Back from the rabbit hole. Theoretical considerations and practical guidelines on psychedelic integration for mental health specialists.

The growing interest in and prevalence of the use of psychedelics, as well as the potential benefits and negative consequences associated with psychedelic experiences, create a need for mental health specialists to be able to provide adequate and effective intervention regarding the content and consequences of these experiences, that is, psychedelic integration. At the same time, current graduate training in psychiatry, psychology, psychotherapy, counseling, etc., fails to adequately prepare professionals for such interventions. In order to fill this gap, an international, bottom-up project was established to attempt developing guidelines. This project was conducted by means of literature reviews as well as roundtable discussions among project participants, leading to a consensus on the guidelines' final scope and content. Drawing from the outcomes of this project, this article presents proposed comprehensive guidelines covering both theoretical and practical aspects of psychedelic integration, that are intended to serve as a resource for various mental health specialists who may encounter individuals in need of support considering their psychedelic experiences. These guidelines encompass clinician-friendly information on the effects of psychedelics, a definition of psychedelic integration, the general theoretical considerations linked to utilization of psychedelic experiences in clinical practice, a simple model organizing the course of psychedelic integration practice, as well as an overview of the current models of psychedelic integration, along with a selective presentation of basic and specific interventions derived from various psychotherapeutic approaches that can be employed in the practice of psychedelic integration.

Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously.

AIM: AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR). METHODS AND RESULTS: Patients with AF episodes of duration 3 h to 3 months were randomized in a 3:1 ratio to receive a maximum 30 min intravenous infusion of AZD1305 or matching placebo. The primary efficacy endpoint was the proportion of patients converting within 90 min of the start of infusion, after which patients who had not converted were to undergo direct current (DC) cardioversion. Four ascending AZD1305 dose groups were assigned sequentially, with dose rates of 50, 100, 130, and 180 mg/h. A total of 171 patients were randomized. Pharmacological conversion was achieved in 0 of 43 patients (0%) in the placebo group, and in 2 of 26 (8%; P= 0.14 vs. placebo), 8 of 45 (18%; P= 0.006), 17 of 45 (38%; P< 0.001), and 6 of 12 patients (50%; P< 0.001) in AZD1305 dose groups 1-4, respectively. Maximum QTcF (QT interval corrected according to Fridericia's formula) generally increased dose-dependently up to a plateau, although there was wide variation between patients. Two patients experienced torsade de pointes (TdP): one patient without symptoms in dose group 3, and one patient requiring DC defibrillation in dose group 4. Both patients recovered without sequelae. CONCLUSIONS: AZD1305 was effective in converting AF to SR, but was associated with QT prolongation and TdP. The benefit-risk profile was judged as unfavourable and the AZD1305 development programme was discontinued. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov identifier NCT00915356.

High-fat diet-induced obesity leads to increased NO sensitivity of rat coronary arterioles: role of soluble guanylate cyclase activation.

The impact of obesity on nitric oxide (NO)-mediated coronary microvascular responses is poorly understood. Thus NO-mediated vasomotor responses were investigated in pressurized coronary arterioles ( approximately 100 microm) isolated from lean (on normal diet) and obese (fed with 60% of saturated fat) rats. We found that dilations to acetylcholine (ACh) were not significantly different in obese and lean rats (lean, 83 +/- 4%; and obese, 85 +/- 3% at 1 microM), yet the inhibition of NO synthesis with N(omega)-nitro-l-arginine methyl ester reduced ACh-induced dilations only in vessels of lean controls. The presence of the soluble guanylate cyclase (sGC) inhibitor oxadiazolo-quinoxaline (ODQ) elicited a similar reduction in ACh-induced dilations in the two groups of vessels (lean, 60 +/- 11%; and obese, 57 +/- 3%). Dilations to NO donors, sodium nitroprusside (SNP), and diethylenetriamine (DETA)-NONOate were enhanced in coronary arterioles of obese compared with lean control rats (lean, 63 +/- 6% and 51 +/- 5%; and obese, 78 +/- 5% and 70 +/- 5%, respectively, at 1 microM), whereas dilations to 8-bromo-cGMP were not different in the two groups. In the presence of ODQ, both SNP and DETA-NONOate-induced dilations were reduced to a similar level in lean and obese rats. Moreover, SNP-stimulated cGMP immunoreactivity in coronary arterioles and also cGMP levels in carotid arteries were enhanced in obese rats, whereas the protein expression of endothelial NOS and the sGC beta1-subunit were not different in the two groups. Collectively, these findings suggest that in coronary arterioles of obese rats, the increased activity of sGC leads to an enhanced sensitivity to NO, which may contribute to the maintenance of NO-mediated dilations and coronary perfusion in obesity.

Effect of timing of clopidogrel administration on 30-day clinical outcomes: 300-mg loading dose immediately after coronary stenting versus pretreatment 6 to 24 hours before stenting in a large unselected patient cohort.

BACKGROUND: The aim of our prospective multicenter Clopidogrel Registry was to evaluate the efficacy and safety of a 300-mg loading dose of clopidogrel at the time of ad hoc stenting in patients with suspected coronary artery disease who were not pretreated with clopidogrel for any reason, and to compare the 30-day clinical event rates with the outcome of patients pretreated with a loading dose of clopidogrel 6 to 24 hours before stenting. METHODS: Between March 2002 and February 2004, 4160 consecutively included patients received a 300-mg loading dose of clopidogrel immediately after (group 1, n = 2679) or 6 to 24 hours before stenting (group 2, n = 1481). RESULTS: The primary end point (triple composite end point of acute myocardial infarction, all-cause death, and urgent repeat target vessel revascularization) at 30 days occurred in 4.74% versus 2.77% in groups 1 and 2, respectively (P = .002). The secondary end point events, the stent thrombosis, occurred significantly more frequently in group 1, with a trend toward increase in incidence of death, target vessel revascularization, or need for glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention. Pretreatment with clopidogrel was associated with more major bleeding (secondary safety end point) (0.41% vs 1.35% in groups 1 and 2, respectively; P = .001). CONCLUSIONS: The results of our multicenter prospective Clopidogrel Registry demonstrate lower efficacy of a 300-mg loading dose of clopidogrel at the time of stenting compared with pretreatment 6 to 24 hours before percutaneous coronary intervention on the 30-day composite clinical end point in the large unselected patient cohort, which suggests the benefit of clopidogrel pretreatment in all incoming patients with suspected significant coronary artery disease scheduled for coronary angiography.

Effects of long-term transdermal nitrate treatment on left ventricular function in patients following myocardial infarction.

BACKGROUND: [corrected] Nitrates are widely used for the treatment of myocardial infarction (MI). The large megatrials (GISSI-3 and ISIS-4) did not in fact demonstrate a significant decrease in mortality in the nitrate-treated group. However, examination of the number of postinfarction angina episodes and the occurrence of cardiogenic shock in the GISSI-3 study did reveal significant decreases. HYPOTHESIS: It was hypothesized that chronic nitrate treatment after an MI preserves left ventricular systolic and/or diastolic functions. METHODS: Patients were divided into two groups: those receiving chronic nitrate treatment for 6 months after an MI (n = 30), and those without such treatment (n = 29). Echocardiography was performed 3, 14, 42, and 180 days after the infarction. The changes in early diastolic and atrial contraction-related mitral valve inflow pattern and deceleration time were assayed. Alterations in systolic, diastolic, and atrial reverse flow velocities in the pulmonary vein were measured, as were ejection fraction (EF), the number of registered angina episodes, and the maximal ST-segment depression in response to the stress test. RESULTS: During the 6-month study period, the increase in systolic pulmonary venous flow velocity was significantly larger in the nitrate group than in the controls. The decreases in the velocities of the diastolic and the atrial reverse flow were also more pronounced in the nitrate group than in the controls. The EF was improved only in the nitrate group. Examination of the maximal ST-segment depression in response to the stress test revealed a significant decrease in the nitrate group only. There were no significant differences between the two groups in the number of registered angina episodes or mitral inflow pattern. CONCLUSIONS: The study showed that prolonged nitrate treatment after an MI may help preserve diastolic left ventricular function.