Symptoms In Healthy Volunteers Research Articles

Beneficial Effect of Heat-Killed Lactic Acid Bacterium Lactobacillus johnsonii No. 1088 on Temporal Gastroesophageal Reflux-Related Symptoms in Healthy Volunteers: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Study.

A randomized, placebo-controlled, double-blind, parallel-group clinical study was conducted to examine the effects of ingesting a heat-killed lactic acid bacterium, Lactobacillus johnsonii No. 1088 (LJ88) on temporal gastroesophageal reflux-related symptoms in healthy volunteers. A total of 120 healthy Japanese volunteers of both sexes, aged between 21 and 63 years, whose Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) total score was 8 or greater, but who were not diagnosed with functional dyspepsia according to the Rome IV classification, were enrolled. They were randomly assigned to either the LJ88 or placebo group and instructed to ingest the test food (1 billion heat-killed LJ88 or placebo) once a day for six weeks. Gastroesophageal reflux-related symptoms were evaluated using FSSG scores as a primary endpoint. The Gastrointestinal Symptoms Rating Scale (GSRS), stomach state questionnaire, and serum gastrin concentration were used as secondary endpoints. In the FSSG evaluation, the heartburn score was significantly improved at 6 weeks in the LJ88 group compared to the placebo group. No severe adverse events related to the test food were observed. In conclusion, daily ingestion of heat-killed LJ88 improved temporal heartburn symptoms in non-diseased individuals.

Effects of Abexol (D-002): A Mixture of Beeswax Alcohols, on Joint Discomforting Symptoms in Healthy Volunteers

Effects of Abexol (D-002): A Mixture of Beeswax Alcohols, on Joint Discomforting Symptoms in Healthy Volunteers

Lung function and self-rated symptoms in healthy volunteers after exposure to hydrotreated vegetable oil (HVO) exhaust with and without particles

BackgroundDiesel engine exhaust causes adverse health effects. Meanwhile, the impact of renewable diesel exhaust, such as hydrotreated vegetable oil (HVO), on human health is less known. Nineteen healthy volunteers were exposed to HVO exhaust for 3 h in a chamber with a double-blind, randomized setup. Exposure scenarios comprised of HVO exhaust from two modern non-road vehicles with 1) no aftertreatment system (‘HVOPM+NOx’ PM1: 93 µg m−3, EC: 54 µg m−3, NO: 3.4 ppm, NO2: 0.6 ppm), 2) an aftertreatment system containing a diesel oxidation catalyst and a diesel particulate filter (‘HVONOx’ PM1: ~ 1 µg m−3, NO: 2.0 ppm, NO2: 0.7 ppm) and 3) filtered air (FA) as control. The exposure concentrations were in line with current EU occupational exposure limits (OELs) of NO, NO2, formaldehyde, polycyclic aromatic hydrocarbons (PAHs), and the future OEL (2023) of elemental carbon (EC). The effect on nasal patency, pulmonary function, and self-rated symptoms were assessed. Calculated predicted lung deposition of HVO exhaust particles was compared to data from an earlier diesel exhaust study.ResultsThe average total respiratory tract deposition of PM1 during HVOPM+NOx was 27 µg h−1. The estimated deposition fraction of HVO PM1 was 40–50% higher compared to diesel exhaust PM1 from an older vehicle (earlier study), due to smaller particle sizes of the HVOPM+NOx exhaust. Compared to FA, exposure to HVOPM+NOx and HVONOx caused higher incidence of self-reported symptoms (78%, 63%, respectively, vs. 28% for FA, p < 0.03). Especially, exposure to HVOPM+NOx showed 40–50% higher eye and throat irritation symptoms. Compared to FA, a decrement in nasal patency was found for the HVONOx exposures (− 18.1, 95% CI: − 27.3 to − 8.8 L min−1, p < 0.001), and for the HVOPM+NOx (− 7.4 (− 15.6 to 0.8) L min−1, p = 0.08). Overall, no clinically significant change was indicated in the pulmonary function tests (spirometry, peak expiratory flow, forced oscillation technique).ConclusionShort-term exposure to HVO exhaust concentrations corresponding to EU OELs for one workday did not cause adverse pulmonary function changes in healthy subjects. However, an increase in self-rated mild irritation symptoms, and mild decrease in nasal patency after both HVO exposures, may indicate irritative effects from exposure to HVO exhaust from modern non-road vehicles, with and without aftertreatment systems.

Salivary cortisol levels in relation to depression and anxiety symptoms in healthy volunteers following a chronic stress period

Salivary cortisol levels in relation to depression and anxiety symptoms in healthy volunteers following a chronic stress period

Painful and non-painful symptoms evoked by experimental bracing and thrusting of the mandible in healthy individuals.

Bruxism may involve bracing and thrusting of the mandible, in addition to clenching or grinding of the teeth. It is unclear how bracing and thrusting may contribute to potential musculoskeletal symptoms associated with bruxism. To examine the effect of experimental bracing and thrusting of the mandible on the development of musculoskeletal symptoms in healthy volunteers. Thirty healthy volunteers performed six trials of 5min of repeated bracing and thrusting of the mandible. Bracing involved forcefully maintaining maximum protruded position (5s with 1s rest in between), whereas thrusting involved forcefully moving the mandible in a forward direction and back (1Hz). The participants rated pain, unpleasantness, soreness, fatigue, tension, stiffness, stress and headache on 10-cm visual analogue scales (VAS) before, immediately and 24h after the tasks. Pain drawings were obtained and maximum voluntary protrusive force (MVPF) was determined before and after the tasks. The outcome parameters for each task were compared between the time points. There was a significant increase in the VAS scores (2-4/10) of pain, unpleasantness, soreness, fatigue, tension, stiffness and stress immediately following the tasks compared to baseline and 24h after the tasks (p<.008). Pain was frequently reported in masseter muscles. MVPF values were significantly higher immediately (p<.001) and 24h after thrusting (p<.001) and bracing (p=.012) tasks compared to the baseline. Experimental bracing and thrusting of the mandible evoked transient, mild-to-moderate levels of muscle pain, fatigue, tension and stiffness and increased unpleasantness and stress scores in healthy volunteers.

Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers.

BackgroundNitrous oxide (N2O) is an anesthetic gas with both therapeutic and abuse potential. Because N2O is an NMDA receptor (NMDAR) antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. In this study, we examined the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also tested for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity.MethodsHealthy volunteers were randomly assigned to either 50% N2O (n = 40) or medical air (n = 40). Self-reported rewarding (liking and wanting), and alcohol-like effects were assessed pre-, peri- and post inhalation.ResultsEffect sizes for the various rewarding/alcohol-like effects of N2O were generally similar to those reported in studies of moderate-dose ketamine. Impulsivity moderated the subjective reinforcing (liking) effects of inhaled gas, while depressive symptoms moderated motivational (wanting [more]) effects. However, depression and impulsivity had opposite directional influences, such that higher impulsivity was associated with higher N2O liking, and higher depression, with lower N2O wanting.ConclusionTo the extent that static (versus longitudinal) subjective rewarding effects are a reliable indicator of future problematic drug use, our findings suggests that impulsivity and depression may predispose and protect, respectively, against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutic and recreational drugs. Similarities between moderate-dose N2O and moderate-dose ketamine in the intensity of certain subjective effects suggest that N2O may, at least to some extent, serve as substitute for ketamine as a safe and easily implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans.

Noninvasive monitoring of fibre fermentation in healthy volunteers by analyzing breath volatile metabolites: lessons from the FiberTAG intervention study

ABSTRACT The fermentation of dietary fibre (DF) leads to the production of bioactive metabolites, the most volatile ones being excreted in the breath. The aim of this study was to analyze the profile of exhaled breath volatile metabolites (BVM) and gastrointestinal symptoms in healthy volunteers after a single ingestion of maltodextrin (placebo) versus chitin-glucan (CG), an insoluble DF previously shown to be fermented into short-chain fatty acids (SCFA) by the human microbiota in vitro. Maltodextrin (4.5 g at day 0) or CG (4.5 g at day 2) were added to a standardized breakfast in fasting healthy volunteers (n = 15). BVM were measured using selected ion flow tube mass spectrometry (SIFT-MS) throughout the day. A single ingestion of 4.5 g CG did not induce significant gastrointestinal discomfort. Untargeted metabolomics analysis of breath highlighted that 13 MS-fragments (among 408 obtained from ionizations of breath) discriminated CG versus maltodextrin acute intake in the posprandial state. The targeted analysis revealed that CG increased exhaled butyrate and 5 other BVM – including the microbial metabolites 2,3-butanedione and 3-hydroxybutanone – with a peak observed 6 h after CG intake. Correlation analyses with fecal microbiota (Illumina 16S rRNA sequencing) spotlighted Mitsuokella as a potential genus responsible for the presence of butyric acid, triethylamine and 3-hydroxybutanone in the breath. In conclusion, measuring BMV in the breath reveals the microbial signature of the fermentation of DF after a single ingestion. This protocol allows to analyze the time-course of released bioactive metabolites that could be proposed as new biomarkers of DF fermentation, potentially linked to their biological properties. Trial registration: Clinical Trials NCT03494491. Registered 11 April 2018 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03494491

Acute Effects of Red Chili, a Natural Capsaicin Receptor Agonist, on Gastric Accommodation and Upper Gastrointestinal Symptoms in Healthy Volunteers and Gastroesophageal Reflux Disease Patients.

The effects of chili on gastric accommodation (GA) in gastroesophageal reflux disease (GERD) patients have not been explored. Methods: In total, 15 healthy volunteers (HV) and 15 pH-positive non-erosive GERD (NERD) patients underwent single-photon emission computed tomography after ingesting 2 g of chili or placebo in capsules in a randomized double-blind crossover fashion with a one-week washout period. GA was the maximal postprandial gastric volume (GV) after 250 mL of Ensure® minus the fasting GV. Upper gastrointestinal symptoms were evaluated by using a visual analog scale. Results: NERD patients but not HV had significantly greater GA after chili compared to a placebo (451 ± 89 vs. 375 ± 81 mL, p < 0.05). After chili, the postprandial GVs at 10, 20, and 30 min in NERD patients were significantly greater than HV (10 min, 600 ± 73 vs. 526 ± 70 mL; 20 min, 576 ± 81 vs. 492 ± 78 mL; 30 min, 532 ± 81 vs. 466 ± 86 mL, all p < 0.05). In NERD, chili was associated with significantly less satiety, more severe abdominal burning (p < 0.05), and a trend of more severe heartburn (p = 0.06) compared to the placebo. In HV, postprandial symptoms after chili and placebo ingestion were similar (p > 0.05). Conclusions: Chili enhanced GA in NERD patients but not in HV. This suggests that the modulation of GA in NERD is abnormal and likely involves transient receptor potential vanilloid 1 (TRPV1) sensitive pathways.

Sumatriptan Does Not Antagonize CGRP‐Induced Symptoms in Healthy Volunteers

Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing. Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double-blind cross-over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0-2hours after infusion start and in headache intensity 2hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. CGRP-induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUCheadache, 0-2hours between the days (P=.794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P<.001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120minutes on the placebo day, P<.001). The diameter of peripheral arteries increased statistically significant on both days (P<.001). Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2-hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20-minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti-migraine drugs.

The Effects of a Long-lasting Infusion of Vasoactive Intestinal Peptide (VIP) on Headache, Cranial Hemodynamic and Autonomic Symptoms in Healthy Volunteers

The Effects of a Long-lasting Infusion of Vasoactive Intestinal Peptide (VIP) on Headache, Cranial Hemodynamic and Autonomic Symptoms in Healthy Volunteers

RETRACTED: Gluten Does Not Induce Gastrointestinal Symptoms in Healthy Volunteers: A Double-Blind Randomized Placebo Trial

RETRACTED: Gluten Does Not Induce Gastrointestinal Symptoms in Healthy Volunteers: A Double-Blind Randomized Placebo Trial

Gastric accommodation in healthy subjects studied by ultrasound, manometry, and impedancemetry.

Gastric accommodation to a meal may be important in the pathogenesis of upper gastrointestinal disorders, but has been difficult to investigate in a minimally invasive fashion. We studied gastric and lower esophageal physiology during food intake, combining transabdominal ultrasound, multichannel high-resolution impedance-manometry (HRIM) and a symptom questionnaire. A HRIM catheter was distally positioned at incisura angularis and 300mL saline with 75g glucose was ingested. Target variables were recorded for 30min after fluid intake. Fifteen healthy subjects' participated (11W/4M, median age 23.8y) and all accepted the meal with few symptoms. At incisura angularis maximum change in pressure from pre-intake values was -7.4mmHg after 60s (P<.0001), rising to pre-intake values within 20min. The corresponding area increased significantly from pre-intake values of 8.0cm2 to 14.1cm2 shortly after intake (P=.0012), peaked at 5min and slowly decreased towards 30min. The corresponding maximum change in stress from pre-intake pressure values was -59.2mmHg shortly after (P<.0001), reaching pre-intake values within 20min. Strain rose from 0 shortly before to 0.36 shortly after (P<.0001), peaking at 5min. At incisura angularis, fullness was positively correlated with area and to strain, while fullness, area, and stress were negatively correlated with pressure. The multimodal method enabled assessment of the gastric accommodation reflex, stress and strain in the stomach. It triggered few symptoms in healthy volunteers. We propose it to be a more physiological replacement of the barostat technique.

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans.

Targeting the N-methyl-D-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers. We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization. Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus. The sample included only men within a tight age range of 20-32 years. The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.

Effect of combined consumption of Lactobacillus brevis KB290 and β-carotene on minor diarrhoea-predominant irritable bowel syndrome-like symptoms in healthy subjects: a randomised, double-blind, placebo-controlled, parallel-group trial

People with non-pathological diarrhoea-predominant irritable bowel syndrome (IBS-D)-like symptoms are present at a significant level even in healthy populations, but established prophylaxis is lacking. Previously, we have found that co-administration of Lactobacillus brevis KB290 (KB290) and β-carotene (βC) attenuated murine colitis (potential cause of IBS-D-like symptoms) significantly. Here, we investigated the effect of KB290 and βC on minor IBS-D-like symptoms in healthy volunteers. After a 4-week run-in period, subjects received a KB290 + βC or placebo capsule for 12 weeks, followed by a 4-week washout period. The KB290 + βC group showed a significant improvement in intensity of abdominal pain and stool frequency compared with the placebo group. The KB290 + βC group showed a significantly higher serum concentration of anti-inflammatory cytokine, interleukin-10, compared with the placebo group. In conclusion, we demonstrated that consumption of KB290 + βC improves minor IBS-D-like symptoms and inflammatory status in healthy volunteers. (UMIN000018002)

Cannabinoids and Psychosis.

There is growing interest in the relationship between cannabis and psychosis. The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication and persisting as long as a month. Exposure to cannabis in adolescence is associated with an increased risk for later psychotic disorder in adulthood; this association is consistent, somewhat specific, shows a dose-response, and is biologically plausible. The link between cannabinoids and psychosis is greater with earlier age of exposure to cannabinoids, childhood abuse and genetic vulnerability. However, cannabinoids are neither necessary nor sufficient to cause a persistent psychotic disorder. More likely cannabinoids are a 'component cause' interacting with other known (family history) and unknown factors to result in psychosis outcomes. While more research is needed to better understand the relationship between cannabinoid use and psychosis, and the neural underpinnings of this link, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis.

Scientific proving of ultra high dilutions on humans

Homeopathic drug provings or pathogenetic trials (HPTs) are the pillar of homeopathy. This review summarizes the authors' findings and interpretations derived from a series of homeopathic drug proving between 1994 and 2015. It gives an overview over a series of attempts to use modern scientific experimental methodology to answer the question, whether such HPTs produce symptoms in healthy volunteers that can be distinguished from placebo symptoms. Various experimental models were used: repeated crossover trials with categorical data collection, and a single-case, randomised study. Final models use diligent qualitative data-collection in experienced volunteers. In those, raters decide whether symptoms are typical for a remedy delivered or not. The design is triple-blind and placebo-controlled. While previous attempts were inconclusive, this new model allowed to separate placebo symptoms from verum symptoms repeatedly in a series of two definitive studies following promising pilot studies. Results were statistically significant. Also, some signs of the purported non-local signature of homeopathic effects were visible, and the consequences for future methodology is discussed. Provided some cautionary notes are taken into account, HPTs can be used to separate out true specific symptoms from placebo symptoms. By the same token this is a road to experimental proof that homeopathic remedies are not just placebos. However, this needs to be taken forward by independent groups.

Optimizing the glutamatergic challenge model for psychosis, using S+ -ketamine to induce psychomimetic symptoms in healthy volunteers.

The psychomimetic effects that occur after acute administration of ketamine can constitute a model of psychosis and antipsychotic drug action. However, the optimal dose/concentration has not been established and there is a large variety in outcome measures. In this study, 36 healthy volunteers (21 males and 15 females) received infusions of S(+)-ketamine or placebo to achieve pseudo-steady state concentrations of 180 and 360 ng/mL during two hours. The target of 360 ng/mL induced increasingly more intensive effects than expected, and the targets were subsequently reduced to 120 and 240 ng/mL, which were considered tolerable. There was a clear, concentration-dependent psychomimetic effect as shown on all subscales of the positive and negative syndrome scale (e.g. positive subscale +43.7%, 95%CI 34.4-53.7%, p < 0.0001 for 120 ng/mL and +70.5%, 95%CI 59.0-82.8%, p < 0.0001 for 240 ng/mL) and different visual analogue scales. The startle reflex was inhibited (prepulse inhibition) by both main target concentrations to a similar extent, suggesting a maximum effect. Ketamine was found to constitute a robust model for induction of psychomimetic symptoms and the optimal concentration range for a drug interaction study would be between 100 and 200 ng/mL.

The Nonsteroidal Anti-inflammatory Drug Diclofenac Reduces Acid-Induced Heartburn Symptoms in Healthy Volunteers

We investigated the effects of diclofenac, a nonsteroidal anti-inflammatory drug that inhibits prostaglandin production, on induction of esophageal sensation by acid perfusion in healthy men. We performed a prospective, double-blind, placebo-controlled, 2-period, cross-over study over 3 visits in 12 healthy men. Diclofenac was given 6 hours and 2 hours before an acid perfusion test. During the test, hydrochloric acid (0.15 mol/L) was perfused into the lower esophagus for 30 minutes; we evaluated upper gastrointestinal symptoms using a validated categoric rating scale. Then, we calculated and assessed the acid perfusion sensitivity score (APSS). Biopsy specimens were collected by endoscopy of the distal esophagus before and after acid perfusion; levels of prostaglandin E2 (PGE2) (pg/mg) were measured in the samples using an enzyme-linked immunosorbent assay. Compared with placebo, diclofenac significantly reduced the APSS for heartburn (82.2 ± 12.2 for placebo and 47.5 ± 8.9 for diclofenac; P < .01). Of the upper gastrointestinal symptoms, only the APSS for heartburn was reduced significantly by diclofenac. Compared with placebo, diclofenac reduced the overproduction of PGE2 by esophageal tissues after acid perfusion (23.3 ± 5.2 for placebo and 11.4 ± 3.5 for diclofenac; P < .05). APSS correlated with the development of heartburn and esophageal levels of PGE2 (r = 0.53; P < .05 for heartburn vs PGE2). Diclofenac attenuated acid-induced heartburn by inhibiting PGE2 overproduction in the esophagus. Esophageal PGE2 might be involved in producing heartburn symptoms. Clinical Trials Registry no: UMIN000014595.

Clozapine and glycinamide prevent MK-801-induced deficits in the novel object recognition (NOR) test in the domestic rabbit (Oryctolagus cuniculus)

Studies in humans indicate that acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, provokes schizophrenic-like symptoms in healthy volunteers, and exacerbates existing symptoms in individuals with schizophrenia. These and other findings suggest that NMDA receptor hypofunction might participate in the pathophysiology of schizophrenia, and have prompted the development of rodent pharmacological models for this disorder based on acute or subchronic treatment with NMDA receptor antagonists, as well as the development of novel pharmacotherapies based on increasing extrasynaptic glycine concentrations. In the present study, we tested whether acute hyperlocomotory behavior and/or deficits in the novel object recognition (NOR) task, induced in male rabbits by the acute subcutaneous (s.c.) administration of MK-801 (0.025 and 0.037mg/kg s.c., respectively), were prevented by prior administration of the atypcial antipsychotic, clozapine (0.2mg/kg, s.c.), or the glycine pro-drug glycinamide (56mg/kg, s.c.). We found that clozapine fully prevented the MK-801-induced hyperlocomotion, and both clozapine and glycinamide prevented MK-801-induced deficits in the NOR task. The present results show that MK-801-induced hyperlocomotion and deficits in the NOR task in the domestic rabbit demonstrate predictive validity as an alternative animal model for symptoms of schizophrenia. Moreover, these results indicate that glycinamide should be investigated in pre-clinical models of neuropsychiatric disorders such as schizophrenia, obsessive compulsive disorder and anxiety disorders, where augmentation of extrasynaptic glycine concentrations may have therapeutic utility.

Impact of Cannabis Use on the Development of Psychotic Disorders.

The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication but resolves within a month. Exposure to cannabis in adolescence is associated with a risk for later psychotic disorder in adulthood; this association is consistent, temporally related, shows a dose-response, and is biologically plausible. However, cannabis is neither necessary nor sufficient to cause a persistent psychotic disorder. More likely it is a component cause that interacts with other factors to result in psychosis. The link between cannabis and psychosis is moderated by age at onset of cannabis use, childhood abuse and genetic vulnerability. While more research is needed to better characterize the relationship between cannabinoid use and the onset and persistence of psychosis, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis.