The story of Shakespeare – the famous playwright and poet, was a fan of the beautiful green plant. Indeed, forensic technology has revealed cannabis residue in pipes found in his Stratford-upon-Avon garden.
The story of CBD goes back thousands of years – as cultures across time have used non-psychoactive varieties of Cannabis for different uses. In 1940 researchers Roger Adams, Madison Hunt and JH Clark published a report indicating the structure of a compound that they extracted and isolated from wild hemp in Minnesota¹. These researchers named this compound, Cannabidiol, or CBD as it would become commonly known. CBD was only the second cannabinoid found in Cannabis at the time, the first being Cannabinol, or CBN – a degradation product of THC.
In 1944 it was discovered that the effects of barbiturates could be extended if administered with CBD, but not with CBN or THC². Their answer to why CBD had this effect would come almost 30 years later. In 1972 it would be discovered that CBD inhibited certain enzymes in the body, which affects how the body metabolizes certain foods and drugs³. This helped begin to complete the puzzle that stemmed from the barbiturate study three decades prior.
In 1981 researchers were able to demonstrate anticonvulsant effects in humans – indicating that it might be an effective treatment for certain forms of epilepsy and spasticity⁴. In 1982 CBD was found to exhibit anti-anxiety effects, which would later be reconfirmed in 1993⁵ ⁶. In 1995 it was discovered that CBD improves symptoms of psychosis⁷. In 1998 the United States government filed a patent on the antioxidant and neuroprotective effects of CBD, as well as THC⁸.
The 2000s would become the decade of elucidating the activity of CBD. In 2001, researchers began to finally understand more about how CBD actually works in the body by revealing that CBD targets non-cannabinoid receptors in the body, stimulates the production of at least one endocannabinoid, Anandamide, and inhibits an enzyme responsible for breaking down Anandamide, effectively allowing it to linger in the body longer⁹.
In 2002 researchers would confirm that CBD exhibits anti-nausea effects, which had already been reported as far back as the 1800s when systematic Cannabis research really began to take shape¹⁰. In 2004 it was discovered that at certain serving sizes of CBD can increase wakefulness and counteract THC induced sedation¹¹. So if you are feeling sleepy after using THC-rich Cannabis, a little bit of CBD might wake you back up! However, be careful, because CBD exhibits what is known as biphasic activity, meaning it acts differently in low doses versus high doses. At high doses, CBD can actually be sedating¹².
In 2005 it was discovered that CBD interacts with certain serotonin receptors in the body¹³. In 2006 researchers would go on to discover that CBD also enhances adenosine receptor signaling, which is associated with heart health, blood pressure, and body temperature regulation¹⁴. It was also in 2006 that researchers discovered that CBD can kill breast cancer cells – bringing significant attention to the compound as a potential anti-cancer drug¹⁵.
In 2007 researchers began to understand why CBD reduced the effects of THC in some of their prior research. It turns out that CBD changes the shape and activity of CB1 receptors, even though it does not exhibit much affinity for them directly¹⁶. In this way, it changes the way that THC binds to the CB1 receptor, modulating its activity. This kind of activity is called allosteric modulation, and CBD is considered an allosteric modulator of the CB1 receptor. This is why CBD is able to reduce the high associated with THC – it essentially deforms the CB1 receptor so that THC cannot stimulate the receptor as well as it normally would.
In 2008 it was discovered that CBD was a potent antibiotic against MRSA – a powerful infection that is commonly picked up in hospitals and often resists treatment¹⁷. In 2012 researchers discovered that CBD may be as effective as standard antipsychotics¹⁸. In 2014 it was discovered that CBD might be able to effectively treat acne in the skin by reducing inflammation, fighting bacteria on the skin, and changing the way that the skin produces oil¹⁹.
The Modern CBD Industry
In 2018 in the United States, The Agricultural Improvement Act of 2018, also known as the 2018 Farm Bill, was passed, which effectively legalized hemp and hemp derived products across the United States, including all of the cannabinoids and other chemical constituents of hemp varieties of Cannabis with THC concentrations below 0.3%, and CBD was removed from the Controlled Substances list, as long as the CBD was hemp derived²⁰ ²¹. Some may say that the CBD market began at this time, but CBD products had already been available in foods, cosmetics, and dietary supplements widely for years prior to the legalization of hemp, operating in somewhat of a regulatory grey area. In 2018, Epidiolex would officially become FDA approved prescription cannabidiol (CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome, or tuberous sclerosis complex (TSC) in patients 1 year of age and older²².
¹ Adams R, Hunt M, Clark JH. 1940. Structure of cannabidiol, a product isolated form the marihuana extract of Minnesota wild hemp. I. J Am Chem Soc. 62(1): 196-200
² Loewe S. 1944. Studies on the pharmacology of marihuana The Marihuana Problems in the City of New Yorked. The Mayor’s Committee on Marihuana. pp. 149–212.Lancaster, PA: The Jaques Cattell Press
³ Paton WDM, Pertwee RG. 1972. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br J Pharmacol. 44: 250-261
⁴ Carlini EA, Cunha JM. 1981. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 21(S1): 417S-427S.
⁵ Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. 1982. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl). 76(3): 245-250
⁶ Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. 1993. Effects of ipsapirone an dcannabidiol on human experimental anxiety. J Psychopharmacol. 7(1 Suppl): 82-88
⁷ Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R. 1995. Antipsychotic effect of cannabidiol. 56(10): 485-486
⁸ https://patents.google.com/patent/US6630507B1/en
⁹ Bisogno T et al. 2001. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 134(4): 845-852
¹⁰ Parker LA, Mechoulam R, Schlievert C. 2002. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport. 13(5): 567-570
¹¹ Nicholson AN, Turner C, Stone BM, Robson PJ. 2004. Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol. 24(3): 305-313
¹² Zuardi AW, Guimarães FS, Moreira AC. 1993. Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers. Braz J Med Biol Res. 26(2): 213-7
¹³ Russo EB, Burnett A, Hall B, Parker KK. 2005. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 30(8): 1037-1043
¹⁴ Carrier EJ, Auchampach JA, Hillard CJ. 2006. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 103(20): 7895 – 7900
¹⁵ Ligresti A et al. 2006. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 318(3): 1375-1387
¹⁶ Thomas et al. 2007. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 150(5): 613-623
¹⁷ Appendino G et al. 2008. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 71(8): 1427-1430.
¹⁸ Leweke FM et al. 2012. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2(3): e94
¹⁹ Olah A et al. 2014. Cannabidiol exerts sebostatic and anti-inflammatory effects on human sebocytes. J Clin Invest. 124(9): 3713-3724.
²⁰ Corroon J, Kight R. Regulatory Status of Cannabidiol in the United States: A Perspective. Cannabis Cannabinoid Res. 2018. 3(1): 190-194
²¹ United States H.R.2 115 Agriculture Improvement Act of 2018, Sec. 297A Definitions (1)
²² https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient- derived-marijuana-treat-rare-severe-forms
Written in collaboration with Jason Wilson, MS – a science educator, natural products researcher, an expert on cannabis and cannabinoid science, and creator of the Curious About Cannabis Podcast.
