Cannabis (Cannabis sativa)
A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray
CSV
JSON
Purpose To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/can- nabidiol (CBD) spray, an endocannabinoid system modula- tor, when administered to healthy male subjects.
Methods Twelve subjects took part in this fed–fasted cross- over study and received a single dose of THC/CBD spray (4 sprays 0 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time- points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC).
Results Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80– 14.91 ng/ml) and lower in 5 subjects (2.81–3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97– 9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0–t), AUC(0–inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2–2.5 h. Only mild adverse events were reported.
Conclusions The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.
1 . Plasma Concentration of THC when Fasting (id=NPDI-I4ebig)
In Vivo Pharmacokinetics Study
Table 1
Results
Values from Table 1.
The following values are from the fed state (Figure 1a and Table 1):
Cmax: 6.2 ± 1.3 ng/mL
AUC(0-inf): 34.99 (16.41) h*ng/mL
AUC(0-t): 32.7 (16.75) h*ng/mL
CL/F: 403 (261) L/h
t1/2: 3.58 (1.6) h
tmax: 4 (2-4.08) h
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Randomized crossover
Single dosing
Healthy volunteers
Males
No alcohol drinking
No marijuana use
Nonsmokers
Asian
Black or African American
White
12
Subjects were 19 to 44 years of age with a mean (SD) age of 28.5 (7.55) years. Subjects’ BMI ranged from 18 to 28 kg/m2 with a mean (SD) BMI of 24.8 (2.99) kg/m2 and a mean (SD) bodyweight of 74.02 (11.25) kg at screening. Of the 12 subjects who took part, 8 were white/Caucasian, 2 were black/African–American and 2 were Asian in ethnicity. All subjects were considered healthy at screening and admission and the investigator did not consider any of the reported medical history abnormalities to preclude the participation of any of the subjects who entered into the trial. Additionally, all subjects tested negative for CBs during screening and at admission.
0, 3, 6, 9, 12, 15, 21, 24 h
Drug or Natural Product Administration
Oral
Oromucosal spray
10 mg THC + 10 mg CBD
Fasted
Once
Not provided
The THC/CBD spray is a solution containing ethanol, propylene glycol and peppermint oil flavouring for oromucosal use through a sealed pump-action spray device, which was delivered either underneath the tongue, or to the inside of the cheek.
Pharmacodynamics (PD) & Adverse Events
At each visit (during each session) the incidence of adverse events (AEs) was recorded. Laboratory parameters, vital signs, physical examination, oral examination, and checks on concomitant medication were also performed. The reference ranges for vital signs were 34–100 bpm for standing pulse rate, 90–160 mmHg for standing systolic blood pressure and 40–100 mmHg for standing diastolic blood pressure. A clinically significant change was defined as a change from baseline of at least 20 mmHg in systolic blood pressure, of 10 mmHg in diastolic blood pressure and of 10 bpm in pulse rate.
Cardiac disorders
35200000
Fed (no. of events, n=12)
Nervous system disorders:
Dizziness 3
Paraesthesia 1
Somnolence 1
Psychiatric disorders:
Daydreaming 1
Dissociation 0
Euphoric mood 1
Inappropriate effect 1
Metabolism and nutrition disorders: Increased appetite 1
Respiratory, thoracic and mediastinal disorders: Dry throat 1
Injury, poisoning and procedural complications: Procedural site reaction 1
Fasted (no. of events, n=12)
Somnolence 1
Feeling abnormal 1
General disorders and administration site conditions
35800000
Injury, poisoning and procedural complications
36200000
Metabolism and nutrition disorders
36400000
Nervous system disorders
36700000
Psychiatric disorders
36900000
Respiratory, thoracic and mediastinal disorders
37200000
No serious AEs (SAEs) were reported during the course of this study, and all AEs were classified as being mild in severity. All AEs occurring in one or more subjects are presented in Table 3. The most common AE was dizziness in 3 fed subjects. Four AEs were reported by 2 fasted subjects (17%) and 11 AEs were reported by 7 fed subjects (58%), suggesting that THC/CBD spray might be better tolerated by subjects under fasted conditions. However, there was no apparent relationship between the occurrence of AEs and the PKs in these subjects. In the subjects who experienced an AE in the fed state, the Cmax for THC was higher than in the fasted state in 3 subjects, but was lower than in the fasted state in 4 subjects.
2 . Plasma Concentration of 11-OH-THC when Fed (id=NPDI-37uQKw)
In Vivo Pharmacokinetics Study
Table 1
This studies the active metabolite of THC
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Randomized crossover
Single dosing
Healthy volunteers
Males
No alcohol drinking
No marijuana use
Nonsmokers
Asian
Black or African American
White
12
Subjects were 19 to 44 years of age with a mean (SD) age of 28.5 (7.55) years. Subjects’ BMI ranged from 18 to 28 kg/m2 with a mean (SD) BMI of 24.8 (2.99) kg/m2 and a mean (SD) bodyweight of 74.02 (11.25) kg at screening. Of the 12 subjects who took part, 8 were white/Caucasian, 2 were black/African–American and 2 were Asian in ethnicity. All subjects were considered healthy at screening and admission and the investigator did not consider any of the reported medical history abnormalities to preclude the participation of any of the subjects who entered into the trial. Additionally, all subjects tested negative for CBs during screening and at admission.
0, 3, 6, 9, 12, 15, 21, 24 h
Drug or Natural Product Administration
Oral
Oromucosal spray
10 mg THC + 10 mg CBD
Fed
Once
Not provided
The THC/CBD spray is a solution containing ethanol, propylene glycol and peppermint oil flavouring for oromucosal use through a sealed pump-action spray device, which was delivered either underneath the tongue, or to the inside of the cheek.
Pharmacodynamics (PD) & Adverse Events
At each visit (during each session) the incidence of adverse events (AEs) was recorded. Laboratory parameters, vital signs, physical examination, oral examination, and checks on concomitant medication were also performed. The reference ranges for vital signs were 34–100 bpm for standing pulse rate, 90–160 mmHg for standing systolic blood pressure and 40–100 mmHg for standing diastolic blood pressure. A clinically significant change was defined as a change from baseline of at least 20 mmHg in systolic blood pressure, of 10 mmHg in diastolic blood pressure and of 10 bpm in pulse rate.
Cardiac disorders
35200000
Fed (no. of events, n=12)
Nervous system disorders:
Dizziness 3
Paraesthesia 1
Somnolence 1
Psychiatric disorders:
Daydreaming 1
Dissociation 0
Euphoric mood 1
Inappropriate effect 1
Metabolism and nutrition disorders: Increased appetite 1
Respiratory, thoracic and mediastinal disorders: Dry throat 1
Injury, poisoning and procedural complications: Procedural site reaction 1
Fasted (no. of events, n=12)
Somnolence 1
Feeling abnormal 1
General disorders and administration site conditions
35800000
Injury, poisoning and procedural complications
36200000
Metabolism and nutrition disorders
36400000
Nervous system disorders
36700000
Psychiatric disorders
36900000
Respiratory, thoracic and mediastinal disorders
37200000
No serious AEs (SAEs) were reported during the course of this study, and all AEs were classified as being mild in severity. All AEs occurring in one or more subjects are presented in Table 3. The most common AE was dizziness in 3 fed subjects. Four AEs were reported by 2 fasted subjects (17%) and 11 AEs were reported by 7 fed subjects (58%), suggesting that THC/CBD spray might be better tolerated by subjects under fasted conditions. However, there was no apparent relationship between the occurrence of AEs and the PKs in these subjects. In the subjects who experienced an AE in the fed state, the Cmax for THC was higher than in the fasted state in 3 subjects, but was lower than in the fasted state in 4 subjects.
3 . Plasma Concentration of CBD when Fasting (id=NPDI-hnUjdg)
In Vivo Pharmacokinetics Study
Table 1
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Randomized crossover
Single dosing
Healthy volunteers
Males
No alcohol drinking
No marijuana use
Nonsmokers
Asian
Black or African American
White
12
Subjects were 19 to 44 years of age with a mean (SD) age of 28.5 (7.55) years. Subjects’ BMI ranged from 18 to 28 kg/m2 with a mean (SD) BMI of 24.8 (2.99) kg/m2 and a mean (SD) bodyweight of 74.02 (11.25) kg at screening. Of the 12 subjects who took part, 8 were white/Caucasian, 2 were black/African–American and 2 were Asian in ethnicity. All subjects were considered healthy at screening and admission and the investigator did not consider any of the reported medical history abnormalities to preclude the participation of any of the subjects who entered into the trial. Additionally, all subjects tested negative for CBs during screening and at admission.
0, 3, 6, 9, 12, 15, 21, 24 h
Drug or Natural Product Administration
Oral
Oromucosal spray
10 mg THC + 10 mg CBD
Fasted
Once
Not provided
The THC/CBD spray is a solution containing ethanol, propylene glycol and peppermint oil flavouring for oromucosal use through a sealed pump-action spray device, which was delivered either underneath the tongue, or to the inside of the cheek.
Pharmacodynamics (PD) & Adverse Events
At each visit (during each session) the incidence of adverse events (AEs) was recorded. Laboratory parameters, vital signs, physical examination, oral examination, and checks on concomitant medication were also performed. The reference ranges for vital signs were 34–100 bpm for standing pulse rate, 90–160 mmHg for standing systolic blood pressure and 40–100 mmHg for standing diastolic blood pressure. A clinically significant change was defined as a change from baseline of at least 20 mmHg in systolic blood pressure, of 10 mmHg in diastolic blood pressure and of 10 bpm in pulse rate.
Cardiac disorders
35200000
Fed (no. of events, n=12)
Nervous system disorders:
Dizziness 3
Paraesthesia 1
Somnolence 1
Psychiatric disorders:
Daydreaming 1
Dissociation 0
Euphoric mood 1
Inappropriate effect 1
Metabolism and nutrition disorders: Increased appetite 1
Respiratory, thoracic and mediastinal disorders: Dry throat 1
Injury, poisoning and procedural complications: Procedural site reaction 1
Fasted (no. of events, n=12)
Somnolence 1
Feeling abnormal 1
General disorders and administration site conditions
35800000
Injury, poisoning and procedural complications
36200000
Metabolism and nutrition disorders
36400000
Nervous system disorders
36700000
Psychiatric disorders
36900000
Respiratory, thoracic and mediastinal disorders
37200000
No serious AEs (SAEs) were reported during the course of this study, and all AEs were classified as being mild in severity. All AEs occurring in one or more subjects are presented in Table 3. The most common AE was dizziness in 3 fed subjects. Four AEs were reported by 2 fasted subjects (17%) and 11 AEs were reported by 7 fed subjects (58%), suggesting that THC/CBD spray might be better tolerated by subjects under fasted conditions. However, there was no apparent relationship between the occurrence of AEs and the PKs in these subjects. In the subjects who experienced an AE in the fed state, the Cmax for THC was higher than in the fasted state in 3 subjects, but was lower than in the fasted state in 4 subjects.
4 . Plasma Concentration of 11-OH-THC when Fasting (id=NPDI-csAo1g)
In Vivo Pharmacokinetics Study
Table 1
This studies the active metabolite of THC
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Randomized crossover
Single dosing
Healthy volunteers
Males
No alcohol drinking
No marijuana use
Nonsmokers
Asian
Black or African American
White
12
Subjects were 19 to 44 years of age with a mean (SD) age of 28.5 (7.55) years. Subjects’ BMI ranged from 18 to 28 kg/m2 with a mean (SD) BMI of 24.8 (2.99) kg/m2 and a mean (SD) bodyweight of 74.02 (11.25) kg at screening. Of the 12 subjects who took part, 8 were white/Caucasian, 2 were black/African–American and 2 were Asian in ethnicity. All subjects were considered healthy at screening and admission and the investigator did not consider any of the reported medical history abnormalities to preclude the participation of any of the subjects who entered into the trial. Additionally, all subjects tested negative for CBs during screening and at admission.
0, 3, 6, 9, 12, 15, 21, 24 h
Drug or Natural Product Administration
Oral
Oromucosal spray
10 mg THC + 10 mg CBD
Fasted
Once
Not provided
The THC/CBD spray is a solution containing ethanol, propylene glycol and peppermint oil flavouring for oromucosal use through a sealed pump-action spray device, which was delivered either underneath the tongue, or to the inside of the cheek.
Pharmacodynamics (PD) & Adverse Events
At each visit (during each session) the incidence of adverse events (AEs) was recorded. Laboratory parameters, vital signs, physical examination, oral examination, and checks on concomitant medication were also performed. The reference ranges for vital signs were 34–100 bpm for standing pulse rate, 90–160 mmHg for standing systolic blood pressure and 40–100 mmHg for standing diastolic blood pressure. A clinically significant change was defined as a change from baseline of at least 20 mmHg in systolic blood pressure, of 10 mmHg in diastolic blood pressure and of 10 bpm in pulse rate.
Cardiac disorders
35200000
Fed (no. of events, n=12)
Nervous system disorders:
Dizziness 3
Paraesthesia 1
Somnolence 1
Psychiatric disorders:
Daydreaming 1
Dissociation 0
Euphoric mood 1
Inappropriate effect 1
Metabolism and nutrition disorders: Increased appetite 1
Respiratory, thoracic and mediastinal disorders: Dry throat 1
Injury, poisoning and procedural complications: Procedural site reaction 1
Fasted (no. of events, n=12)
Somnolence 1
Feeling abnormal 1
General disorders and administration site conditions
35800000
Injury, poisoning and procedural complications
36200000
Metabolism and nutrition disorders
36400000
Nervous system disorders
36700000
Psychiatric disorders
36900000
Respiratory, thoracic and mediastinal disorders
37200000
No serious AEs (SAEs) were reported during the course of this study, and all AEs were classified as being mild in severity. All AEs occurring in one or more subjects are presented in Table 3. The most common AE was dizziness in 3 fed subjects. Four AEs were reported by 2 fasted subjects (17%) and 11 AEs were reported by 7 fed subjects (58%), suggesting that THC/CBD spray might be better tolerated by subjects under fasted conditions. However, there was no apparent relationship between the occurrence of AEs and the PKs in these subjects. In the subjects who experienced an AE in the fed state, the Cmax for THC was higher than in the fasted state in 3 subjects, but was lower than in the fasted state in 4 subjects.
5 . Plasma Concentration of CBD when Fed (id=NPDI-wx2mcg)
In Vivo Pharmacokinetics Study
(Table 1)
Results
Results from Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Randomized crossover
Single dosing
Healthy volunteers
Males
No alcohol drinking
No marijuana use
Nonsmokers
Asian
Black or African American
White
12
Subjects were 19 to 44 years of age with a mean (SD) age of 28.5 (7.55) years. Subjects’ BMI ranged from 18 to 28 kg/m2 with a mean (SD) BMI of 24.8 (2.99) kg/m2 and a mean (SD) bodyweight of 74.02 (11.25) kg at screening. Of the 12 subjects who took part, 8 were white/Caucasian, 2 were black/African–American and 2 were Asian in ethnicity. All subjects were considered healthy at screening and admission and the investigator did not consider any of the reported medical history abnormalities to preclude the participation of any of the subjects who entered into the trial. Additionally, all subjects tested negative for CBs during screening and at admission.
0, 3, 6, 9, 12, 15, 21, 24 h
Drug or Natural Product Administration
Oral
Oromucosal spray
10.8 mg THC + 10 mg CBD
Fed
Standardized meals
Once
Not specified
The THC/CBD spray is a solution containing ethanol, propylene glycol and peppermint oil flavouring for oromucosal use through a sealed pump-action spray device, which was delivered either underneath the tongue, or to the inside of the cheek.
Pharmacodynamics (PD) & Adverse Events
At each visit (during each session) the incidence of adverse events (AEs) was recorded. Laboratory parameters, vital signs, physical examination, oral examination, and checks on concomitant medication were also performed. The reference ranges for vital signs were 34–100 bpm for standing pulse rate, 90–160 mmHg for standing systolic blood pressure and 40–100 mmHg for standing diastolic blood pressure. A clinically significant change was defined as a change from baseline of at least 20 mmHg in systolic blood pressure, of 10 mmHg in diastolic blood pressure and of 10 bpm in pulse rate.
Cardiac disorders
35200000
Fed (no. of events, n=12)
Nervous system disorders:
Dizziness 3
Paraesthesia 1
Somnolence 1
Psychiatric disorders:
Daydreaming 1
Dissociation 0
Euphoric mood 1
Inappropriate effect 1
Metabolism and nutrition disorders: Increased appetite 1
Respiratory, thoracic and mediastinal disorders: Dry throat 1
Injury, poisoning and procedural complications: Procedural site reaction 1
Fasted (no. of events, n=12)
Somnolence 1
Feeling abnormal 1
General disorders and administration site conditions
35800000
Injury, poisoning and procedural complications
36200000
Metabolism and nutrition disorders
36400000
Nervous system disorders
36700000
Psychiatric disorders
36900000
Respiratory, thoracic and mediastinal disorders
37200000
No serious AEs (SAEs) were reported during the course of this study, and all AEs were classified as being mild in severity. All AEs occurring in one or more subjects are presented in Table 3. The most common AE was dizziness in 3 fed subjects. Four AEs were reported by 2 fasted subjects (17%) and 11 AEs were reported by 7 fed subjects (58%), suggesting that THC/CBD spray might be better tolerated by subjects under fasted conditions. However, there was no apparent relationship between the occurrence of AEs and the PKs in these subjects. In the subjects who experienced an AE in the fed state, the Cmax for THC was higher than in the fasted state in 3 subjects, but was lower than in the fasted state in 4 subjects.
6 . Plasma Concentration of THC when Fed (id=NPDI-px3AyQ)
In Vivo Pharmacokinetics Study
Table 1
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Randomized crossover
Single dosing
Healthy volunteers
Males
No alcohol drinking
No marijuana use
Nonsmokers
Asian
Black or African American
White
12
Subjects were 19 to 44 years of age with a mean (SD) age of 28.5 (7.55) years. Subjects’ BMI ranged from 18 to 28 kg/m2 with a mean (SD) BMI of 24.8 (2.99) kg/m2 and a mean (SD) bodyweight of 74.02 (11.25) kg at screening. Of the 12 subjects who took part, 8 were white/Caucasian, 2 were black/African–American and 2 were Asian in ethnicity. All subjects were considered healthy at screening and admission and the investigator did not consider any of the reported medical history abnormalities to preclude the participation of any of the subjects who entered into the trial. Additionally, all subjects tested negative for CBs during screening and at admission.
0, 3, 6, 9, 12, 15, 21, 24 h
Drug or Natural Product Administration
Oral
Oromucosal spray
10.8 mg THC + 10 mg CBD
Fed
Once
Not provided
The THC/CBD spray is a solution containing ethanol, propylene glycol and peppermint oil flavouring for oromucosal use through a sealed pump-action spray device, which was delivered either underneath the tongue, or to the inside of the cheek.
Pharmacodynamics (PD) & Adverse Events
At each visit (during each session) the incidence of adverse events (AEs) was recorded. Laboratory parameters, vital signs, physical examination, oral examination, and checks on concomitant medication were also performed. The reference ranges for vital signs were 34–100 bpm for standing pulse rate, 90–160 mmHg for standing systolic blood pressure and 40–100 mmHg for standing diastolic blood pressure. A clinically significant change was defined as a change from baseline of at least 20 mmHg in systolic blood pressure, of 10 mmHg in diastolic blood pressure and of 10 bpm in pulse rate.
Cardiac disorders
35200000
Fed (no. of events, n=12)
Nervous system disorders:
Dizziness 3
Paraesthesia 1
Somnolence 1
Psychiatric disorders:
Daydreaming 1
Dissociation 0
Euphoric mood 1
Inappropriate effect 1
Metabolism and nutrition disorders: Increased appetite 1
Respiratory, thoracic and mediastinal disorders: Dry throat 1
Injury, poisoning and procedural complications: Procedural site reaction 1
Fasted (no. of events, n=12)
Somnolence 1
Feeling abnormal 1
General disorders and administration site conditions
35800000
Injury, poisoning and procedural complications
36200000
Metabolism and nutrition disorders
36400000
Nervous system disorders
36700000
Psychiatric disorders
36900000
Respiratory, thoracic and mediastinal disorders
37200000
No serious AEs (SAEs) were reported during the course of this study, and all AEs were classified as being mild in severity. All AEs occurring in one or more subjects are presented in Table 3. The most common AE was dizziness in 3 fed subjects. Four AEs were reported by 2 fasted subjects (17%) and 11 AEs were reported by 7 fed subjects (58%), suggesting that THC/CBD spray might be better tolerated by subjects under fasted conditions. However, there was no apparent relationship between the occurrence of AEs and the PKs in these subjects. In the subjects who experienced an AE in the fed state, the Cmax for THC was higher than in the fasted state in 3 subjects, but was lower than in the fasted state in 4 subjects.