Oral Cannabidiol Effect on Blood Pressure in Hypertensive Patients
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 1

Summary: 
      The objective of this randomized, placebo-controlled and crossover study is to extend the
      findings from the acute studies into more chronic administration of CBD in individuals with
      mild or moderate hypertension who are either untreated or receiving standard care therapy.
      The hypothesis is that the hypotensive effects of CBD will be apparent in both untreated and
      treated hypertension and reflected in improved vascular biomarkers and psychological
      well-being.
    

Detailed description: 
      Research Design A double-blind, placebo-controlled, cross-over pilot study in which 60
      volunteers (aged 40-70 years) will visit to laboratory on six occasions following an
      overnight fast. All participants will provide written informed consent. Eligible participants
      will then be randomized. The sequence of conditions the participant will receive will be
      generated by a research randomizer web-service (https://www.randomizer.org) and participants
      will complete: 1) placebo-control and 2) DehydraTECHTM CBD (225 to 300 mg split over three
      times daily for the initial 2.5 weeks and 375 to 450 mg split over three times for the
      following 2.5 weeks) - see "dosing" below for further details . Following a two-week washout,
      volunteers will then repeat testing for another five weeks under the different condition. The
      study design, implementation and reporting will following the CONSORT guidelines, including
      the 25-item checklist and a flow diagram.

      DehydraTECH is a patented formulation processing technology developed by Lexaria Bioscience
      Corp. that has been shown to enhance the performance of lipophilic beneficial compounds in
      oral ingestible products by way of increased rate and extent of intestinal bioabsorption and
      systemic uptake. DehydraTECH formulations have been prepared with a range of lipophilic
      molecules of interest and administered orally to animals and/or humans to investigate
      pharmacokinetic and pharmacodynamic performance attributes. For example, in young healthy
      humans, DehydraTECH technology has been studied in an oral CBD formulation and shown to
      result in higher and more rapid levels of delivery that was reflected in lower blood pressure
      when compared to positive controls with matching CBD concentrations (Patrician et al., 2019).
      Moreover, in volunteers with pre-hypertension, there were significant reductions in systolic,
      mean arterial blood pressure and arterial stiffness over an ambulatory 24-hr monitoring
      period following administration of oral DehydraTECH2.0 (150 mgs per 8 hours totalling 450
      mgs) when compared to placebo. The DehydraTECH2.0 CBD was well tolerated with no ill-reported
      effects.

      Both researchers and subjects will be blinded to the performed conditions on testing days by
      having a research associate who is not involved in any other aspect of the study supply the
      capsules according to the randomization schedule. When reporting to the laboratory in the
      morning will be in the fasted state (no food or drinks for at least 10 hours).

      Visit 1 - Screening

      On the initial visit potential participants will read through the information and consent
      form, ask any questions, and provide written informed consent. Following informed consent the
      participants will complete a customized Medical and Health Status Questionnaire that will be
      used to assess inclusion/exclusion criteria and prior history of medical conditions.
      Thereafter, the following questionnaires will be completed: Memory Assessment Clinic
      questionnaire(MAC-Q); Beck Anxiety Inventory (BAI); Perceived Stress Scale Questionnaire
      (PSS); Short Form 36 Health Survey Questionnaire (SF-36); Beck Depression Inventory (BDI);
      Global Physical Activity Questionnaire (GPAQ); State trait Anxiety Inventory (STAI); Big Life
      sodium calculator (BLSC). Sleep Questionnaires, including the Pittsburgh Sleep Quality Index
      (PSQI) and Epworth Sleepiness Scale (ESS); and the;); Stop-Bang Questionnaire (S-BANG).

      Anthropometric and physiologic measurements will be collected (height, body weight, waist
      circumferences, bio-electrical impedance, blood pressure) for baseline participant
      characterization. After the completion of the screening procedures, the participants will be
      randomly assigned to one of the two experimental groups. Following randomization,
      participants will undergo first set of physiological, neuroimaging, sleep, and cognitive
      factors and will complete several lifestyle and psychological questionnaires. This battery of
      assessments will be completed again following either week 2.5 of week 5 before the washout
      period begins.

      All subjects will be instructed to keep a food and physical-activity diary in the 24 h
      preceding the first laboratory visit and asked to replicate food consumption and physical
      activity as much as possible in the 24 h preceding subsequent visits. Subjects will be
      instructed to refrain from caffeine and alcohol-containing drinks for 6 and 12 h before each
      laboratory visit, respectively

      Visit 2, 3 & 4 - Experimental Trials

      The second visit will be scheduled at least 24 hours after the first visit to the laboratory
      and will require participants to be in the laboratory for <2 hours. Participants will report
      to the laboratory after an overnight fast (>10 hours) and around 07:30. Water intake will be
      measured and allowed ad-lib.

      Dosing: For the initial 2.5 weeks, oral DehydraTECHTM CBD or the placebo control will be
      administered in the following doses during approx. 8-hr intervals for: a) males or females
      (who weigh>75 kg); 75mg at ~08:00, 75mg ~14:00 and 150mg ~22:00, total 300mg), b) males or
      females who weigh <75kg; (75mg at ~08:00, 75mg ~14:00 and 75mg ~22:00, total 225mg). For the
      final 2.5 weeks, upon confirmation of normal blood chemistry, the following doses during
      approx. 8-hr intervals for: a) males or females who weigh <100 kg; 75mg at ~8:00, 150 mg
      ~14:00 and 150mg ~22:00, total 375mg), b) males or females who weigh >100kg; (150 mg at
      ~8:00, 150 mg ~14:00 and 150mg ~22:00, total 450mg). The DehydraTECHTM CBD or the placebo
      control will be administered ~30 mins following consumption of a meal (to aid absorption).
      The timing of this dosing will be recorded by each subject and continue each day for the
      5-week study duration. If a dose is missed, the subject will contact a member of the research
      team. he final daily dose (450 mg) will be the maximal dose approx. equally to 4.5 mg/kg/day.
      This dose is 2-4-fold less than the reported 1500mg/kg/day of CBD (or 10-20mg/kg/day) in the
      recent Phase 1 trial by Watkins and colleagues that revealed peak serum alanine
      aminotransferase values were above the upper limit of normal in 7 (44%) out of the 16
      participants and exceeded international criteria for drug-induced liver injury in 5 (31%) of
      these participants (Watkins et al., 2021). The most common all-causality adverse events AEs
      by preferred term were gastrointestinal disorders, including diarrhea in eight (50%)
      participants and abdominal discomfort in five (31%) participants. Most of these AEs were
      first experienced during the CBD titration phase. AEs mild (31%) or moderate (50%) in
      severity.

      Dosing diary and contingency for missed dosing: Each subject will be provided with a diary to
      confirm the timing of each daily dose of the CBD or placebo capsules. In the event of a
      missed dose, a maximum of one capsule (75mg) will be added to the next dose. The safety (lack
      of AEs) of acute dosing of 300 mg DehydraTECH2.0 CBD has been established; and previous
      studies have used much higher acute dosing without reports of related AEs (Sultan et al.,
      2020)

      The 24-hour food log will be reviewed and a copy will be provided to subjects who will be
      asked to repeat the diet 24 hours before the following visit as closely as possible. Subjects
      will be reminded to not perform exercise or to consume alcohol 24 hours prior to the next
      visit. Subjects will return fasted to the laboratory approx. 17±2 days (~2.5 weeks) and 35±2
      days (~5 weeks) after the second visit. Adherence to the 24-hour diet will be confirmed upon
      arrival in the laboratory and the snacks will be provided for each session. The subjects
      "dosing diary" will also be returned. Subjects will be instructed to identify any deviations
      in diet or dosing (from the food log and dairy) before beginning the previous trial.

      Following the initial blood sample and questionnaires, subjects will then be instrumented
      with the 24-hour ambulatory blood pressure monitor (ABPM; TM-2430) that will be used to
      assess continuous blood pressure measurements away from the laboratory. The device will be
      set to take measurements every 30 minutes through the day (08:30-23:00) and every hour
      through the night (23:00-8:00). Subjects will be also instrumented with 24-hour ECG monitor.
      Subjects will also be asked to wear a Fitbit activity and sleep monitor (Fitbit Inc, San
      Francisco, CA, USA). This is a wrist-based device with a large organic light-emitting diode
      screen featuring heartrate monitoring and tracking of steps, distance, calories burned,
      floors climbed, active minutes, and sleep duration. The protocol will be the same as the
      other visit. Following the last visit and a 2-3 week washout period, subjects will receive
      one of the other two conditions.

      Sample size Preliminary estimates of the effect sizes for improvement (lowering) of 24-hr
      ambulatory blood pressure following DehydraTECH2.0 are based on the results of the
      investigators' previous acute study that used similar active intervention and outcomes. This
      study will recruit a total of 70 participants, which will include a split of those who are
      either untreated or receiving standard care antihypertensive therapy. This power calculation,
      which is based on a sample size calculation formula for a mixed model for repeated measures
      data with attrition (Lu et al., 2008), provides 80% power to detect 0.4 standard deviation
      between-group difference for an average repeated measurement correlation of 0.6 and three
      repeated measurements, taking 20% attrition into consideration.

      Statistical Analysis Continuous variables will be summarized with means ± standard deviation
      (SD) and/or 95% confidence intervals. Data will be analyzed for repeated measures analysis
      using either general or mixed linear models (with sex, body mass, medication and age as a
      co-variates). Significance will be set at 5% alpha and analyses will be calculated by SPSS
      version 21 software (IBM, Chicago, IL). A final analysis plan, which includes analyses of the
      secondary outcomes and strategies for handling missing/incomplete data, will be formalized by
      the biostatistician prior to breaking the blind. The data analysis will only begin once data
      collection is complete.

      Significance The results of this study will help determine the effectiveness of Lexaria CBD
      technology as a novel anti-hypertensive agent, both in isolation and in combination with
      standard care therapy. Understanding new approaches to CBD delivery has major implications
      for more precise recommendations of CBD usage in health and disease states.
    

Intervention name(s): Cannabidiol; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Cannabidiol tablets; Cannabidiol-matched placebo tablets
Intervention MeSH terms: Cannabidiol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: hypertension; cannabidiol; arterial stiffness