Corresponding Author: Zhao-Hui Song
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, 40292 (USA)
Tel. +1-502-852-5160, Fax +1-502-852-7868, E-Mail email@example.com
Cannabidiol Signaling in the Eye and Its Potential as an Ocular Therapeutic Agent
Alyssa Aebersold Max Duff Lucy Sloan Zhao-Hui Song
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
A brief history of cannabis
Cannabis sativa is a plant species that includes both cannabis and hemp. It first appeared in Chinese medical texts around 2000 years ago . Records from Britain indicate that cannabis was brought from Egypt by Napoleon’s troops in the early 1800s . Shortly thereafter, hemp was introduced to Western medicine when in 1840, a hemp tincture from ground plant matter was reported to be an effective treatment for convulsive disorders and tetanus . By 1851, a cannabis extract was included in the 3rd edition of the Unites States Pharmacopoeia and readily available in American pharmacies [4, 5].
In 1913, however, cannabis was made illegal in California due to a wide-spread anti-narcotics campaign . Cannabis became federally illegal when Harry Anslinger from California introduced the Marijuana Tax Act of 1937 banning the sale and use of cannabis nationally [5, 6]. A negative stigma continued to develop in the US around cannabis, then associated with narcotics, that culminated with the Controlled Substances Act (CSA) of 1970, which classified cannabis and cannabinoids as Schedule I with no recognized medical use . Recently, America is witnessing a revival in the popularity of cannabis, both medically and recreationally. In 1996, California was the first state to legalize cannabis for medical use and more states have followed California in recent years . To date, 16 states and Washington D.C. have legalized both medical and recreational cannabis with an additional 26 states legalizing medical cannabis at varying degrees. Moreover, the Agricultural Acts of 2014 and 2018 removed hemp from the list of controlled substances and redefined industrial hemp as cannabis containing less than 0.3% THC [9, 10]. As a result of the recent wave of recreational and medical cannabis legalization, in conjunction with the end to the prohibition of hemp, cannabis research is quickly expanding.
Cannabidiol (CBD) is one of over 120 chemicals produced by the Cannabis sativa plant termed phytocannabinoids [11, 12]. There are potentially more, as 21 previously unknown cannabinoids were recently identified . The two most abundant phytocannabinoids in cannabis are psychoactive and intoxicating D9-tetrahydrocannabinol (THC) and non-intoxicating CBD.
CBD was first isolated in the 1940 and its structure and stereochemistry fully determined in 1963 [14, 15]. CBD and THC are both derived from cannabigerolic acid . Although the structure of CBD was discovered before THC [15, 17], THC had been the major focus of research related to cannabis and cannabinoids. This focus is driven, in part, by the activity of THC at the canonical cannabinoid receptors, CB1 and CB2. However, there are many targets for cannabinoids other than CB1 and CB2. For example, CBD has upwards of 65 known targets consisting of receptors, enzymes, ion channels and transient receptor potential (TRP) channels .
Cannabinoids in pharmaceuticals
Cannabinoid containing drugs are approved for medical use in the USA and other countries. The drugs differ in their formulation and indicated uses. Dronabinol (Marinol) was the first cannabinoid-containing medicine approved by the FDA in 1985. It is a soft gel capsule containing synthetic THC . Syndros is an oral solution of dronabinol . Cesamet (nabilone) is the third synthetic cannabinoid drug approved by the FDA in May of 2006 . All three are prescribed for anorexia associated with weight loss in AIDS patients and nausea/vomiting in cancer patients [19-22]. While plant-derived THC is a Schedule I substance, Marinol is listed under Schedule III and Cesamet and Syndros are controlled under Schedule II [19-21].
Epidiolex is an oil formulation of CBD approved by the FDA in June of 2018 for treatment of Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of pediatric epilepsy . In July of 2020, it was approved for treating seizures in a rare genetic disease, tuberous sclerosis complex (TSC) . Epidiolex is the only FDA approved drug containing a compound directly derived from cannabis. It was originally classified as schedule V, but is no longer a controlled substance as the FDA deemed it safe and effective for treatment of the aforementioned conditions . Sativex is a 1:1 alcohol solution of THC and CBD administered as an oromucosal spray that is approved in 25 countries for the treatment of pain and spasticity in multiple sclerosis patients . Despite its approval in other countries, Sativex is not yet approved by the FDA in the US.
Research on cannabidiol
CBD, through a variety of mechanisms and targets, has numerous potential therapeutic uses for a plethora of conditions. The assertion of potential therapeutic actions of CBD is based on pre-clinical data, limited clinical data and ongoing human clinical trials. Pre-clinical studies show that CBD has antioxidant [27, 28] anti-inflammatory , anti-
convulsant [29, 30], neuroprotective , and anti-cancer properties . CBD also shows potential as a therapeutic agent in cardiovascular , neurological, and neuropsychiatric disorders . The completed clinical trials involve CBD use in epilepsy and seizures disorders (21 trials), general pain and pain associated disorders (19 trials), drug abuse and use disorders (14 trials), other neurologic conditions (4 trials) and psychiatric conditions (11 trials). In addition, there are currently 85 active clinical trials in the United States containing CBD (including Epidiolex and Sativex) on clinicaltrials.gov.
Over the past two decades, multiple studies have investigated the therapeutic potentials of CBD in the eye. There are several published reviews of cannabinoids for treatment of glaucoma [34, 35], and retinal disorders [36, 37]. Nevertheless, there are currently no reviews that focus solely on CBD for ocular conditions. In this review, we aim to fill the gap in literature with a focus on CBD ocular pharmacology. We will discuss therapeutic potentials of CBD for ocular conditions, ocular molecular targets for CBD, and mechanisms of actions of CBD in the eye.
Therapeutic potentials of cannabidiol for ocular conditions
CBD is recognized for its antioxidant, anti-inflammatory and neuroprotective properties. In this section, we discuss the observed effects of CBD in ocular tissues and its indication for ocular disorders. Specifically, we will discuss studies of CBD in corneal inflammation and pain, endotoxin-induced inflammation, excitotoxicity, diabetic retinopathy, and intraocular pressure (Table 1 and Table 2).
The authors acknowledge the support of Department of Pharmacology and Toxicology, University of Louisville School of Medicine.
AA and MD wrote the initial versions of the review. LS and ZHS edited and finalized the manuscript.
While writing this manuscript, AA is supported in part by NIH grant T32 ES011564; MD is supported in part by NIH grant R25 CA134283; LS is supported in part by University of Louisville Integrated Programs in Biomedical Sciences (IPIBS) Fellowship; and ZHS is supported in part by NIH grant EY030186.
Statement of Ethics
The authors have no ethical conflicts to disclose.
The authors have no conflicts of interest to declare.
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