The global use of cannabis for both recreational and medical purposes has deep historical origins. Medicinal cannabis has traditionally been used to treat nausea, inflammation, vomiting and pain. The use of cannabis is widespread, with over 147 million people worldwide consuming cannabis annually ). While cannabis regulations for recreational use have traditionally followed the prohibitionist model, Canadian legalization is expected to loosen the barriers to access and research of its potential medicinal and therapeutic benefits.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are two naturally occurring phytocannabinoids found in cannabis. THC is the main psychoactive compound of cannabis and gives users a distinguished "high" feeling, whereas CBD studies have shown it does not have any mind-altering effects. Differences in molecular interactions and structural properties are responsible for the varied pharmacological effects of THC and CBD. Both Δ9-THC and CBD exert their effects by interacting with the receptors of the endocannabinoid system (ECS), CB1 and CB2, with varying affinities.

The ECS plays an integral role in regulatory functions implicated in health and disease as well as in downregulating stress signals that cause pain and inflammation. Endocannabinoid receptors are ubiquitous in the body, and due to their extensive presence, the ECS is referred to as a 'bridge between mind and body. Cutaneously, the role of the ECS is to regulate skin cell proliferation, survival, and differentiation. CB1 receptors are found mainly in the brain and central nervous system and are involved in coordination, movement, pain, memory and mood, whereas CB2 receptors are found mainly in peripheral organs and are linked with reducing inflammation, pain and tissue damage. Differential activation of CB1 and CB2 receptors, whether individually or simultaneously, could lead to varied physiological effects.

The differences in neurological outcomes between THC and CBD may be linked to their contrasting interactions with the CB1 receptor. THC is a potential partial agonist of the CB1 receptor, and it produces its effects through direct binding. CBD, on the other hand, is a negative allosteric modulator of CB1 and it induces a conformational change to inhibit other agonists from binding. The binding of CB1 receptors is also responsible for the antinociceptive activity of THC, which makes it an effective analgesic agent. In addition, THC has been shown to improve food intake and weight gain in wasting conditions such as cancer, Crohn's disease and AIDS, as well as in the treatment of glaucoma, nausea, multiple sclerosis, epilepsy and inflammation in a series of preclinical and clinical studies. CBD, on the other hand, shows immense therapeutic potential without the psychoactive effects of THC. It has shown promise in the treatment of anxiety, epilepsy, schizophrenia, Parkinson's disease, Alzheimer's disease, multiple sclerosis and sleep management. Studies have shown that CBD and THC acting together can be more potent than their individual effects. Oral supplementation of THC alone is not as effective as their combination, which has been shown to significantly relieve neuropathic pain. CBD can also lower the psychoactive effects of THC and thus produce their combined benefits by enhancing THC tolerability.

The bioavailability of cannabinoids differs immensely for different routes of administration. When taken orally, CBD and THC are digested in the stomach and intestines. Further the CBD and THC will undergo first-pass metabolism after digestion. When taken sublingually, they bypass first-pass metabolism, which increases their bioavailabilities. When inhaled, CBD and THC are immediately absorbed through the lungs resulting in a faster response and higher bioavailability in comparison with oral products. When applied topically to the skin, they are absorbed through the epidermis or hair follicles while interacting with receptors to provide localized effects. A common route of administration for recreational purposes is inhalation through smoking as it yields very high concentrations rapidly, but this is not ideal due to risks such as toxicity and loss of activity through combustion. To take advantage of the lungs' efficient drug delivery and avoid the harm associated with smoking, inhalation can be achieved via aerosolization or vaporization. Systemically, the bioavailability of inhaled CBD using these two methods has been reported to be 31%, and the peak plasma concentration was reached within 10 minutes. The terminal half-life of CBD following inhalation was found to be 27-35 hours, following intravenous injection it was 18-33 hours and following oral administration it was 2-5 days. The terminal half-life of THC after inhalation was found to be 21-31 hours and following intravenous injection it was 24 hours. Bioavailability of oral CBD was found to be around 6%, and bioavailability for oral THC was shown to be 4-12%.

The pharmacokinetics of CBD and THC after transdermal administration have not been extensively studied. When applied with the GT4 technology, the CBD and THC are expected to be absorbed through the stratum corneum and other epidermal layers, the basement membrane and into the dermis rapidly. Once in the dermis CBD and THC can enter the capillary bed aided by increased blood flow and then the systemic circulation. In addition to avoiding the negative effects of inhalation, transdermal administration is superior to oral ingestion as this route provides a way to avoid gastrointestinal involvement and first pass metabolism. Further, transdermal delivery may generate more constant plasma levels. It can also be designed for targeted delivery where the IP and specific tissues within the cutaneous ECS can interact. Pharmaceuticals with the GT4 technology have had over 1,000 prescriptions filled in the United States to deliver 10% gabapentin and 5% naproxen sodium for treatment of severe muscular skeletal pain. This technology has allowed physicians to treat severe pain without or with significantly less opioids. To date, no adverse events have been reported.

The objective of this open-label study is to investigate the bioavailability and skin absorption of CBD and THC delivered using GT4 technology in a healthy adult population. Participants will be healthy men and women between the ages of 25-65 and will be occasional cannabis users. They will have used cannabis at least once in the past 6 months and 4 times in their lifetime but no more than 3 times per week. Participants must have experienced psychotropic effects related to cannabis without having severe adverse events. In the area of application, participants must not have received laser hair removal, shaved, or waxed within 14 days or have any acute or chronic skin diseases or dermatological conditions to avoid interfering with the test product. Participants must not be using medicinal cannabis. They must not be receiving any treatments that may confound results, such as prescribed medications, over-the-counter medications, supplements, and food/drinks that will interact with the test product or that contain CBD and THC. Based on the short half lives of CBD and THC, recreational users must refrain from cannabis for 48 hours. The inclusion and exclusion criteria in this study ensure a homogeneous population of participants who are healthy, stable, and have no comorbidities.