Anxiety Inequalities Among U.S. College Students in the Time of COVID-19.

Cannabidiol: Recent advances and new insights for neuropsychiatric disorders treatment.

For millennia, there has been interest in the use of cannabis for the treatment of epilepsy However, it is only recently that appropriately powered controlled studies have been completed In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19 EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD Understanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy

Cannabis for the Treatment of Epilepsy: an Update

Men who do not seek help for mental health problems may experience unnecessary suffering which ultimately affects the well-being of themselves and others. Gendered manifestations of depressive symp...

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Gendered Manifestations of Depression and Help Seeking Among Men.

GPR55, an orphan G-protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs' functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long-term potentiation, a common form of synaptic plasticity. Using quantitative RT-PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT-PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55+/+ mice significantly enhanced CA1 LTP. This effect was absent in GPR55-/- mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired-pulse ratios of GPR55-/- and GPR55+/+ mice with or without LPI and noted significant enhancement in paired-pulse ratios by LPI in GPR55+/+ mice. Behaviorally, GPR55-/- and GPR55+/+ mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55-/- mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity.

A Putative Lysophosphatidylinositol Receptor GPR55 Modulates Hippocampal Synaptic Plasticity

Depression and Suicide Risk at the Cross-Section of Sexual Orientation and Gender Identity for Youth

The impact of social support on suicide is understudied among youth experiencing homelessness (YEH). This is problematic because assumptions about the protectiveness of relationships may not generalize to conflictive YEH environments. This study, which included 1047 YEH, used path modeling with a logistic regression estimator to examine associations between social support from family, home-based friends, and street-based friends and past-year suicide attempt. Social support from home-based friends but not family or street-based friends decreased suicide attempt risk. Moreover, social support from home-based friends moderated the association between depression and attempt risk. Targeted programming strengthening home-based-friend relationships represents a valuable endeavor.

Does the source matter? Social support and suicide attempts among homeless youth

Transgender and nonbinary (TNB) individuals face disparities in nearly every aspect of health. One factor associated with poor health outcomes in other marginalized populations is health literacy, yet no identified studies examine health literacy in TNB samples. Moreover, most health literacy frameworks focus primarily on the capacities of individual patients to understand and use healthcare information, with little attention given to provider literacy and environmental factors. In partnership with a statewide LGBTQ advocacy organization, we recruited 46 transgender and nonbinary individuals to participate in seven focus groups conducted in urban, suburban, and rural locations throughout Colorado. TNB participants consistently engaged in efforts to increase their own health literacy and that of their medical providers yet faced multiple barriers to improve care. Difficulty identifying and physically reaching care, insurance and out-of-pocket expenses, negative experiences with healthcare providers and staff, provider incompetence, discriminatory and oppressive practices, and exclusionary forms and processes emerged as barriers to enacted health literacy among participants. Conversely, facilitators of enacted healthcare literacy included positive experiences with healthcare providers and staff, and inclusive forms and processes.

/pdf/we-are-doing-the-absolute-most-that-we-can-and-no-one-is-3iw5xkbt.pdf

“We Are Doing the Absolute Most That We Can, and No One Is Listening”: Barriers and Facilitators to Health Literacy within Transgender and Nonbinary Communities

Jarrod Call

Papers

Gendered Manifestations of Depression and Help Seeking Among Men.

A Putative Lysophosphatidylinositol Receptor GPR55 Modulates Hippocampal Synaptic Plasticity

Depression and Suicide Risk at the Cross-Section of Sexual Orientation and Gender Identity for Youth

Does the source matter? Social support and suicide attempts among homeless youth

“We Are Doing the Absolute Most That We Can, and No One Is Listening”: Barriers and Facilitators to Health Literacy within Transgender and Nonbinary Communities