Mateus M. Bergamaschi

Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients

Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.

Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: A case series

Cannabidiol (CBD) is the main non‐psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinsons disease.

Effects of cannabidiol in the treatment of patients with Parkinson’s disease: An exploratory double-blind trial

Introduction: Parkinson’s disease (PD) has a progressive course and is characterized by the degeneration of dopaminergic neurons. Although no neuroprotective treatments for PD have been found to date, the endocannabinoid system has emerged as a promising target. Methods: From a sample of 119 patients consecutively evaluated in a specialized movement disorders outpatient clinic, we selected 21 PD patients without dementia or comorbid psychiatric conditions. Participants were assigned to three groups of seven subjects each who were treated with placebo, cannabidiol (CBD) 75 mg/day or CBD 300 mg/day. One week before the trial and in the last week of treatment participants were assessed in respect to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and H1-MRS). Results: We found no statistically significant differences in UPDRS scores, plasma BDNF levels or H1-MRS measures. However, the groups treated with placebo and CBD 300 mg/day had significantly different mean total scores in the PDQ-39 (p = 0.05). Conclusions: Our findings point to a possible effect of CBD in improving quality of life measures in PD patients with no psychiatric comorbidities; however, studies with larger samples and specific objectives are required before definitive conclusions can be drawn.

Rifampicin determination in plasma by stir bar-sorptive extraction and liquid chromatography

A sensitive and reproducible stir bar-sorptive extraction and high performance liquid chromatography-UV detection (SBSE/HPLC-UV) method for therapeutic drug monitoring of rifampicin in plasma samples is described and compared with a liquid:liquid extraction (LLE/HPLC-UV) method. This miniaturized method can result in faster analysis, higher sample throughput, lower solvent consumption and less workload per sample while maintaining or even improving sensitivity. Important factors in the optimization of SBSE efficiency such as pH, temperature, extraction time and desorption conditions (solvents, mode magnetic stir, mode ultrasonic stir, time and number of steps) were optimized recoveries ranging from 75 to 80%. Separation was obtained using a reverse phase C(8) column with UV detection (254nm). The mobile phase consisted of methanol:0.25N sodium acetate buffer, pH 5.0 (58:42, v/v). The SBSE/HPLC-UV method was linear over a working range of 0.125-50.0microgmL(-1). The intra-assay and inter-assay precision and accuracy were studied at three concentrations (1.25, 6.25 and 25.0microgmL(-1)). The intra-assay coefficients of variation (CVs) for all compounds were less than 10% and all inter-CVs were less than 10%. Limits of quantification were 0.125microgmL(-1). Stability studies showed rifampicin was stable in plasma for 12h after thawing; the samples were also stable for 24h after preparation. Based on the figures of merit results, the SBSE/HPLC-UV proved to be adequate to the rifampicin analyses from therapeutic to toxic levels. This method was successfully applied to the analysis of real samples and was as effective as the LLE/HPLC-UV method.

Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report

What is known and Objective: Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC.

Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans.

Objectives:Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods:This double-blind, placebo-controlled cross-over study of CBD, coadministered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21 to 65 years with prior opioid exposure, regardless of the route. Blood samples were obtained before and after 400 or 800 mg of CBD pretreatment, followed by a single 0.5 (session 1) or 1.0 &mgr;g/kg (session 2) of intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results:SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. After low-dose CBD, tmax occurred at 3 and 1.5 hours in sessions 1 and 2, respectively. After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC P = NS) between sessions. Conclusions:Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.

Rimonabant effects on anxiety induced by simulated public speaking in healthy humans: a preliminary report

We investigated the hypothesis that rimonabant, a cannabinoid antagonist/inverse agonist, would increase anxiety in healthy subjects during a simulation of the public speaking test.

Why should cannabis be considered doping in sports

Recent debate and cases involving elite athletes raised the question whether or not Cannabis sativa (cannabis) should be considered doping in sports. Results from a 2010 report in the United States (Substance Abuse and Mental Health Services Administration, 2011) showed that cannabis is the most used illicit drug, with 17.4 million users smoking cannabis and 6.9 million users smoking cannabis on a daily or near daily basis. The World Anti-Doping Agency (WADA) included cannabis in its Prohibited List in 2004, claiming that cannabis may improve performance in some sports and is an illegal drug in most countries (Huestis et al., 2011); however, the inclusion of a substance in the Code (World Anti-Doping Agency, 2009) is complex, requiring intense debate among delegates and the fulfillment of specific criteria. For instance, Section 4 of the Code establishes that a substance be considered for inclusion in the Prohibited List if it is a masking agent or meets two of the three following criteria: (i) potential to enhance performance in sports – smoked cannabis affects cognition and performance, causes memory loss, executive function, and motor impairment, among other undesirable effect (Saugy et al., 2006). Cannabis smoking can be helpful for some activities such as extreme sports, as it improves muscle relaxation, reduces anxiety, and extincts fear memories (e.g., negative experiences) leading to enhanced performance. It is also worthwhile to note that cannabis smoking improves sleep time and recovery, which may favor performance when an athlete is facing multiple competitions in a short period of time. In light of these positive effects, one can assume cannabis is a doping substance that relaxes the mind and improves recovery (Huestis et al., 2011); (ii) potential or actual health risk – cannabis’ cognitive effects in chronic users are still unclear, but it may downregulate CB1 receptors, affect executive functions, and cause motor impairment, reversed only after weeks of abstinence (Hirvonen et al., 2012). It seems unlikely that athletes are chronic cannabis smokers due to the detrimental effects of chronic use including inconsistent performance, concentration, and motivation. Cyclists who smoked cannabis had a 1-min decrease in maximal exercise performance at 10 min after smoking (Renaud and Cormier, 1986). These negative effects on cognition and performance can impair critical skills (e.g., decision making, vigilance, alertness) required in high-risk sports to avoid accidents and/or injuries; or (iii) violation of the spirit of sport – doping is essentially contrary to the spirit of sport, which is the principle of Olympism, characterized by several values, such as ethics, fair play and honesty, health, respect for rules and laws, and respect for self and other participants (World Anti-Doping Agency, 2009). Over 60 cannabinoids are present in cannabis, with Δ9-tetrahydrocannabinol (THC) the main psychoactive constituent and responsible for the observed toxic effects after smoking, while other cannabinoids are responsible for minor effects, such as cannabinol (CBN), which is 10% as psychoactive as THC (Huestis, 2005). THC is lipophilic and stores in several organs, especially in adipose tissue; this extensive body burden explains the prolonged cannabinoid detection rate in blood and urine for at least 4 weeks in chronic daily cannabis smokers (Lowe et al., 2009; Bergamaschi et al., 2013). The WADA (World Anti-Doping Agency, 2013) establishes a 15 ng/mL urinary 11-nor-9-carboxy-THC (THCCOOH) threshold; urine analyses involves THCCOOH-glucuronide conjugates cleavage, which significantly increases free THCCOOH concentrations and detection time. Urinary THCCOOH concentrations above the 15 ng/mL threshold are considered Adverse Analytical Findings and may be interpreted as a violation of anti-doping rules (World Anti-Doping Agency, 2009). Studies showed that even occasional and single cannabis smoking might yield a THCCOOH positive result (≥15 ng/mL) for up to 5 days (Huestis et al., 1996). Thus, consuming cannabis even weeks before a match may imply a considerable risk of being detected in a doping test. In light of this considerable risk, some users started using a new preparation of herbal smoking blends named “Spice.” Such substances are highly potent cannabinoid analogs, with unknown and potentially harmful toxicological properties that may cause prolonged intoxication. These substances mimic or worsen cannabis’ toxic effects provoking cognitive and motor impairment (UNODC, 2011). The non-psychoactive cannabidiol (CBD) is anxiolytic in humans following a single dose (Zuardi et al., 1993; Bergamaschi et al., 2011); decreased anxiety and fear memories extinction after oral CBD intake may enhance sports performance with no “violation” of the Code, as no THCCOOH is detected in urine. One way to protect athletes’ health and to promote health, fairness, and equality in sports is to include any illicit drugs, their constituents and analogs in the anti-doping program. The sports may assist to create educational program for youth and athletes as an alternative to keep them away from drugs and to preserve the intrinsic value about the “spirit of sport.”

Quantification of Nicotine in Commercial Brand Cigarettes: How Much Is Inhaled by the Smoker?.

The main objective of this experiment is to determine the amount of nicotine in commercial brand cigarettes by means of a nonaqueous acid‐base titration. A simple glass device simulating a smoker is proposed, which allows the determination of the volatilized, filter retained, and inhaled portions. Students will readily see that the amount of nicotine/cigarette stated on the label (∼0.5–1.0 mg) refers indeed to the inhaled portion only, rather than to the total amount/cigarette (usually more than 10 mg). Even so, values for inhaled nicotine may be significantly higher than those reported for several brands. Students will also be able to make a critical evaluation of the true content of nicotine in the inhaled portion and confront it with the reported value for a given brand. In addition, the theoretical approach, supported by HPLC data, provides an excellent experience on nonaqueous acid‐base volumetric analysis.

Curcumin could prevent methemoglobinemia induced by dapsone in rats

The curcumins effect given orally by gavage in single- or multiple-dose regimens on methemoglobinemia induced by dapsone (DDS) was investigated in male Wistar rats. In the single-dose regimen, groups of 10 rats received either vehicle alone, or curcumin at 0.1, 1.0, 10, or 30 mg/kg body weight (bw), or curcumin at 0.02, 0.1, 1, 10, or 30 mg/kg bw plus DDS at 40 mg/kg bw, intraperitoneally (i.p.), 2 hours after. In the multiple-dose regimen, groups of 10 rats received either vehicle alone, or curcumin at 0.1, 1.0, 10, or 30 mg/kg bw for 5 days, with or without DDS (40 mg/kg bw, i.p.) 2 hours after on the fifth day. In both regimens, further groups of 10 rats were given DDS alone (positive controls) or normal saline (negative controls) i.p. Single-dose treatment with curcumin at 0.02 and 0.1 mg/kg bw significantly reduced DDS-induced methemoglobin formation, while the higher doses showed a pro-oxidant effect, significantly increasing DDS-induced methemoglobinemia. In the multiple-dose regimen, treatment with curcumin at 0.1 mg/kg bw significantly reduced DDS-induced methemoglobin formation, but the higher doses were without significant effect compared to DDS alone. It is concluded that curcumin at low doses mitigates methemoglobinemia induced by dapsone in rats, both in single- and multiple-dose regimens.