Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation

Background: Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals. The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD. Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD. In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear. Method: Male Sprague-Dawley rats received six 1.0 mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context. Immediately following memory retrieval (recall) rats received oral administration of low dose THC, high dose THC, CBD, CBD + low THC, CBD + high THC [as isolated phytochemicals and, in separate experiments, in combination with plant background material (BM)]. Rodents were tested for freezing response context re-exposure at 24 h and 7 days following training. Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM. Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning

Extract and Active Principal of the Neotropical Vine Souroubea sympetala Gilg. Block Fear Memory Reconsolidation

Background: Souroubea sympetala Gilg. is a neotropical vine native to Central America, investigated as part of a targeted study of the plant family Marcgraviaceae. Our previous research showed that extract of S. sympetala leaf and small branch extract had anxiolytic effects in animals and acts as an agonist for the GABAA receptor at the benzodiazepine binding site. To date, the potential effects of S. sympetala and its constituents on reconsolidation have not been assessed. Reconsolidation, the process by which formed memories are rendered labile and susceptible to change, may offer a window of opportunity for pharmacological manipulation of learned fear. Here, we assessed the effects of S. sympetala crude extract and isolated phytochemicals (orally administered) on the reconsolidation of conditioned fear. In addition, we explored whether betulin (BE), a closely related molecule to betulinic acid (BA, an active principal component of S. sympetala), has effects on reconsolidation of learned fear and whether BE may synergize with BA to enhance attenuation of learned fear. Method: Male Sprague–Dawley rats received six 1.0-mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context (but in the absence of foot shocks). Immediately following memory retrieval (recall), rats received oral administration of S. sympetala extract at various doses (8–75 mg/kg) or diazepam (1 mg/kg). In separate experiments, we compared the effects of BA (2 mg/kg), BE (2 mg/kg), and BA + BE (2 mg/kg BA + 2 mg/kg BE). The freezing response was assessed either 24 h later (day 3) or 5 days later (day 7). Effects of phytochemicals on fear expression were also explored using the elevated plus maze paradigm. Results: S. sympetala leaf extract significantly attenuated the reconsolidation of contextual fear at the 25- and 75-mg/kg doses, but not at the 8-mg/kg dose. Furthermore, BA + BE, but not BA or BE alone, attenuated the reconsolidation of learned fear and exerted an anxiolytic-like effect on fear expression

Efficacy of Souroubea-Platanus Dietary Supplement Containing Triterpenes in Beagle Dogs Using a Thunderstorm Noise-Induced Model of Fear and Anxiety

A novel botanical dietary supplement, formulated as a chewable tablet containing a defined mixture of Souroubea spp. vine and Platanus spp. Bark, was tested as a canine anxiolytic for thunderstorm noise-induced stress (noise aversion). The tablet contained five highly stable triterpenes and delivered 10 mg of the active ingredient betulinic acid (BA) for an intended 1 mg/kg dose in a 10 kg dog. BA in tablets was stable for 30 months in storage at 23 °C. Efficacy of the tablets in reducing anxiety in dogs was assessed in a blinded, placebo-controlled study by recording changes in blood cortisol levels and measures of behavioral activity in response to recorded intermittent thunder. Sixty beagles were assigned into groups receiving: placebo, 0.5×, 1×, 2×, and 4× dose, or the positive control (diazepam), for five days. Reduction in anxiety measures was partially dose-dependent and the 1× dose was effective in reducing inactivity time (p = 0.0111) or increased activity time (p = 0.0299) compared with placebo, indicating a decrease in anxiety response. Cortisol measures also showed a dose-dependent reduction in cortisol in dogs treated with the test tablet

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The Journal of Organic Chemistry 55 3 1093 1096

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Clinical observations and safety profile of oral herbal products, souroubea and platanus spp: a pilot-toxicology study in dogs

This pilot-study evaluated the toxicity and safety profi le of two herbal products Souroubea spp Botanical Blend (SSBB) and Platanus Tree Bark (PTB) after oral administration to dogs at elevated doses for 28 days. SSBB and PTB botanicals are the major active ingredients of Sin Susto, a novel natural product for the treatment of anxiety in dogs. Three healthy female dogs were administered elevated doses of either SSBB, PTB or a placebo and then monitored for the occurrence of any systemic and local adverse events. Data from this pilot-study revealed that SSBB and PTB had no untoward effects on the health of dogs and were deemed safe which enabled the design and execution of a larger controlled target safety and toxicology study for Sin Susto.Este estudio piloto evaluó la toxicidad y el perfil de seguridad de dos productos herbales Souroubea spp (SSBB) y Platanus Tree Bark (PTB) tras su administración oral a perros en dosis elevadas durante 28 días. perros a dosis elevadas durante 28 días. Los productos botánicos SSBB y PTB son los principales ingredientes activos de Sin Susto™, un nuevo producto natural para el tratamiento de la ansiedad en perros. A tres perras sanas se les administraron dosis elevadas de SSBB, PTB o un placebo, y luego se controló la aparición de cualquier efecto adverso sistémico y local. sistémicos y locales. Los datos de este estudio piloto revelaron que el SSBB y el PTB no tuvieron efectos adversos en la salud de los perros y se consideraron seguros, lo que permitió el diseño y la ejecución de un estudio controlado de seguridad y toxicología para Sin Susto™.Universidad Nacional, Costa RicaEscuela de Ciencias Ambientale

Clinical Observations and Safety Profile of Oral Herbal Products, Souroubea and Platanus Spp; a Pilot-Toxicology Study in Dogs

This pilot-study evaluated the toxicity and safety profile of two herbal products Souroubea spp Botanical Blend (SSBB) and Platanus Tree Bark (PTB) after oral administration to dogs at elevated doses for 28 days. SSBB and PTB botanicals are the major active ingredients of Sin Susto™, a novel natural product for the treatment of anxiety in dogs. Three healthy female dogs were administered elevated doses of either SSBB, PTB or a placebo and then monitored for the occurrence of any systemic and local adverse events. Data from this pilot-study revealed that SSBB and PTB had no untoward effects on the health of dogs and were deemed safe which enabled the design and execution of a larger controlled target safety and toxicology study for Sin Susto.Ova preliminarna studija procenjuje toksičnost i bezbednost dva biljna sastojka Souroubea spp Botanical Blend (SSBB) i Platanus Tree Bark (PTB) nakon oralne primene kod pasa u povišenim dozama u trajanju od 28 dana. Biljne mešavine SSBB i PTB su dva glavna aktivna sastojka u Sin Susto™, novog prirodnog proizvoda registrovanog za preventivu/smanjenje anksioznosti kod pasa. Tri zdrave ženke pasa su primale povišene doze SSBB, PTB ili placebo nakon čega je praćena pojava sistemskih ili lokalnih neželjenih efekata. Podaci iz ovog preliminarnog istraživanja su pokazali da SSBB i PTB nisu izazvali nikakve neželjene efekte kod pasa i mogu se smatrati bezbednim što je omogućilo dalje istraživanje i izvođenje kontrolisanih ispitivanja u cilju demonstriranja bezbednosti i toksičnosti preparata Sin Susto™ kod pasa