Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission.

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 µg/kg) injection failed to increase SB. However, repeated LSD (30 µg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

Discontinuing Cancer Screening for Older Adults: a Comparison of Clinician Decision-Making for Breast, Colorectal, and Prostate Cancer Screenings.

BACKGROUND: While guidelines recommend against routine screening for breast, prostate, and colorectal cancers in older adults (65+ years) with <10-year life expectancy, many of these patients continue to be screened. How clinicians consider screening cessation across multiple cancer screening types is unknown. OBJECTIVE: To compare and contrast clinicians' perspectives on discontinuing breast, prostate, and colorectal cancer screenings in older adults. DESIGN: Qualitative, semi-structured interviews. PARTICIPANTS: Primary care clinicians in Maryland (N=30) APPROACH: We conducted semi-structured interviews with individual clinicians. Interviews were recorded, transcribed, and analyzed using standard techniques of qualitative content analysis to identify major themes. KEY RESULTS: Participants were mostly physicians (24/30) and women (16/30). Four major themes highlighted differences in decision-making across cancer screenings: (1) Clinicians reported more often screening beyond guideline-recommended ages for breast and prostate cancers than colorectal cancer; (2) clinicians had different priorities when considering the benefits/harms of each screening; for example, some prioritized continuing colorectal cancer screening due to the test's high efficacy while others prioritized stopping colorectal cancer screening due to high procedural risk; some prioritized continuing prostate cancer screening due to poor outcomes from advanced prostate cancer while others prioritized stopping prostate cancer screening due to high false positive test rates and harms from downstream tests; (3) clinicians discussed harms of prostate and colorectal cancer screening more readily than for breast cancer screening; (4) clinicians perceived more involvement with gastroenterologists in colonoscopy decisions and less involvement from specialists for prostate and breast cancer screening. CONCLUSIONS: Our results highlight the need for more explicit guidance on how to weigh competing considerations in cancer screening (such as test accuracy versus ease of cancer treatment after detection). Recognizing the complexity of the benefit/harms analysis as clinicians consider multiple cancer screenings, future decision support tools, and clinician education materials can specifically address the competing considerations.

Pituitary apoplexy as a mimicker of infectious meningitis in an adolescent female patient.

Pituitary apoplexy can cause a chemical meningitis and its mimicry in presentation with infectious meningitis poses a diagnostic challenge. Here we report an 18-year-old woman who presented with acute headache, altered mental status, and cerebral spinal fluid (CSF) pleocytosis, and clinically improved with antibiotics and steroids. Despite an unremarkable head computed tomography scan, brain magnetic resonance imaging showed a pituitary macroadenoma with apoplexy. This is one of the first reports of an adolescent with pituitary apoplexy masquerading as infectious meningitis and underscores the importance of keeping this rare condition, often missed on CT scans, on the differential for CSF pleocytosis.

Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline.

Lysergic acid diethylamide (LSD) is a serotonergic psychedelic compound receiving increasing interest due to putative anxiolytic and antidepressant properties. However, the potential neurobiological mechanisms mediating these effects remain elusive. Employing in vivo electrophysiology, microionthophoresis, behavioral paradigms and morphology assays, we assessed the impact of acute and chronic LSD administration on anxiety-like behavior, on the cortical dendritic spines and on the activity of serotonin (5-HT) neurons originating in the dorsal raphe nucleus (DRN) in male mice exposed to chronic restraint stress. We found that while the acute intraperitoneal (i.p.) administration of LSD (5, 15 and 30 and 60 µg/kg) did not produce any anxiolytic or antidepressant effects in non-stressed mice, the dose of 30 µg/kg (daily for 7 days) prevented the stress-induced anxiety-like behavior and the stress-induced decrease of cortical spine densitiy. Interestingly, while LSD acutely decreased the firing activity of 5-HT neurons, repeated LSD increased their basal firing rate and restored the low 5-HT firing induced by stress. This effect was accompanied by a decreased inhibitory response of 5-HT neurons to microiontophoretic applications of the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-N,N-dipropyl-2-aminotetralin). In conclusion, repeated LSD prevents the exacerbation of anxiety-like behavior following chronic stress exposure, but has no behavioral effects in non-stressed mice. These effects are paralleled by increased cortical spinogenesis and an enhancement of 5-HT neurotransmission which might be due to 5-HT1A receptors desensitization. Increased cortical spine density and enhancement of serotonergic neurotransmission may thus represent a candidate mechanism which mediate the therapeutic effects of serotonergic psychedelics on stress-induced anxiety.

d-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders.

Depression and anxiety are psychiatric diagnoses commonly associated with low quality of life and low percentage of responsiveness by patients treated with currently available drugs. Thus, research into alternative compounds to treat these disorders is essential to guarantee a patient's remission. The last decade has witnessed a revamped interest for the application of psychedelic medicine for the treatment of mental disorders due to anecdotal reports and clinical studies which show that low doses of d-lysergic acid diethylamide (LSD) and psilocybin may have antidepressant effects. LSD and psilocybin have demonstrated mood-modulating properties likely due to their capacity to modulate serotonergic (5-HT), dopaminergic (DA) and glutamatergic systems. LSD, belonging to the category of "classic halluginogens," interacts with the 5-HT system through 5HT1A, and 5HT2A receptors, with the DA system through D2 receptors, and indirectly also the glutamatergic neurotransmission thought the recruitment of N-methyl-d-aspartate (NMDA) receptors. Randomized clinical studies have confirmed its antidepressant and anxiolytic effects in humans. Thus, in this chapter, we will review the pharmacology of psychedelic drugs, report the most striking clinical evidence which substantiate the therapeutic potentials of these fascinating compounds in mood disorders, and look into the horizon of where psychedelic medicine is heading.