The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability.

BACKGROUND: Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB1 inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated the effects of the CB1 neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats. METHODS: Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine, and cue-, nicotine priming- and yohimbine-induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depression-like effects of AM4113 and rimonabant were evaluated 24h after chronic (21 days) pretreatment (0, 1, 3, and 10mg/kg, 1/d). RESULTS: AM4113 significantly attenuated nicotine taking, motivation for nicotine, as well as cue-, priming- and stress-induced reinstatement of nicotine-seeking behavior. These effects were accompanied by a decrease of the firing and burst rates in the ventral tegmental area dopamine neurons in response to nicotine. On the other hand, AM4113 pretreatment did not have effects on operant responding for food. Importantly, AM4113 did not have effects on anxiety and showed antidepressant-like effects. CONCLUSION: Our results indicate that AM4113 could be a promising therapeutic option for the prevention of relapse to nicotine-seeking while lacking anxiety/depression-like side effects.

Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling.

It is estimated that 0.6-1% of the population in the USA and Canada fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) criteria for gambling disorders (GD). To date, there are no approved pharmacological treatments for GD. The rat gambling task (rGT) is a recently developed rodent analogue of the Iowa gambling task in which rats are trained to associate four response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. Similar to healthy human volunteers, most rats adopt the optimal strategies (optimal group). However, a subset of animals show preference for the disadvantageous options (suboptimal group), mimicking the choice pattern of patients with GD. Here, we explored for the first time the effects of various cannabinoid ligands (WIN 55,212-2, AM 4113, AM 630 and URB 597) on the rGT. Administration of the cannabinoid agonist CB1/CB2 WIN 55,212-2 improved choice strategy and increased choice latency in the suboptimal group, but only increased perseverative behaviour, when punished, in the optimal group. Blockade of CB1 or CB2 receptors or inhibition of fatty-acid amide hydrolase did not affect rGT performance. These results suggest that stimulation of cannabinoid receptors could affect gambling choice behaviours differentially in some subgroups of subjects.

5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence.

BACKGROUND: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. METHODS: Mice lacking the 5-HT reuptake carrier (5-HTT(-/-)) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR-induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos-induced expression) levels. RESULTS: Although 5-HTT(-/-) mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR-mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT(-/-) mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT(-/-) mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT(-/-) mutants. CONCLUSIONS: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT(-/-) mice.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-related head and neck cancer.

BACKGROUND: Human papillomavirus (HPV)-related head and neck cancer has been associated with an improved prognosis in patients treated with radiotherapy (RT) +/- chemotherapy (CT); however, RT combined with epidermal growth factor receptor (EGFR) inhibitors has not been fully studied in this group of patients. METHODS: Immunohistochemical expression of p16 and PCR of HPV16 DNA were retrospectively analyzed in tumor blocks from 108 stage III/IV head and neck cancer patients treated with RT+CT (56) or RT+EGFR inhibitors (52). Disease-free survival (DFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. RESULTS: DNA of HPV16 was found in 12 of 108 tumors (11%) and p16 positivity in 18 tumors (17%), with similar rates in both arms of treatment. After a median follow-up time of 35 months (range 6-135), p16-positive patients treated with RT+EGFR inhibitors showed improved survival compared with those treated with RT+CT (2-year OS 88% vs. 60%, HR 0.18; 95% CI 0.04 to 0.88; p = 0.01; and 2-year DFS 75% vs. 47%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.01). However, no differences were observed in p16-negative patients (2-year OS 56% vs. 53%, HR 0.97; 95% CI 0.55 to 1.7; p = 0.9; and 2-year DFS 43% vs. 45%, HR 0.99; 95% CI 0.57 to 1.7; p = 0.9). CONCLUSIONS: This is the first study to show that p16-positive patients may benefit more from RT+EGFR inhibitors than conventional RT+CT. These results are hypothesis-generating and should be confirmed in prospective trials.

Effects of sub-chronic nabiximols on biological markers of individuals undergoing a clinical trial for the treatment of cannabis use disorder.

OBJECTIVE: Nabiximols is used for treating various symptoms associated with multiple sclerosis (MS). Nabiximols is also being investigated as a potential treatment medication for individuals with cannabis use disorder (CUD). A variety of investigations have shown that, at low doses, nabiximols is overall well tolerated for MS treatment. However, due to tolerance, the management of CUD would likely require much higher doses of nabiximols to be effective. The effects of high doses of nabiximols on clinical laboratory tests remain unclear. Therefore, we investigated the sub-chronic effects of high doses of nabiximols on liver function, renal function, and other routine blood tests in this prospective study. METHODS: We performed a secondary analysis of various blood markers results collected during a double-blind, placebo-controlled randomized clinical trial (Sativex and Behavioral-relapse Prevention Strategy in Cannabis Dependence, NCT01747850, https://clinicaltrials.gov/ct2/show/record/NCT01747850). This trial tested the impact of the 12-week administration of nabiximols with a maximum daily dose of up to 113.4 mg THC/105 mg CBD. RESULTS: The measurements of the various biomarkers were in the normal range during the 12-week time frame. The results indicate an overall good tolerability of high-dose nabiximols on the blood markers measured. CONCLUSION: Our preliminary results suggest that high doses of nabiximols might be well tolerated by individuals with CUD.

A Delphi consensus panel about clinical management of early-stage EGFR-mutated non-small cell lung cancer (NSCLC) in Spain: a Delphi consensus panel study.

PURPOSE: This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements). RESULTS: In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB-IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib. CONCLUSIONS: This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario.

Epidemiology, treatment, and survival in small cell lung cancer in Spain: Data from the Thoracic Tumor Registry.

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce. PATIENTS AND METHODS: This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed. RESULTS: With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8-10.2 months), with an estimated rate of 70.3% (95% CI 67.2-73.4%), 38.9% (95% CI 35.4-42.4%), and 14.8% (95% CI 11.8-17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1-2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis. CONCLUSION: This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.

Nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and trastuzumab in HER-2-overexpressing breast cancer: a multicenter phase I/II study.

PURPOSE: To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) >50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter. RESULTS: Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC). The recommended doses of TLC-D99 and paclitaxel were 50 mg/m(2) every 3 weeks and 80 mg/m(2)/wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to >or=50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1 months (95% confidence interval, 16.4-46.3) in MBC patients. CONCLUSIONS: Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.

Nicotine Self-Administration as Paradigm for Medication Discovery for Smoking Cessation: Recent Findings in Medications Targeting the Cholinergic System.

Tobacco kills every year approximately six million people as a direct result of direct use, and it is still considered one of the most excruciating threats for human health worldwide. The low successful rates of the currently available pharmacotherapies to assist in quitting tobacco use suggest there is a need for more effective treatments.The intravenous self-administration (IVSA) paradigm is considered the gold standard to study voluntary drug intake in animal models, including nicotine. The IVSA paradigm has been used to identify key mechanisms involved in the addictive properties of nicotine in both rodents and nonhuman primates. In this chapter we describe how the IVSA paradigm has served to further investigate the role of nicotinic acetylcholine receptors (nAChRs) in the reinforcing properties of nicotine. Notably, this review will cover recent advances (i.e., research carried out during the past decade) using the IVSA paradigm, with a focus on the status of research on current smoking cessation medications (such as varenicline and bupropion) and of other nAChR ligands.The combination of the IVSA paradigm with pharmacological and genetic tools (e.g., knockout animals) has greatly contributed to our understanding of the role of specific subtype nAChRs in nicotine reinforcement processes. We also discuss some of the limitations of the IVSA paradigm so these can be taken into consideration when interpreting and designing new studies.

Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: a dose-escalation study.

Capecitabine added to docetaxel extends survival in metastatic breast cancer (MBC) and shows additive efficacy with erlotinib in pre-clinical studies. This study aimed to determine the maximum-tolerated dose (MTD) of capecitabine/docetaxel with erlotinib and assess tolerability, anti-tumour activity and potential pharmacokinetic interactions. Three treatment cohorts were assessed, using different dosing regimens. A total of 24 women with MBC were enrolled sequentially. The regimen comprising erlotinib 100mg/day continuously, capecitabine 825mg/m2 bid on days 1 to 14 and docetaxel 75mg/m2 intravenously every 3 weeks on day 1 was well tolerated and was established as the MTD. Overall response rate was 67%, comprising two complete and 12 partial responders in 21 assessable patients. The most common treatment-related adverse events were gastrointestinal disorders and skin toxicities. Pharmacokinetic studies showed that exposure to the three drugs was not reduced when given in combination. These encouraging preliminary results warrant further trials of the combination in MBC.

Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial.

BACKGROUND: The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Δ9-tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex®) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment-seeking cannabis-dependent participants. METHODS: Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time. RESULTS: Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores. CONCLUSIONS: Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence.

Symptom and Quality of Life Improvement in LUX-Lung 8, an Open-Label Phase III Study of Second-Line Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung After First-Line Platinum-Based Chemotherapy.

INTRODUCTION: In the phase III LUX-Lung 8 trial, afatinib significantly improved progression-free survival (PFS) and overall survival (OS) versus erlotinib in patients with squamous cell carcinoma (SCC) of the lung progressing during or after platinum-based chemotherapy. Patient-reported outcomes (PROs) and health-related quality of life (QoL) in these patients are presented. PATIENTS AND METHODS: Patients (n = 795) were randomized 1:1 to oral afatinib (40 mg/d) or erlotinib (150 mg/d). PROs were collected (baseline, every 28 days until progression, 28 days after discontinuation) using the European Organization for Research and Treatment of Cancer QoL questionnaire and lung cancer-specific module. The percentage of patients improved during therapy, time to deterioration (TTD), and changes over time were analyzed for prespecified lung cancer-related symptoms and global health status (GHS)/QoL. RESULTS: Questionnaire compliance was 77.3% to 99.0% and 68.7% to 99.0% with afatinib and erlotinib, respectively. Significantly more patients who received afatinib versus erlotinib experienced improved scores for GHS/QoL (36% vs. 28%; P = .041) and cough (43% vs. 35%; P = .029). Afatinib significantly delayed TTD in dyspnea (P = .008) versus erlotinib, but not cough (P = .256) or pain (P = .869). Changes in mean scores favored afatinib for cough (P = .0022), dyspnea (P = .0007), pain (P = .0224), GHS/QoL (P = .0320), and all functional scales. Differences in adverse events between afatinib and erlotinib, specifically diarrhea, did not affect GHS/QoL. CONCLUSION: In patients with SCC of the lung, second-line afatinib was associated with improved prespecified disease-related symptoms and GHS/QoL versus erlotinib, complementing PFS and OS benefits with afatinib.

Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.

Behavioural and neurochemical effects of combined MDMA and THC administration in mice.

RATIONALE: Cannabis is the most widely consumed drug associated with 3,4-methylenedioxymethamphetamine (MDMA) use. OBJECTIVES: This study examines whether low doses of MDMA and delta-9-tetrahydrocannabinol (THC) produce synergistic rewarding/reinforcing effects in mice using the conditioned place preference (CPP) and operant self-administration paradigms. Changes in dopamine (DA) outflow were monitored in the nucleus accumbens (NAC) after single or combined administration of these compounds. RESULTS: MDMA induced a significant CPP at the dose of 10 mg/kg but not at the dose of 3 mg/kg. THC (0.3 mg/kg) by itself was also ineffective in this paradigm. The combined administration of the low dose of MDMA (3 mg/kg) and THC (0.3 mg/kg) produced CPP, whereas the combination of MDMA (10 mg/kg) and THC (0.3 mg/kg) significantly decreased CPP. Animals treated with THC self-administered a sub-threshold dose of MDMA (0.06 mg/kg per infusion), while animals receiving vehicle did not. However, THC did not modify the self-administration of an effective dose of MDMA (0.125 mg/kg per infusion). In microdialysis studies, a low dose of THC significantly increased DA outflow in the NAC, while a low dose of MDMA did not. When MDMA was administered before THC, DA levels decreased with respect to THC. However, when THC was administered before MDMA, DA levels were not significantly modified with respect to THC. CONCLUSIONS: These results demonstrate that a low dose of THC modifies in different ways (increases and decreases) the sensitivity of animals to the behavioural effects of MDMA and that THC and MDMA converge at a common mechanism modulating DA outflow in the NAC of mice.

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. RESULTS: The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. CONCLUSION: The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.

Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice.

RATIONALE: Tobacco smoking is still a major population health issue. The endocannabinoid system has been shown to control drug-seeking behaviors. There are two main endocannabinoids: anandamide degraded by fatty acid amide hydrolase (FAAH) and 2-arachidonoylglycerol (2-AG) degraded by monoacylglycerol lipase (MAGL). OBJECTIVES: The role of MAGL has only been explored recently, and so far, no study have been performed to evaluate the effects of MAGL inhibitor on nicotine reinforcing properties and cue-induced reinstatement of nicotine seeking. METHODS: Here, we investigated the effects of the MAGL inhibitor JZL184 on nicotine self-administration under fixed and progressive-ratio schedules of reinforcement and on cue-induced reinstatement of nicotine seeking in mice. We also evaluated the effects of JZL184 on food self-administration for possible non-specific effects. RESULTS: JZL184 (0, 8, and 16 mg/kg) did not affect food taking, nicotine taking, or motivation for nicotine. MAGL inhibition by JZL184 (16 mg/kg) increased reinstatement of previously extinguished nicotine seeking induced by presentation of nicotine-associated cues, but did not produce reinstatement on its own. CONCLUSIONS: This study implicates involvement of 2-AG in nicotine-seeking behaviors.

Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series.

OBJECTIVES: Cannabis is the most commonly used illicit drug; a substantial minority of users develop dependence. The current lack of pharmacological treatments for cannabis dependence warrants the use of novel approaches and further investigation of promising pharmacotherapy. In this case series, we assessed the use of self-titrated dosages of Sativex (1:1, Δ-tetrahydrocannabinol [THC]/cannabidiol [CBD] combination) and motivational enhancement therapy and cognitive behavioral therapy (MET/CBT) for the treatment of cannabis dependence among 5 treatment-seeking community-recruited cannabis-dependent subjects. METHODS: Participants underwent a 3-month open-label self-titration phase with Sativex (up to 113.4 of THC/105 mg of CBD) and weekly MET/CBT, with a 3-month follow-up. RESULTS: Sativex was well-tolerated by all participants (average dosage 77.5 THC/71.7 mg CBD). The combination of Sativex and MET/CBT reduced the amount of cannabis use and progressively reduced craving and withdrawal scores. THC/CBD metabolite concentration indicated reduced cannabis use and compliance with medication. CONCLUSIONS: In summary, this pilot study found that with Sativex in combination with MET/CBT reduced cannabis use while preventing increases in craving and withdrawal in the 4 participants completing the study. Further systematic exploration of Sativex as a pharmacological treatment option for cannabis dependence should be performed.

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings.

BACKGROUND: There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. METHODS: Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B-E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. RESULTS: High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower "high" following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. CONCLUSIONS: The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence.