A Study to Investigate the Bioavailability and Skin Absorption of CBD and THC From GT4 Technology in Healthy Adults
Condition: Biological Availability; Skin Absorption; CBD; THC
Study type: Interventional
Phase: Phase 1

Summary: 
      The bioavailability of cannabinoids differs greatly for different routes of administration.
      When applied topically to the skin, they are absorbed through the skin or hair follicles
      while interacting with receptors to provide localized effects. To gain more information on
      the potential of this route of administration in therapeutic applications, this open-label
      study will investigate the skin absorption and bioavailability of CBD and THC delivered
      trans-dermally.
    

Detailed description: 
      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.
    

Intervention name(s): CBD and THC with GT4 technology
Intervention type(s): Combination Product
Intervention description(s): A single topical dose of CBD and THC will be administered with GT4 technology. The material will be provided in a single use pre-filled syringe.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: CBD; THC; GT4 Technology