ARMR’s experimental vaccine is designed to neutralize fentanyl in the bloodstream before it reaches the brain. Keeping fentanyl out of the brain would prevent the respiratory failure that comes with overdose, which causes death, as well as the euphoric high people get while taking fentanyl.

The basic idea behind ARMR’s shot is the same as any other vaccine. It trains the body’s immune system to make antibodies that recognize a foreign invader. But since fentanyl is much smaller than the pathogens our current vaccines target, it doesn’t trigger a natural antibody response on its own. To stimulate antibody production, ARMR has paired a fentanyl-like molecule with a ‘carrier’ protein—a deactivated diphtheria toxin that’s already used in several approved medical products…

…If a vaccinated person encounters fentanyl, antibodies in the blood would then bind to the drug and prevent it from traveling to the brain. Normally, fentanyl molecules can pass through the blood-brain barrier with ease, in part because of their small size. But fentanyl molecules with antibodies attached would be too big to get through. The result? No high and no overdose. The antibody-bound fentanyl molecules would eventually be passed in the urine.

The vaccine is based on work from the University of Houston, with collaborators at Tulane University designing an adjuvant derived from E.coli bacteria to boost the immune response to the vaccine. In rats, the shot blocked 92 to 98 percent of fentanyl from entering the brain and prevented the behavioral effects of the drug. The effects lasted for at least 20 weeks in the rats, which Gage thinks could translate to a year of protection in people.

---

ARMR Sciences of New York is trialing a vaccine in the Netherlands to protect against fentanyl-related overdose and death.

CSF α-Synuclein Seed Amplification Assays and Alzheimer Disease Biomarkers in Dementia With Lewy Bodies: Presentation and Progression.

In line with the original observation by Selye of an involution of the thymus and other lymphoid organs in response to stress (205) and the subsequent demonstration of the immunosuppressive effects of glucocorticoids (101), glucocorticoids have traditionally been seen as the hormonal mediators of the immunosuppressive effects of stressors. We will not delve into the details of the vast literature on the effects of stress on immunity, as this topic has been reviewed on several occasions and it is not directly relevant to the present review (3, 9, 160, 169, 204, 220).

Glucocorticoids act on their cellular targets by binding to glucocorticoid receptors (GRs). GRs normally reside in the cytosol in the form of a protein complex that brings together heat-shock proteins and FK506 binding protein 52. Upon binding to their ligand, GRs dissociate from this complex to form monomers or dimers and translocate to the nucleus The anti-inflammatory effects of glucocorticoids are mediated by transcriptional repression following nuclear translocation and tethering of monomeric GRs to the glucocorticoid-response elements of transcription factors such as NF-κB, activator protein (AP)-1, and IFN-regulating factor-3 (234). This results in the downregulation of genes coding for inflammatory mediators, enzymes, and adhesion molecules. Although the hypothesis is still controversial, GR dimerization and transactivation are thought to play an important role in the anti-inflammatory activity of glucocorticoids. This phenomenon is illustrated by data obtained in GR(dim/dim) mutant mice that show reduced GR dimerization and increased sensitivity to TNF-induced inflammation, and to experimental models of sepsis induced by LPS or cecal ligation and puncture (123, 235).

Glucocorticoids can be proinflammatory under certain conditions. This effect can be secondary to the selection of corticoid-resistant inflammatory cells, such as pathogenic Th17 cells that overexpress IL-23 receptor and multidrug-resistance protein and that are found in inflamed gut tissue from patients with Crohn’s disease (186). The proinflammatory effect of glucocorticoids may also result from inhibition of the production and release of anti-inflammatory factors, or conversely from enhanced production and release of proinflammatory mediators. In the first case, dexamethasone administered 24 h before LPS was found to enhance the placenta’s proinflammatory cytokine response to LPS as a consequence of the inhibition of lipoxin A4 synthesis (255). In the second case, it is the dose of glucocorticoids that makes the difference: as mentioned above, physiological glucocorticoid levels can be proinflammatory in some circumstances, whereas high or pharmacological levels are anti-inflammatory. For instance, low doses of glucocorticoids increase the production of macrophage migration inhibitory factor, and this effect is sufficient to override glucocorticoid-mediated inhibition of cytokine production and release by LPS-stimulated monocytes (39).

An international collaboration led by Cornell researchers used a combination of psilocybin and the rabies virus to map how—and where—the psychedelic compound rewires the connections in the brain.

Specifically, they showed psilocybin weakens the cortico-cortical feedback loops that can lock people into negative thinking. Psilocybin also strengthens pathways to subcortical regions that turn sensory perceptions into action, essentially enhancing sensory-motor responses.

The findings were published Dec. 5 in Cell. The lead author is postdoctoral researcher Quan Jiang.