Using insurance data to quantify the multidimensional impacts of warming temperatures on yield risk.

Previous research predicts significant negative yield impacts from warming temperatures, but estimating the effects on yield risk and disentangling the relative causes of these losses remains challenging. Here we present new evidence on these issues by leveraging a unique publicly available dataset consisting of roughly 30,000 county-by-year observations on insurance-based measures of yield risk from 1989-2014 for U.S. corn and soybeans. Our results suggest that yield risk will increase in response to warmer temperatures, with a 1 °C increase associated with yield risk increases of approximately 32% and 11% for corn and soybeans, respectively. Using cause of loss information, we also find that additional losses under warming temperatures primarily result from additional reported occurrences of drought, with reported losses due to heat stress playing a smaller role. An implication of our findings is that the cost of purchasing crop insurance will increase for producers as a result of warming temperatures.

Prolonged Response to Pembrolizumab in Spindle Cell Squamous Cell Carcinoma Metastatic to the Central Nervous System.

BACKGROUND: Cutaneous squamous cell carcinoma is a common type of skin cancer, with aggressive metastatic or locally advanced disease representing an uncommon minority of presentations. Emerging data have supported the Food and Drug Administration approval of the anti-PD1 human monoclonal antibody cemiplimab in select patients with advanced disease. However, there is limited data regarding durability of effect and generalizability of anti-PD1 effectiveness across therapies. Additionally, information regarding applicability of these regimens to the rare spindle cell variant and to central nervous system metastases for cutaneous squamous cell carcinoma is unfortunately limited. CASE PRESENTATION: A 72-year-old gentleman presented with facial neurological deficits and a dermal nodule and was diagnosed with spindle cell squamous cell carcinoma with perineural invasion. His course was notable for early intracranial metastasis with progressive neurological deficits despite recurrent radiation therapy with intermittent response. When progressive left-sided weakness prompted imaging evaluation that was concerning for disease recurrence after exhaustion of radiation therapy options, the patient was started on systemic therapy with the anti-PD-1 monoclonal antibody treatment prior to the approval of cemiplimab. Pembrolizumab was chosen due to the fact that the patient was ineligible for clinical trials and for its every 21-day dosing. With this treatment, he has achieved a durable clinical response, resulting in near resolution of neurological deficits and more than a year of progression-free survival to date, despite aggressive intracranial disease. CONCLUSIONS: This case suggests that anti-PD-1 therapy with pembrolizumab may represent an effective and well-tolerated treatment for patients with metastatic spindle cell squamous cell carcinoma including patients with metastatic disease to the central nervous system.

Genetically engineered crops and pesticide use in U.S. maize and soybeans.

The widespread adoption of genetically engineered (GE) crops has clearly led to changes in pesticide use, but the nature and extent of these impacts remain open questions. We study this issue with a unique, large, and representative sample of plot-level choices made by U.S. maize and soybean farmers from 1998 to 2011. On average, adopters of GE glyphosate-tolerant (GT) soybeans used 28% (0.30 kg/ha) more herbicide than nonadopters, adopters of GT maize used 1.2% (0.03 kg/ha) less herbicide than nonadopters, and adopters of GE insect-resistant (IR) maize used 11.2% (0.013 kg/ha) less insecticide than nonadopters. When pesticides are weighted by the environmental impact quotient, however, we find that (relative to nonadopters) GE adopters used about the same amount of soybean herbicides, 9.8% less of maize herbicides, and 10.4% less of maize insecticides. In addition, the results indicate that the difference in pesticide use between GE and non-GE adopters has changed significantly over time. For both soybean and maize, GT adopters used increasingly more herbicides relative to nonadopters, whereas adopters of IR maize used increasingly less insecticides. The estimated pattern of change in herbicide use over time is consistent with the emergence of glyphosate weed resistance.

Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans.

BACKGROUND: N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR) stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a non-competitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers. METHODS: From an initial sample of 17 subjects (age range 18-55 years), 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects Positive and Negative Syndrome Scale, perceptual alterations Clinician Administered Dissociative Symptoms Scale, subjective effects Visual Analog Scale and auditory event-related brain potentials (mismatch negativity, MMN; P300) were assessed during each test session. RESULTS: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target (P3b) or novel (P3a) stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. CONCLUSION: Nicotine failed to modulate ketamine-induced neurophysiological and behavioral effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.

Neurotraumatology.

Neurotraumatology has its roots in ancient history, but its modern foundations are the physical examination, imaging to localize the pathology, and thoughtful medical and surgical decision making. The neurobiology of cranial and spinal injury is similar, with the main goal of therapies being to limit secondary injury. Brain injury treatment focuses on minimizing parenchymal swelling within the confined cranial vault. Spine injury treatment has the additional consideration of spinal coumn stability. Current guidelines for non-operative and operative management are reviewed in this chapter.

Feasibility, safety, and efficacy of the combination of D-serine and computerized cognitive retraining in schizophrenia: an international collaborative pilot study.

The combination of pharmacotherapy and cognitive retraining (CRT) for the cognitive deficits of schizophrenia may be more efficacious than either approach alone, but this has not yet been tested. This study evaluated the feasibility, safety, tolerability, and efficacy of 12 weeks of D-serine, combined with CRT in the treatment of cognitive deficits in schizophrenia at two academic sites in parallel, in India and the United States. In a randomized, partial double-blind, placebo-controlled, parallel-group design, 104 schizophrenia subjects (US site=22, Indian site=82) were randomized to: (1) D-serine (30 mg/kg)+CRT (5 h/week), (2) D-serine+control CRT, (3) CRT+placebo D-serine, and (4) placebo+control CRT. Completion rates were 84 and 100% in the Indian and US samples, respectively. On various outcome measures of safety and tolerability, the interventions were well tolerated. D-Serine and CRT did not show any significant effect on the Global Cognitive Index, although both interventions showed differential site effects on individual test performance. CRT resulted in a significant improvement in Verbal Working Memory, and a trend toward improvement in Attention/Vigilance. This is the first study to demonstrating the feasibility, safety, and tolerability of combination pharmacotherapy and CRT in a multicenter international clinical trial. These preliminary findings provide support for future studies using higher doses of D-serine that have been shown to be efficacious or other pharmacotherapies, along with the newer cognitive remediation strategies that are individualized and that target basic information processing.

Primary cutaneous anaplastic large-cell lymphoma.

Since the recognition of the anaplastic large-cell lymphomas in the 1980s, much has been learned about the diagnosis, clinical presentation, and treatment of these malignant conditions. The systemic and primary cutaneous types of anaplastic large cell lymphomas have been differentiated on clinical and immunophenotypical findings, but further research is required to elucidate their exact etiologies and pathogeneses. Primary cutaneous anaplastic large-cell lymphoma has a 95% disease-specific 5-year survival, owing partly to the relatively benign course of the disease and partly to the variety of effective treatments that are available. As with many other oncological diseases, new drugs are continually being tested and developed, with immunotherapy and biological response modifiers showing promise.

Naltrexone does not attenuate the effects of intravenous Δ9-tetrahydrocannabinol in healthy humans.

Although a wealth of preclinical evidence indicates an interplay between the µ-opioid (MOR) and cannabinoid 1 receptor (CB1R) systems, the precise nature of the cross modulation in humans is unclear. The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist, naltrexone, on the subjective, behavioural and cognitive effects of the CB1R agonist, Δ9-tetrahydrocannabinol (THC), in healthy human subjects. Healthy human subjects, screened carefully for any medical or psychiatric illness, were administered either placebo or active naltrexone (25 mg) orally on each test day, followed 45 min later by placebo and 165 min later by active i.v. THC (0.025 mg/kg) in a randomized, fixed-order, double-blind manner. Subjective, behavioural and cognitive effects were assessed before and at several points after each drug administration. THC produced expected effects, including euphoria, anxiety, transient perceptual alterations, transient psychotomimetic effects and cognitive impairments. However, naltrexone did not produce any effects alone, nor did it attenuate any of THC's effects. Thus, in healthy human subjects who use cannabis intermittently, MOR antagonism does not modulate the common acute subjective, behavioural and cognitive effects of THC.

The safety of studies with intravenous Δ9-tetrahydrocannabinol in humans, with case histories.

RATIONALE: Delta-9-tetrahydrocannabinol (THC) is one of the few cannabinoid receptor ligands that can be used to probe the cannabinoid system in humans. Despite increasing interest in the cannabinoid receptor system, use of intravenous THC as a research tool has been limited by concerns about its abuse liability and psychoactive effects. OBJECTIVES: This study aims to evaluate the safety of all intravenous THC studies conducted at this center for the past 13 years. METHODS: Included were 11 studies with 266 subjects (14 schizophrenia patients and 252 healthy subjects, of whom 76 were frequent cannabis users), 351 active THC infusions, and 226 placebo infusions. Subjects were monitored for subjective and physical adverse events and followed up to 12 months beyond study participation. RESULTS: There was one serious and 70 minor adverse events in 9.7% of subjects and 7.4% of infusions, with 8.5% occurring after the end of the test day. Nausea and dizziness were the most frequent side effects. Adverse events were more likely to be associated with faster infusion rates (2-5 min) and higher doses (>2.1 mg/70 kg). Of 149 subjects on whom long-term follow-up data were gathered, 94% reported either no change or a reduction in their desire to use cannabis in the post-study period, 18% stated that their cannabis use decreased, and 3% stated that it increased in the post-study period. CONCLUSIONS: With careful subject selection and screening, risk to subjects is relatively low. Safeguards are generally sufficient and effective, reducing both the duration and severity of adverse events.

Preliminary findings on the interactive effects of IV ethanol and IV nicotine on human behavior and cognition: a laboratory study.

INTRODUCTION: There are mixed reports on nicotine's effects on alcohol-induced impairment in cognitive performance and behavior in humans. The main objective of this study was to characterize the interactive effects of acute intravenous (IV) alcohol and nicotine administration on behavior and cognition in healthy nonsmokers. METHODS: Healthy subjects aged 21-44 years participated in 3 test days. On each test day, they received in a double-blind randomized manner one of three IV alcohol infusion conditions using a "clamp": placebo, targeted breathalyzer of 40 mg%, or targeted breathalyzer of 80 mg%. Alcohol infusion was delivered over 20 min and lasted for 120 min. They also received both placebo and active nicotine in a fixed order delivered intravenously. Placebo nicotine was delivered first over 10 min at the timepoint when the breath alcohol was "clamped"; active nicotine (1.0 mcg/kg/min) was delivered for 10 min, 70 min after the alcohol infusion was clamped. Subjective effects of alcohol were measured using the Biphasic Alcohol Effects Scale and the Number of Drinks Scale. Cognitive inhibition and attention were measured by the Continuous Performance Task-Identical Pairs and working memory by the Rey Auditory Verbal Learning Task (RAVLT). RESULTS: Nicotine significantly reversed subjective intoxication and sedation of alcohol at the low dose. Alcohol impaired performance on the RAVLT, and nicotine further impaired verbal learning and recall at both doses of alcohol. CONCLUSIONS: The data showed that nicotine had an effect on subjective alcohol effects but did not reverse and actually worsened alcohol-induced deficits in memory.

Brain ß2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler.

The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (ß2*-nAChRs). Previous studies examined ß2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of ß2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of ß2*-nAChRs 2-5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5-5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of ß2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms.

Clinical significance of neurological soft signs in schizophrenia: factor analysis of the Neurological Evaluation Scale.

BACKGROUND: Nonlocalizing neurologic deficits detectable by clinical evaluation-"soft signs"-are a robust finding in patients diagnosed with schizophrenia, but their conceptual and neuroanatomical correlates remain unclear. The purpose of this study was to evaluate the organization of these deficits and their clinical correlates using the Neurological Evaluation Scale (NES). METHODS: Ninety-three male veterans with schizophrenia and schizoaffective disorder were evaluated using a detailed clinical assessment that included the NES, the Extrapyramidal Symptom Rating Scale, the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale, the Positive and Negative Syndrome Scale, the Wisconsin Card Sorting Test (WCST), the Schedule for the Deficit Syndrome (SDS), and the Digit Symbol Substitution Task (DSST). RESULTS: Four factors explained 73% of the variance and had distinct clinical and neuropsychological correlates. Factor 1 reflected deficits involved with memory and sensory integration, and was associated with lower PANSS positive and higher AIMS scores. Factor 2 reflected impairments in motor control, and was associated with lower intelligence, more cognitive deficits, and deficit-syndrome schizophrenia. Factor 3 was related to lower intelligence and more perseverative errors on the WCST. Factor 4 was related to increasing age, more extrapyramidal symptoms, more perseverative errors, and worse scores on the DSST. CONCLUSIONS: Neurologic deficits in schizophrenia have an intrinsic organization that appears to have clinical significance, highlighting the continued utility of the NES in studies of neurological deficits in schizophrenia patients. The theoretical underpinning of this organization remains unclear.

What's new in the diagnosis and treatment of peripheral nerve entrapment neuropathies.

Entrapment neuropathies can be common conditions with the potential to cause significant disability. Correct diagnosis is essential for proper management. This article is a review of recent developments related to diagnosis and treatment of various common and uncommon nerve entrapment disorders. When combined with classical peripheral nerve examination techniques, innovations in imaging modalities have led to more reliable diagnoses. Moreover, innovations in conservative and surgical techniques have been controversial as to their effects on patient outcome, but randomized controlled trials have provided important information regarding common operative techniques. Treatment strategies for painful peripheral neuropathies are also reviewed.

SPECT imaging of nicotinic acetylcholine receptors in nonsmoking heavy alcohol drinking individuals.

BACKGROUND: The high rate of comorbidity of tobacco smoking with alcohol drinking suggests common neural substrates mediate the two addictive disorders. The beta(2)*-containing nicotinic acetylcholine receptor (beta(2)*-nAChR) has recently emerged as a prime candidate because some alpha and beta subunit genes have been linked to alcohol consumption and alcohol use behaviors. We hypothesized that beta(2)*-nAChR availability would be altered by alcohol in heavy drinking nonsmokers. METHODS: Eleven heavy drinking (mean age 39.6+/-12.1 years) and 11 age and sex-matched control (mean age 40.8+/-14.1 years) nonsmokers were imaged using [(123)I]5-IA-85380 ([(123)I]5-IA) single photon emission computed tomography (SPECT). Heavy alcohol drinkers drank varied amounts of alcohol (70-428/month) to facilitate exploratory linear analyses of the possible effects of alcohol. RESULTS: Heavy drinkers consumed on average 9.1+/-7.3 drinks/occasion; whereas controls drank 1.2+/-0.9 drinks/occasion. Heavy drinkers were imaged 2.0+/-1.6 days after last alcoholic beverage. Overall, there were no significant differences in beta(2)*-nAChR availability between the heavy drinking and control nonsmokers. Exploratory analyses of other factors that may be uniquely regulated by alcohol suggested no effects of age, number of alcohol drinks, years drinking, severity of drinking, craving or withdrawal. CONCLUSIONS: These preliminary analyses do not suggest a decrease in receptor availability in heavy drinking nonsmokers as compared to control nonsmokers. However, a larger study is warranted to explore effects of heavy alcohol drinking on other variables, such as sex, smoking, and genetic make up.

The rare case of an intramedullary cervical spinal cord teratoma in an elderly adult: case report and literature review.

STUDY DESIGN.: Case report and literature review. OBJECTIVES.: To report the very rare case of a mature intramedullary teratoma with exophytic extension localized to the uppermost cervical spinal level in a 65-year-old woman and review the pertinent medical literature. SUMMARY OF BACKGROUND DATA.: Cervical intramedullary teratomas are extremely rare in adults, especially in patients older than 50 years. METHODS.: The patient presented with progressive ataxia, mild bilateral kinetic hand tremors, and dizziness. Magnetic resonance imaging revealed an intramedullary 1.7 x 1.3 x 2.3 cm mass at C1 with exophytic extension. A C1-C2 laminectomy and a partial suboccipital craniotomy were performed, followed by a subtotal microscopic resection of the tumor. Pathology was consistent with a mature teratoma. RESULTS.: After surgery, the patient's ataxia, tremor, and dizziness resolved almost immediately. CONCLUSION.: This report presents the very rare case of a mature intramedullary teratoma located in the upper cervical spine of an elderly patient, possibly the oldest patient documented with this type of lesion. The authors recommend a conservative subtotal surgical resection of cervical intramedullary tumors because it may improve symptoms that relate to direct mechanical cord compression and avoid further harm from a gross resection.

GABAA-benzodiazepine receptor availability in smokers and nonsmokers: relationship to subsyndromal anxiety and depression.

Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. We hypothesized that cortical gamma aminobutyric acid(A)-benzodiazepine receptor (GABA(A)-BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA(A)-BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex-matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [(123)I]iomazenil and single photon emission computed tomography (SPECT). Anxiety and depressive symptoms were measured using the Spielberger's State-Trait Anxiety Index (STAI) and the Center for Epidemiology Scale for Depressive Symptoms (CES-D). The cold pressor task was administered to assess pain tolerance and sensitivity. The relationship between cortical GABA(A)-BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. Surprisingly, there were no statistically significant differences in overall GABA(A)-BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA(A)-BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal (r = -0.47, P = 0.03), frontal (r = -0.46, P = 0.03), anterior cingulate (r = -0.47, P = 0.04), temporal (r = -0.47, P = 0.03), occipital (r = -0.43, P = 0.05) cortices, and cerebellum (r = -0.46, P = 0.04)], trait anxiety [parietal (r = -0.72, P = 0.02), frontal (r = -0.72, P = 0.02), and occipital (r = -0.65, P = 0.04) cortices] and depressive symptoms [parietal (r = -0.68; P = 0.02), frontal (r = -0.65; P = 0.03), anterior cingulate (r = -0.61; P = 0.04), and temporal (r = -0.66; P = 0.02) cortices]. The finding that a similar relationship between GABA(A)-BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA(A)-BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA(A)-BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA(A)-BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression.

beta2-Nicotinic acetylcholine receptor availability during acute and prolonged abstinence from tobacco smoking.

CONTEXT: Available levels of nicotinic acetylcholine receptors containing the beta(2) subunit (beta(2)*-nAChR) are higher in recently abstinent tobacco smokers compared with participants who never smoked. Variations in beta(2)*-nAChR availability during the course of abstinence may be related to the urge to smoke, the extent of nicotine withdrawal, and successful abstinence. OBJECTIVE: To examine changes in beta(2)*-nAChR availability during acute and prolonged abstinence from tobacco smoking and to determine how changes in beta(2)*-nAChR availability were related to clinical features of tobacco smoking. DESIGN: Tobacco smokers participated in up to 4 iodide 123-labeled 5-iodo-A-85380 ([(123)I]5-IA) single-photon emission computed tomography (SPECT) scans during abstinence at 1 day (n = 7) and 1 (n = 17), 2 (n = 7), 4 (n = 11), and 6 to 12 (n = 6) weeks. Age-matched nonsmokers participated in a single [(123)I]5-IA SPECT scan. All participants completed 1 magnetic resonance imaging study. SETTING: Academic imaging center. PARTICIPANTS: Tobacco smokers (n = 19) and an age-matched nonsmoker comparison group (n = 20). Main Outcome Measure The [(123)I]5-IA SPECT images were converted to distribution volume and were analyzed using regions of interest. RESULTS: Compared with nonsmokers, beta(2)*-nAChR availability in the striatum, cortex, and cerebellum of smokers was not different at 1 day of abstinence, was significantly higher at 1 week of abstinence, and was not different at 4 or at 6 to 12 weeks of abstinence. In smokers, beta(2)*-nAChR availability was significantly lower in the cortex and cerebellum at 6 to 12 weeks compared with 1 week of abstinence. In addition, cerebellar beta(2)*-nAChR availability at 4 weeks of abstinence was positively correlated with craving on the day of the SPECT scan. CONCLUSIONS: These data suggest that higher beta(2)*-nAChR availability persists up to 1 month of abstinence and normalizes to nonsmoker levels by 6 to 12 weeks of abstinence from tobacco smoking. These marked and persistent changes in beta(2)*-nAChR availability may contribute to difficulties with tobacco cessation.

Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans.

BACKGROUND: Acute and chronic exposure to cannabinoids has been associated with cognitive deficits, a higher risk for schizophrenia and other drug abuse. However, the precise mechanism underlying such effects is not known. Preclinical studies suggest that cannabinoids modulate brain-derived neurotrophic factor (BDNF). Accordingly, we hypothesized that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the principal active component of cannabis, would alter BDNF levels in humans. MATERIALS AND METHODS: Healthy control subjects (n = 14) and light users of cannabis (n = 9) received intravenous administration of (0.0286 mg/kg) Delta(9)-THC in a double-blind, fixed order, placebo-controlled, laboratory study. Serum sampled at baseline, after placebo administration, and after Delta(9)-THC administration was assayed for BDNF using ELISA. RESULTS: Delta(9)-THC increased serum BDNF levels in healthy controls but not light users of cannabis. Further, light users of cannabis had lower basal BDNF levels. Delta(9)-THC produced psychotomimetic effects, perceptual alterations, and "high" and spatial memory impairments. IMPLICATIONS: The effects of socially relevant doses of cannabinoids on BDNF suggest a possible mechanism underlying the consequences of exposure to cannabis. This may be of particular importance for the developing brain and also in disorders believed to involve altered neurodevelopment such as schizophrenia. Larger studies to investigate the effects of cannabinoids on BDNF and other neurotrophins are warranted.

The effects of cannabinoids on serum cortisol and prolactin in humans.

BACKGROUND: Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n = 6-22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose-response data. Delta-9-tetrahydrocannabinol (Delta-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Delta-9-THC-induced changes of these hormones. MATERIALS AND METHODS: Pooled data from a series of laboratory studies with multiple doses of intravenous Delta-9-THC in healthy control subjects (n = 36) and frequent users of cannabis (n = 40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Delta-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate. RESULTS: At socially relevant doses, Delta-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. CONCLUSIONS: These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in frequent users of cannabis and not a consequence of cannabis use.