Pharmacovigilance of unlicensed cannabidiol in European countries.

Cannabidiol (CBD) is a multitarget agent possessing anti-inflammatory and antioxidant properties. Unlicensed CBD gained public favor for the care of general health and well-being as well as to get comfort from inflammatory complaints, pain, anxiety, mood, and sleep disorders. Safety profile of unlicensed CBD has been not sufficiently described. For this reason, suspected adverse reactions (SARs) to CBD unlicensed products were analyzed. Serious SARs to unlicensed CBD products in EudraVigilance, a system purchased by the European Medicines Agency, were analyzed for age, sex of the patient, adverse reactions, indication for use, and concomitant drugs. Serious SARs were 18.9% of all adverse events to unlicensed CBD; they were more frequent in men and adult people and, to a less extent, in children (3-11 years). About sex, in EudraVigilance serious Individual Cases Safety Reports of SARs to CBD in men are in the largest number (58.8%) with respect to women. Unlicensed CBD was used in the 38.8% of cases for treatment of epilepsy; more frequent adverse effects were: mental disorders, hepatic disorders, and aggravation of pre-existing epilepsy. Drugs or substances more frequently associated with SARs were the antiepileptics clobazam and valproic acid, followed by cannabis. Results suggest that precautions and appropriate surveillance of adverse effects should be taken when unlicensed CBD is used.

Risks and benefits of animal-assisted interventions for critically ill patients admitted to intensive care units.

BACKGROUND: Pets offer significant health benefits, from decreased cardiovascular risks to anxiety and post-traumatic stress improvements. Animal-assisted interventions (AAI) are not frequently practiced in the intensive care unit (ICU) for fear of health risk for critical patients because there is a hypothetical risk of zoonoses. OBJECTIVES: This systematic review aimed to collect and summarize available evidence about AAI in the ICU. The Review questions were "Do AAI improve the clinical outcome of Critically Ill Patients admitted to ICUs?" and "Are the zoonotic infections the cause of negative prognosis?". METHODS: The following databases were searched on 5 January 2023: Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and PubMed. All controlled studies (randomized controlled, quasi-experimental, and observational studies) were included. The systematic review protocol has been registered on the International Prospective Register of Systematic Review (CRD42022344539). RESULTS: A total of 1302 papers were retrieved, 1262 after the duplicate remotion. Of these, only 34 were assessed for eligibility and only 6 were included in the qualitative synthesis. In all the studies included the dog was the animal used for the AAI with a total of 118 cases and 128 controls. Studies have high variability, and no one has used increased survival or zoonotic risk as outcomes. CONCLUSIONS: The evidence on the effectiveness of AAIs in ICU settings is scarce and no data are available on their safety. AAIs use in the ICU must be considered experimental and follow the related regulation until further data will be available. Given the potential positive impact on patient-centered outcomes, a research effort for high-quality studies seems to be justified.

Pharmacological Aspects and Biological Effects of Cannabigerol and Its Synthetic Derivatives.

Cannabigerol (CBG) is a cannabinoid from the plant Cannabis sativa that lacks psychotomimetic effects. Its precursor is the acidic form, cannabigerolic acid (CBGA), which is, in turn, a biosynthetic precursor of the compounds cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBGA decarboxylation leads to the formation of neutral cannabinoid CBG, through a chemical reaction catalyzed by heat. On the basis of the growing interest in CBG and with the aim of highlighting scientific information on this phytocannabinoid, we focused the content of this article on its pharmacokinetic and pharmacodynamic characteristics and on its principal pharmacological effects. CBG is metabolized in the liver by the enzyme CYP2J2 to produce hydroxyl and di-oxygenated products. CBG is considered a partial agonist at the CB1 receptor (R) and CB2R, as well as a regulator of endocannabinoid signaling. Potential pharmacological targets for CBG include transient receptor potential (TRP) channels, cyclooxygenase (COX-1 and COX-2) enzymes, cannabinoid, 5-HT1A, and alpha-2 receptors. Pre-clinical findings show that CBG reduces intraocular pressure, possesses antioxidant, anti-inflammatory, and anti-tumoral activities, and has anti-anxiety, neuroprotective, dermatological, and appetite-stimulating effects. Several findings suggest that research on CBG deserves to be deepened, as it could be used, alone or in association, for novel therapeutic approaches for several disorders.

A standardized extract of Opuntia ficus-indica (L.) Mill and Olea europaea L. improves gastrointestinal discomfort: A double-blinded randomized-controlled study.

Gastrointestinal discomfort (GD), which often includes gastroesophageal reflux disease (GERD), is a common disorder in healthy adults affecting 40% of the worldwide population. The symptoms related to GD can have a negative impact on the quality of life (QoL). Current treatments for GERD are associated with side effects. We conducted a randomized double-blind placebo-controlled trial to assess the effect of a standardized extract of Opuntia ficus-indica L. cladodes and Olea europaea L. leaves on the symptoms and QoL of healthy adults with GD. One hundred healthy participants with GD were enrolled in the study and divided into two groups: 60 participants taking verum (400 mg/day) and 40 taking the placebo for 8 weeks. The Gastrointestinal Quality of Life index (GIQLI) and GERD Symptom Assessment Scale (GSAS) questionnaires were administered at the beginning of the study and after 4 and 8 weeks. The group treated with verum experienced a statistically significant improvement of GIQLI and GSAS scores (p < .001). Moreover, the effect size measured revealed a clinical significance. A day-dependent improvement of symptoms was also observed. The standardized extract represents a fast, effective, and well-tolerated treatment for improving symptoms related to GD and GERD.

Clinical use of omega-3 fatty acids in migraine: A narrative review.

BACKGROUND: Omega-3 fatty acids (FAs) can produce several beneficial effects and are commonly used for the treatment of migraine symptoms. Although current therapeutic measures for migraine included pharmacological therapies, dietary supplements, and herbal ingredients, dietary patterns, acupuncture, relaxation techniques, biofeedback, and psychotherapy, omega-3 FAs therapeutic role seems to be obtained through the inhibition or reduction of the release of inflammatory cytokines. The present review aims to provide updated information about the effects of omega-3 FAs in migraine treatment, investigating their clinical effects alone or in combination with other substances. METHODS: Bibliographic research was conducted by examining scientific literature from January 2000 until January 31, 2020. Ten clinical studies were included in the review. Quality assessment of randomized controlled trials was performed by using the JADAD scale. RESULTS: Clinical studies methodology is not always of good quality and results show moderate evidence concerning the therapeutic role of omega-3 FAs in migraine. CONCLUSION: Further clinical trials are necessary to implement the knowledge concerning the use of omega-3 fatty acids in the treatment of migraine.

Preclinical and Clinical Evidence Supporting Use of Cannabidiol in Psychiatry.

BACKGROUND: Cannabidiol (CBD) is a major chemical compound present in Cannabis sativa. CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders. OBJECTIVE: The aim of this review is to illustrate the state of art about scientific research and the evidence of effectiveness of CBD in psychiatric patients. METHODS: This review collects the main scientific findings on the potential role of CBD in the psychiatric field, and results of clinical trials carried out on psychiatric patients are commented. A research was conducted in the PUBMED, SCOPUS, and ScienceDirect databases using combinations of the words cannabidiol, psychiatry, and neuropsychiatric. RESULTS: Preclinical and clinical studies on potential role of CBD in psychiatry were collected and further discussed. We found four clinical studies describing the effects of CBD in psychiatric patients: two studies about schizophrenic patients and the other two studies carried out on CBD effects in patients affected by generalized social anxiety disorder (SAD). CONCLUSION: Results from these studies are promising and suggest that CBD may have a role in the development of new therapeutic strategies in mental diseases, and they justify an in-depth commitment in this field. However, clinical evidence we show for CBD in psychiatric patients is instead still poor and limited to schizophrenia and anxiety, and it needs to be implemented with further studies carried out on psychiatric patients.

Cannabinoids and spinal cord stimulation for the treatment of failed back surgery syndrome refractory pain.

OBJECTIVE: This study aimed to evaluate pain and its symptoms in patients with failed back surgery syndrome (FBSS) refractory to other therapies, treated with a combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in association with spinal cord stimulation (SCS). SETTINGS: Outpatients referred at Pain Unit of San Vincenzo Hospital in Taormina (Italy), between September 2014 and January 2016. SUBJECTS: Eleven FBSS patients diagnosed with neuropathic pain using the Douleur Neuropathique 4 questionnaire and suffering from moderate to severe chronic refractory pain, and undergoing treatment with SCS and a combination of THC/CBD for 12 consecutive months. MATERIALS AND METHODS: All the included patients discontinued previous unsuccessful therapy at least 2 months before the beginning of the cannabinoid therapy, with the exception of the SCS that was continued. Patients received a fixed dosage of cannabinoid agonists (THC/CBD) that could be increased subjective to pain control response. A Brief Pain Inventory questionnaire was administered to measure pain and its interference with characteristic dimensions of feelings and functions. The duration of treatment with SCS and THC/CBD combination was 12 months. RESULTS: Effective pain management as compared to baseline result was achieved in all the cases studied. The positive effect of cannabinoid agonists on refractory pain was maintained during the entire duration of treatment with minimal dosage titration. Pain perception, evaluated through numeric rating scale, decreased from a baseline mean value of 8.18±1.07-4.72±0.9 by the end of the study duration (12 months) (P<0.001). CONCLUSION: The results indicate that cannabinoid agonists (THC/CBD) can have remarkable analgesic capabilities, as adjuvant of SCS, for the treatment of chronic refractory pain of FBSS patients.

Clinical Pharmacology of Citrus aurantium and Citrus sinensis for the Treatment of Anxiety.

OBJECTIVE: The aim of this review is to analyze preclinical and clinical studies investigating the anxiety effects of Citrus aurantium or Citrus sinensis essential oils (EOs). DESIGN: The bibliographic research was made on the major scientific databases. Analysis included only articles written in English and published on peer-reviewed scientific journals describing preclinical experiments and clinical trials carried out to investigate the antianxiety effects of Citrus aurantium or Citrus sinensis EOs on anxiety disorders. Clinical studies reporting the antianxiety effects of products containing Citrus aurantium or Citrus sinensis EOs in combination with other active substances, including medicinal plants, were excluded. Nine clinical studies fulfilled the criteria adopted for analysis. RESULTS: Data show that Citrus aurantium or Citrus sinensis EOs produce anxiolytic effects both in preclinical experiments and in different clinical conditions. Citrus aurantium EO aromatherapy reduced anxiety level in the great part of stress conditions studied (subjects affected by chronic myeloid leukemia and preoperative patients) except for a sample of patients subjected to colonoscopy. Exposition to Citrus sinensis EO in clinical studies shows to be positive in reducing anxiety level in patients waiting for dental treatment as well as in healthy volunteers submitted to an anxiogenic situation. CONCLUSIONS: Overview of clinical trials conducted with Citrus aurantium or Citrus sinensis on people with anxiety showed that inhalation or oral administration of Citrus aurantium and inhalation of Citrus sinensis can exert beneficial effects on anxiety; however, because of incomplete accuracy in the reporting of methodology, further more complete clinical studies are warranted.