Cannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial.

Background: Treatment resistance is a significant problem among young people experiencing moderate-to-severe anxiety, affecting nearly half of all patients. This study investigated the safety and efficacy of cannabidiol (CBD), a non-intoxicating component of Cannabis sativa, for anxiety disorders in young people who previously failed to respond to standard treatment.Methods: In this open-label trial, 31 young people aged 12-25 years with a DSM-5 anxiety disorder and no clinical improvement despite treatment with cognitive-behavioral therapy and/or antidepressant medication were enrolled between May 16, 2018, and June 28, 2019. All participants received add-on CBD for 12 weeks on a fixed-flexible schedule titrated up to 800 mg/d. The primary outcome was improvement in anxiety severity, measured with the Overall Anxiety Severity and Impairment Scale (OASIS), at week 12. Secondary outcomes included comorbid depressive symptoms, Clinical Global Impressions scale (CGI) score, and social and occupational functioning.Results: Mean (SD) OASIS scores decreased from 10.8 (3.8) at baseline to 6.3 (4.5) at week 12, corresponding to a -42.6% reduction (P < .0001). Depressive symptoms (P < .0001), CGI-Severity scale scores (P = .0008), and functioning (P = .04) improved significantly. Adverse events were reported in 25 (80.6%) of 31 participants and included fatigue, low mood, and hot flushes or cold chills. There were no serious and/or unexpected adverse events.Conclusions: These findings suggest that CBD can reduce anxiety severity and has an adequate safety profile in young people with treatment-resistant anxiety disorders. Randomized controlled trials are needed to confirm the efficacy and longer-term safety of this compound.Trial Registration: New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12617000825358.

The chemistry of novel xanthophyll carotenoids.

Natural product isolates are typically not developed as drug candidates because of the difficulty in obtaining the desired stable molecular orientation (ie, stereochemistry), purity, and scale required to meet pharmaceutical industry standards. Recent advances in medicinal and process chemistry have played key roles in transforming a class of dietary natural products-carotenoids-into potential medical therapeutics. Carotenoids are natural pigments derived from the acyclic C40 isoprenoid lycopene, which can also be classified as a tetraterpene. Carotenoids are classified on their chemical composition as either carotenes or xanthophylls. There are 5 C40 carotenoids manufactured synthetically on an industrial scale, including lycopene, ss,ss-carotene, and canthaxanthin (which are achiral compounds); zeaxanthin (produced in enantiopure form, as the 3R,3'R enantiomer); and astaxanthin (produced as mixture of configurational isomers) for use as nutritional supplements and for animal feed additives in poultry farming and aquaculture that are essential for the animals' growth, health and reproduction. The xanthophyll astaxanthin shows pharmaceutical potential, but the configurational complexity has thus far made it difficult to synthesize an enantiopure form on a large scale. Astaxanthin has 2 identical asymmetric carbon atoms (position 3 and 3') and can therefore exist in 4 different configurations, providing 3 different configurational isomers: (3S,3'S) and (3R,3'R), which are enantiomers, and (3R,3'S) and (3S,3'R), which are identical (a meso form). An enantiopure industrial scale synthesis of astaxanthin (3S,3'S) has recently been developed by BASF AG. The desired stereochemistry (chirality) is introduced early in the synthetic process by a proprietary catalytic reaction using an intermediate of the existing technical astaxanthin production process as a substrate. By controlling this essential process, it is possible to produce pharmaceutical quality astaxanthin in quantities large enough to support drug development programs for medical therapies.

Retrometabolic syntheses of astaxanthin (3,3'-dihydroxy-beta,beta-carotene-4,4'-dione) conjugates: a novel approach to oral and parenteral cardio-protection.

Disodium disuccinate astaxanthin has potent cardioprotective effects in animals, with demonstrated preclinical efficacy in the rat, rabbit, and canine models of experimental infarction. It has been effective in subchronic and acute dosing regimens after parenteral administration, and recently published data in rats demonstrate that oral cardioprotection is also readily achieved. Myocardial salvage in the canine can reach 100% with a 4-day subchronic dosing regimen; single-dose I.V. cardioprotection, when given 2 hours before experimental coronary occlusion, is on average two-thirds of that achieved with the subchronic regimen in dogs. In conscious animals, no effects on hemodynamic parameters have been observed. Recently, the beneficial properties of this prototypical astaxanthin conjugate have been extended to include second- and third-generation compounds with improved pharmacokinetic and/or potency profiles. The primary mechanism of cardioprotection appears to be antioxidant activity: potent direct scavenging of the lynchpin radical in ischemia-reperfusion injury, superoxide anion, has been documented in appropriate model systems. In addition, modulation of serum complement activity, reduction of the levels of deposition of C-reactive protein (CRP) and the membrane attack complex (MAC) in infarcted tissue, and reduction in oxidative stress markers from the arachidonic acid and linoleic acid pathways also suggest a significant anti-inflammatory component to the mechanism of cardioprotection. Favorable plasma protein binding has been demonstrated in vitro for several astaxanthin conjugates; this binding capacity overcomes the supramolecular assembly of the compounds that occurs in aqueous solution, which in itself improves the stability and shelf-life of aqueous formulations. Astaxanthin readily populates cardiac tissue after metabolic hydrolysis of both oral and parenteral administration of the astaxanthin ester derivates, providing a reservoir of cardioprotective agent with a significant half-life due to favorable ADME in mammals. Due to the well-documented safety profile of astaxanthin in humans, disodium disuccinate astaxanthin may well find clinical utility in cardiovascular applications in humans following successful completion of preclinical and clinical pharmacology and toxicology studies in animals and humans, respectively.