CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity.

OBJECTIVE: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). BACKGROUND: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. METHODS: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. RESULTS: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = -0.81), implicating this neural pathway in treatment response. CONCLUSION: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.

Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience.

The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive peroral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.

Amitriptyline accumulation in tissues after coated activated charcoal hemoperfusion-a randomized controlled animal poisoning model.

Amitriptyline poisoning (AT) is a common poisoning, and AT possess the ability to promote life-threatening complications by its main action on the central nervous and cardiovascular systems. The pharmacokinetic properties might be altered at toxic levels compared to therapeutic levels. The effect of coated activated charcoal hemoperfusion (CAC-HP) on the accumulation of AT and its active metabolite nortriptyline (NT) in various tissues was studied in a non-blinded randomized controlled animal trial including 14 female Danish Land Race piglets. All piglets were poisoned with amitriptyline 7.5 mg/kg infused in 20 min, followed by orally instilled activated charcoal at 30 min after infusion cessation. The intervention group received 4 h of CAC-HP followed by a 1-h redistribution phase. At study cessation, the piglets were euthanized, and within 20 min, vitreous fluid, liver tissue, ventricle and septum of the heart, diaphragm and lipoic and brain tissues were collected. AT and NT tissue concentrations were quantified by UHPLC-MS/MS. A 4-h treatment with CAC-HP did not affect the tissue accumulation of AT in the selected organs when tested by Mann-Whitney U test (p values between 0.44 and 0.73). For NT concentrations, p values were between 0.13 and 1.00. Although not significant, an interesting finding was that data showed a tendency of increased tissue accumulation of AT and NT in the CAC-HP group compared with the control group. Coated activated charcoal hemoperfusion does not significantly alter the tissue concentration of AT and NT in the AT-poisoned piglet.

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.

The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin's active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3-30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.

Correction: Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.

The original version of this article contained an error in the labelling of Figures 2 and 3. While the captions and figures themselves are correct, in order to correspond with the in-text references, they have now been re-numbered in both the PDF and HTML versions of the article.

Evaluation of metabolite/drug ratios in blood and urine as a tool for confirmation of a reduced tolerance in methadone-related deaths in Denmark.

BACKGROUND: Methadone blood concentrations in fatal cases are highly variable and there is an appreciable overlap between therapeutic methadone concentrations and the concentrations detected in fatalities. As with other opioids, the background of these methadone-related deaths is unclear. The aim of this study was to investigate if short-time abstinence was contributing to the cause of death in methadone-related deaths by evaluation of the EDDP/methadone ratio in blood and urine. METHODS: Samples of blood and urine were collected from 103 autopsy cases and analysed for the concentrations of methadone and its main metabolite EDDP. The cases were divided into three groups according to the cause of death: cases where methadone was the cause of death (N=67), cases where poly-drug poisoning including methadone was the cause of death (N=24) and cases where death were caused by other factors (N=12). Urine samples from 11 living persons receiving methadone were also included. RESULTS: In general, a substantial overlap of the methadone concentrations in blood and urine was seen between the groups. There was a tendency of lower median EDDP/methadone urinary ratios in the methadone poisoning group (median: 1.0), poly-drug poisoning group (median: 0.94) and in the fatalities not related to methadone (median: 1.1) compared to the living subjects in methadone treatment (median: 1.6), although the differences were not significant. CONCLUSION: It was not possible to reveal a possible abstinence period prior to death by using the EDDP/methadone ratio in blood and urine in methadone-related deaths.

Distribution patterns, dermatomal anesthesia, and ropivacaine serum concentrations after bilateral dual transversus abdominis plane block.

BACKGROUND AND OBJECTIVES: The ability of transversus abdominis plane (TAP) blocks to anesthetize the upper abdomen remains debatable. We aimed to describe the local anesthetic distribution following ultrasound-guided TAP blocks with repeated magnetic resonance imaging investigations and to relate this to the resulting dermatomal anesthesia. METHODS: Eight volunteers were included in a randomized, observer-blinded study. Sixty milliliters of ropivacaine 0.375% was administered: 1 injection of 30 mL as a lateral classic TAP block, followed by a sham upper intercostal TAP block, and on the contralateral side, 2 separate 15-mL injections at the upper intercostal and lateral classic TAP plexuses, respectively. The primary outcome measure was magnetic resonance imaging-assessed area expansion of all injectates over a 6-hr period. Dermatomal anesthesia and sequential serum ropivacaine levels were recorded at the same time intervals. RESULTS: All injectate areas expanded in a statistically significant manner in the anterior abdominal wall. Lateral classic TAP blocks with 30-mL injectates did not extend into the upper intercostal TAP plexus. The dual 15-mL injectates on the other hemiabdomen remained within the upper intercostal and lateral classic TAP compartments and resulted in significantly (P < 0.018) more widespread dermatomal anesthesia. Measured serum ropivacaine concentrations were below the potential level of toxicity. CONCLUSIONS: Magnetic resonance imaging analysis revealed a significant time-dependent expansion of injectates. Magnetic resonance imaging and the degree of dermatomal anesthesia confirmed that the upper and lateral TAP compartments do not appear to communicate. Separate injections at the upper intercostal and lateral classic TAP plexuses are necessary to block the entire abdominal wall.

In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users.

CONTEXT: Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin. OBJECTIVE: To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding. DESIGN: A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ((11)C)-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ((18)F)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14). PARTICIPANTS: Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls. MAIN OUTCOME MEASURES: In vivo cerebral SERT and serotonin(2A) receptor binding. RESULTS: Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, -56%; pallidostriatum, -19%; and amygdala, -32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin(2A) receptor binding in the serotonin(2A) receptor agonist users (both user groups) was also detected. CONCLUSIONS: We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.