Cannabis L. (Cannabis sativa)
Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans CSV JSON

Objectives — Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects.

Methods — This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured.

Results — SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions.

Conclusions — CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.

1 . Plasma CBD Concentrations (id=NPDI-UlPhZQ)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

fentanyl

cannabidiol

(Figure 2)

Results

Value reported estimated at 3 hours with 800 mg CBD (original value reported = ~170 µg/L)
With 400 mg CBD, Cmax mean ± SEM ~ 140 µg/L ± 20 µg/L
Values above converted to ng/mL.
CBD+placebo led to 0 µg/Lconcentration throughout the 8 hours collected.
(Figure 2)

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Biphasic with at least one week interim.
(Figure 1)

Double-blind
Placebo-controlled
Randomized crossover

Population

Healthy volunteers

Healthy alcohol drinking
No marijuana use
Nonsmokers
Smokers

12

Healthy volunteers were recruited through advertisement in the community and local newspapers and assigned a unique identification number. Inclusion Criteria: past exposure at least once to an opioid (i.e. codeine, morphine, fentanyl); and aged between 21 and 65 years. Exclusion Criteria: using any psychoactive drug at any time during the study; current diagnosis of drug dependence (except nicotine dependence) based on Structured Clinical Interview for DSM-IV (SCID-IV) interview; history of cardiac disease, arrhythmias, head trauma, seizures, or Axis I psychiatric conditions under DSM-IV examined with the Mini International Neuropsychiatric Interview-MINI; hypersensitivity to any opioid or cannabinoid; pregnant or breastfeeding; not using an appropriate method of contraception; or intoxication at the time of arrival on the site of the study or positive drug screen (screened for cocaine, cannabis, opiates, benzodiazepines, barbiturates, phencyclidine, amphetamines). Subjects were compensated $150 per session and $10 for screening; compensation was determined based on minimum wage, hours required for study participation and transportation fees. We enrolled 6 subjects per study group similar to CBD studies using the same dose range in healthy subjects (Crippa et al., 2004).

Pharmacokinetic (PK) Sampling Information

Blood: -10 min, 30 min, 90 min, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr; Urine: -2 hr, 30 min, 2 hr, 4 hr, 6 hr, 8 hr

Provided standardized meal

Blood and urine: 1 hr, 3 hr, 5 hr, 7 hr post-administration of fentanyl

Provided standardized meal

Drug or Natural Product Administration

Object Administration — fentanyl

Oral

Capsule

400 mg or 800 mg

Once per session, dose dependent on group

Precipitant Administration — cannabidiol

Intravenous

Solution

0.5 or 1 mcg/kg

Once per session, dose dependent on group

Natural Product Characteristics

Not provided

Pharmacodynamics (PD) & Adverse Events

Clinical monitoring of vital signs (temperature, heart rate, respiratory rate, blood pressure, oxygen saturation) occurred continuously and was analyzed at time points according to Figure 1 using AUC between groups. 

Cardiac disorders 35200000
Respiratory, thoracic and mediastinal disorders 37200000

There were no occurrences of respiratory depression (breaths/min <12) or cardiovascular compromise (mean arterial pressure <60mmHg, heart rate >100) in any subject at any time point. Higher fentanyl dose (1.0 vs. 0.5 mcg/kg) was associated with slightly lower respiratory rate and temperature (mean AUC t-test p<0.05), however, cardiovascular parameters were similar between sessions (p=NS). CBD dose (0 vs. 400 vs. 800mg) was not associated with any significant differences in vital sign parameters throughout the study (mean AUC ANOVA p=NS for all).

Respiratory, thoracic and mediastinal disorders 37200000