Antihypertensives That Stimulate vs Inhibit Type 2 and 4 Angiotensin II Receptors Decrease Dementia 

Marcum et al in JAMA New Open (2023) found that in “57,773 Medicare beneficiaries, initiation of antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors was associated with a statistically significant 16% lower risk of incident dementia, over a median of 6.9 years of follow-up.”

“Angiotensin II receptor type 2 and 4–stimulating antihypertensive medications (hereafter, stimulating medications) included: Angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.
Angiotensin II receptor type 2 and 4–inhibiting antihypertensive medications (hereafter, inhibiting medications) included: angiotensin-converting enzyme (ACE) inhibitors, ?-blockers, and nondihydropyridine calcium channel blockers.”

Editors Note: If you have hypertension and are at risk for cognitive decline, know that your choice of effective antihypertensive drugs can lead to better cognitive outcomes. Drugs that stimulate the angiotensin II receptor type 2 and 4 help prevent dementia. These drugs include:
ARB type 1, dihydropyridine calcium channel blockers, and thiazide diuretics. (Good guys)

Those that inhibit Angiotensin II receptors types 2 and 4 do not prevent dementia. These drugs include:
ACE inhibitors, beta blockers, and non-dihydropyridine calcium channel blockers. (Bad guys)

Talk with your doc about drugs equally for blood pressure control but those that also have benefits for ultimate preservation of cognition.

6 Minutes of Intense Cycling Produces Major Increases in BDNF

Brain derived neurotrophic factor (BDNF) is necessary for new synapses and call survival.  A new study in J. Physiology (2023) reports that the increases in BDNF from short intense cycling exercise are much greater than from prolonged (90-minute) light cycling.  The authors think that this is cause by the increases in lactate produced which helps up regulate BDNF production. This could be good for fighting depression and Alzheimer’s disease, where BDNF levels are low. 

Bottom line:  If you don’t have much time, bust your buns.

Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients

M M Bergamaschi, et al reported in Neuropsychopharmacology volume 36, pages 1219–1226 (2011) that the one of the ingredient in cannabis, the diol or cannabidiol (CBD), containing none of the usual THC which make up the vast majority of plant-based marijuana, reduces the anxiety Induced by simulated public speaking in treatment-naïve social phobia patients.  They used “CBD (600?mg) in powder, ?99.9% pure (kindly supplied by STI-Pharm, Brentwood, UK and THC-Pharm, Frankfurt, Germany),… dissolved in corn oil.”  This CBD has shown efficacy in other anxiety disorders and is FDA approved for one form of seizure disorder.  This pure form of CBD is very expensive and usual preparations of available cannabis contain mostly THC and only minute amounts of CBD.  Thus, the generalizability of these results to people using the widely available preparations of cannabis is extremely unlikely. 

U.S. FDA Approves VRAYLAR® (cariprazine) as an Adjunctive Treatment for Major Depressive Disorder

“A Phase 3 Study 3111-301-001 showed a clinically and statistically significant change from baseline to week six in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score for patients treated with cariprazine at 1.5 mg/day + ADT compared with placebo + ADT. A second registration-enabling study, RGH-MD-75, showed a clinically and statistically significant change from baseline to week eight in the MADRS total score for patients treated with cariprazine at 2-4.5 mg/day (mean dose 2.6 mg) + ADT compared with placebo + ADT.

Cariprazine was generally well tolerated in 6- and 8-week studies. Mean weight change was < 2lbs and ? 3% of patients had a weight increase of ? 7%.

The starting dosage of VRAYLAR is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions. The maximum recommended dosage is 3 mg once daily.

Most common adverse reactions observed in the adjunctive MDD studies (? 5% and at least twice the rate of placebo) were:

Akathisia, nausea, and insomnia at the recommended doses in 6-week, fixed-dose trials

Akathisia, restlessness, fatigue, constipation, nausea, increased appetite, dizziness, insomnia, and extrapyramidal symptoms in one 8-week flexible-dose trial at a titration of less than 14 days”

Potential Treatment for “Brain Fog” in Long COVID Patients: Guanfacine plus NAC

As announced in Yale on December 13, 2022 by Isabella Backman “A new Yale case study finds that two medications used for treating traumatic brain injuries, when taken together, can mitigate and sometimes eliminate the cognitive impairments known as “brain fog,” common among people with persistent COVID-19 symptoms….Individuals with long COVID, sometimes referred to as “long-haulers,” experience symptoms that may persist for weeks, months, or even years after their acute viral infection. While symptoms vary widely, a common complaint among patients is “brain fog”—a colloquial term for significant, persistent cognitive deficits, with consistent impairment of executive functioning and working memory. Long-haulers may experience a lack of mental clarity, poor focus and concentration, memory problems, difficulty with multi-tasking, and more. Brain fog can be debilitating, but there currently are no treatment options that are approved for the condition. 

Cold Water Immersion Can Have Benefits

From:

Medscape Staff, December 08, 2022

Bathing in cold water or ice may cut “bad” body fat and reduce the risk of disorders such as diabetes, but other claims of health benefits are less defined, according to researchers from the Arctic University of Norway and the University Hospital of North Norway.

WHAT TO KNOW:

  • Immersion in cold water has a major impact on the body. It elevates the heart rate and has positive effects on brown adipose tissue, a type of “good” body fat that is activated by cold and may protect against obesity and cardiovascular disease.
  • Exposure to cold water or cold air also appears to increase the production of the protein adiponectin by adipose tissue. Adiponectin plays a key role in protecting against insulin resistance, diabetes, and other diseases.
  • Repeated cold-water immersions by inexperienced as well as experienced swimmers during the winter months significantly increased insulin sensitivity and decreased insulin concentrations.
  • Numerous health and well-being claims from regular exposure to the cold, such as weight loss, better mental health, and increased libido, may be explained by other factors, including an active lifestyle, trained stress handling, social interactions, as well as a positive mindset.
  • Those seeking to voluntarily practice cold-water emersion need to be educated about possible health risks associated with taking a dip in icy water, which include the consequences of hypothermia, and of heart and lung problems, which are often related to the shock from the cold.”

Intermittent theta burst magnetic stimulation (iTBS) is FDA approved.

As reported in Psych. News:?The Food and Drug Administration (FDA) has cleared the SAINT Neuromodulation System for the treatment of refractory depression in adults, Magnus Medical Inc. (the manufacturer of the product)?announced?Tuesday. SAINT is a?modified form of transcranial magnetic stimulation?(TMS) that compresses weeks of conventional TMS therapy into just five days”. ?Regular TMS takes 20-30 minutes per daily session while iTBS takes about 5 minutes and thus can be applied many times in a single day. ?”As demonstrated in a clinical trial?published?in?The American Journal of Psychiatry, Montgomery-Åsberg Depression Rating Scale (MADRS) scores dropped by 62% among participants following five days of SAINT stimulation compared with a 14% drop among participants receiving sham stimulation. These improvements were sustained over a four-week follow-up.” ?The method was developed by Nolan Williams and he used MRI to best target the site of stimulation 

Mindfulness-Based Stress Reduction Equivalent to Escitalopram for Treatment of  Anxiety Disorders

December 1, 2022 · Posted in Current Treatments, Potential Treatments · Comment 

Hoge et al reported in JAMA Psychiatry (2022) that in a randomized clinical trial of 276 adults with anxiety disorders, 8-week treatment with mindfulness-based stress reduction (MBSR) was noninferior to escitalopram.  The “MBSR is a manualized 8-week protocol with weekly 2.5-hour long classes, a day-long retreat weekend class during the fifth or sixth week, and 45-minute daily home practice exercises…. Qualified instructors taught the theory and practice of several forms of mindfulness meditation, such as breath awareness (focusing attention on the breath and other physical sensations), a body scan (directing attention to one body part at a time and observing how that body part feels), and mindful movement (stretching and movements designed to bring awareness to the body and increase interoceptive awareness)….Escitalopram was initiated at 10 mg daily orally and increased to 20 mg daily at week 2 if well tolerated or delayed if not.”  The investigators concluded that “mindfulness-based stress reduction was a well-tolerated treatment option with comparable effectiveness to a first-line medication for patients with anxiety disorders.”

Review Describes Latest Findings on the Mechanisms of Psychedelic Drugs and Their Therapeutic Potential

In a 2021 review article in a special issue of the Journal of Neurochemistry devoted to “Psychedelics and Neurochemistry,” researcher Alaina M. Jaster and colleagues summarized recent findings on psychedelic drugs, including their potential as treatments for psychiatric disorders and the structural changes they produce in the brain. The review article focused on findings in humans and provided background context based on findings in animals, particularly rodents.

In the article, Jaster and colleagues write that psychedelics “have in common a battery of acute (within minutes to hours) effects in humans that include profound changes in processes related to perception, cognition, sensory processing, and mood.” They are not considered to be addictive, and recent research has identified fast-acting and long-lasting therapeutic effects of psychedelics, particularly for the treatment of depression and substance abuse.

While psychedelic drugs interact with the brain in complicated ways, the role of serotonin 5-HT2A receptors seems to be crucial to their effects. Psychedelics have classically been divided into two groups based on their chemical structures: phenethylamines (which include mescaline and its synthetic analog DOI) and tryptamines (which include psilocybin/“magic mushrooms,” DMT/ayahuasca, and ergolines like LSD, which are sometimes separated into a third category). The authors of the review highlight that other substances with different chemical structures that do not fit into this classification can also function as psychedelics. Examples include efavirenz and quipazine, which both activate serotonin 5-HT2A receptors and change rodent behavior in the same way that other psychedelic drugs do. These drugs are providing new directions for research into how psychedelics work at both serotonin 5-HT2A receptors and monoaminergic G protein-coupled receptors (GPCRs).

An image from the review article shows the effects of various psychedelic drugs on different receptors.

Rodent studies are often used to investigate how psychedelic drugs work. Rodent behaviors such as ear scratching and head twitching increase when the rodents are given drugs that have psychedelic effects in humans. These behaviors return to normal when rodents are given drugs that function as serotonin 5-HT2A receptor antagonists, preventing the stimulation of these serotonin receptors.

While it has been established that serotonin 5-HT2A receptors play an important role in the hallucinogenic effects of psychedelic drugs, how serotonin receptors are involved in some of the therapeutic effects of psychedelics, such as antidepressant effects and changes to synaptic plasticity, is not yet clear.

According to the review, “A number of studies in animal models as well as postmortem human brain samples from subjects with depression and controls has provided evidence that mood disorders occur in conjunction with a reduction in the density of dendritic spines, particularly in the frontal cortex.” Dendrites are the projections from the cell bodies of neurons upon which nerve endings from the axons of other neurons synapse. The surface of these dendrites is covered in mushroom-shaped spines that help create these synaptic connections. The review describes in vitro and in vivo research on mice that suggests that the psychedelics DOI, DMT, and LSD can remodel dendritic spines.

At a recent scientific meeting, researcher Javier González-Maeso, one of the authors of the review, described findings from a recent study of mice given DOI. The structure of the dendritic spines in the prefrontal cortex changed rapidly in these mice. They had also been conditioned to produce a fear response, and the extinction process to get rid of this learned fear was sped up in the mice given DOI. These effects occurred via the serotonin 5-HT2 receptors. The exposure to the psychedelic also affected the regulation of genes involved in synaptic assembly for days, suggesting that epigenetic-induced changes in synaptic plasticity may underlie some of the long-lasting therapeutic effects of psychedelics.

The review also addressed “microdosing,” the recreational practice of consuming small amounts of psychedelics such as psilocybin or LSD, based on the theory that amounts too small to create a hallucinogenic effect may instead produce therapeutic results. The authors find limited data to support microdosing. Most studies in humans and rodents have found no effect or, in the case of one rat study, a worsening of dendritic spine density following microdosing.

Psilocybin Comparable to Escitalopram in the Treatment of Depression

March 2, 2022 · Posted in Peer-Reviewed Published Data, Potential Treatments · Comment 
ingredient in magic mushrooms may treat depression

Four randomized, controlled clinical trials have established that psilocybin, the hallucinogenic compound in “magic mushrooms,” has anti-depressant effects. Recently, a phase 2 clinical trial compared the effects of psilocybin to a US Food and Drug Administration (FDA)–approved treatment for depression, the selective serotonin-reuptake inhibitor (SSRI) escitalopram. The study by Robin Carhart-Harris and colleagues was published in the New England Journal of Medicine in 2021.

The 59 participants in the 6-week study, which took place in the United Kingdom, had longstanding moderate-to-severe major depressive disorder. They were randomized to two groups. The psilocybin group received two separate doses of 25 mg of psilocybin 3 weeks apart, plus 6 weeks of daily placebo. The escitalopram group received two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram. (The small doses of psilocybin administered to the escitalopram group were assumed to have negligible psychiatric effects.) All participants were told they would receive psilocybin (though not the dose) in order to standardize their expectations.

In addition to the drug treatments, all participants also received psychological support, which consisted of monitoring immediately after the administration of the drugs (given the expectation that the 25mg dose of psilocybin would produce an “altered quality of conscious experience”), psychological debriefings, and an active listening session.

Psilocybin improved depression symptoms to a greater extent than escitalopram did. Among the participants, 70% of the psilocybin group responded to the treatment, compared with 48% of the escitalopram group. Remission occurred in 57% of the psilocybin group compared with 28% of the escitalopram group. These differences in the outcomes for the two groups were not statistically significant.

The FDA has designated psilocybin a “Breakthrough Therapy” for severe depression, which indicates that the therapy may be a substantial improvement over existing therapies for a serious condition. The designation is intended to speed up the drug development and review process.

The state of Oregon legalized psilocybin-assisted therapy in 2020.

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