Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin-prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT 2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT 2A receptor-mediated excitation of deep pyramidal cells.

Background-The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. Methods and Results-This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (nϭ30) were compared with healthy controls (nϭ153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (ϩ0.49, ϩ0.45 SD, respectively). HRV and total power were lower among cases (both Ϫ0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (ϩ0.89, ϩ0.51, and ϩ0.72 SD). Lower HRV was associated with higher normetanephrine output (rϭϪ0.19; Pϭ0.03). Among former cases (MS 5 years previously, nϭ23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. Conclusions-Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required.

The cortisol response to meals may have implications for the effects of meal composition on mood, cognitive function, and food choice. The measurement of free cortisol in saliva provides a psychologically stress-free and reliable technique to assess the cortisol response to a standard protein-rich meal, ie, a physiological challenge to the HPA axis in men and women that could be investigated in naturalistic settings outside the laboratory.

We have validated the use of prolonged inhalation of 7.5% carbon dioxide (CO(2)) as a human model of anxiety and have shown that drugs from two prototypical classes of anxiolytics, benzodiazepines and a serotonin reuptake inhibitor, attenuate CO(2)-induced symptoms (Bailey et al., 2007a). Preclinical evidence suggests that drugs acting at the corticotropin-releasing factor (CRF) system may be useful for the treatment of depression, anxiety, and other stress-related disorders (Valdez, 2006), hence we have now examined the effects of a CRF(1) receptor antagonist in the 7.5% CO(2) model. In a randomized double-blind, placebo-controlled, study in 32 healthy participants we examined the effects of 7 days of treatment with the CRF(1) receptor antagonist, R317573, at a dose that shows a favourable safety profile and is comparable with those effective in preclinical models (40 mg). On day 8, eight of the placebo-treated group received lorazepam (LZP) 2 mg as a positive control. All participants underwent 20 min inhalation of 7.5% CO(2)-enriched air. Subjective reports of peak gas effects were assessed using visual analogue scales and questionnaires. The mean age of participants was 26 years, and 13 were male. The peak effects of CO(2) were expressed as a difference from baseline scores obtained while breathing air alone. Compared with placebo (PLAC), both drug groups showed a decrease in all subjective symptoms, total score on the panic symptom inventory (CRF 11 [2.6], PLAC 16.4 [3.1], LZP 2.9 [3.0]) and a generalized anxiety disorder symptom scale (CRF 2.2 [1.5], PLAC 8.2 [2.2], LZP 1.1 [1.5]). We have shown that a drug that acts to inhibit the CRF(1) receptor shows efficacy in the 7.5% CO(2) model of anxiety in healthy participants.

We have shown that at lower anxiety levels, D-cycloserine 50 mg improved the performance of this challenging visuospatial cognitive task. This increase in performance was not seen when anxiety was higher, and D-cycloserine did not appear to increase subjective anxiety. These data lend support to the use of D-cycloserine and related glutamate enhancers as cognitive modulators and suggest that the actions of D-cycloserine are not simply related to increased arousal or anxiety.