Original Papers

Heat Exposure of Cannabis sativa Extracts Affects the Pharmacokinetic and Metabolic Profile in Healthy Male Subjects

Authors

Martin Eichler 1*, Luca Spinedi 1*, Sandra Unfer-Grauwiler 1, Michael Bodmer 1, Christian Surber 2, Markus Luedi 3, Juergen Drewe 1

Affiliations

1

3

Key words " Cannabis sativa L. l " Cannabaceae l " tetrahydrocannabinol l " THC l " THC metabolites l " CBD l " pharmacokinetics l

Departments of Clinical Pharmacology and Gastroenterology & Hepatology, University Hospital Basel, Basel, Switzerland Institute for Hospital Pharmacy, University Hospital Basel, Basel, Switzerland Cannapharm Ltd., Burgdorf, Switzerland

Abstract !

The most important psychoactive constituent of Cannabis sativa L. is Δ9-tetrahydrocannabinol (THC). Cannabidiol (CBD), another important constituent, is able to modulate the distinct unwanted psychotropic effect of THC. In natural plant extracts of C. sativa, large amounts of THC and CBD appear in the form of THCA‑A (THC-acid-A) and CBDA (cannabidiolic acid), which can be transformed to THC and CBD by heating. Previous reports of medicinal use of cannabis or cannabis preparations with higher CBD/THC ratios and use in its natural, unheated form have demonstrated that pharmacological effects were often accompanied with a lower rate of adverse effects. Therefore, in the present study, the pharmacokinetics and metabolic profiles of two different C. sativa extracts (heated and unheated) with a CBD/THC ratio > 1 were compared to synthetic THC (dro-

Introduction ! received revised accepted

January 2, 2012 February 6, 2012 February 10, 2012

Bibliography DOI http://dx.doi.org/ 10.1055/s-0031-1298334 Published online Planta Med © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943 Correspondence Prof. Juergen Drewe, MD, MSc Department of Gastroenterology & Hepatology University Hospital Basel Petersgraben 4 4031 Basel Switzerland Phone: + 41 7 89 23 27 44 Fax: + 41 61 2 65 85 81 [email protected]

The use of cannabinoids in several clinical indications is currently under evaluation [1–6]. The most active agent of Cannabis sativa L. (Cannabaceae) is Δ9-tetrahydrocannabinol (THC). When ingested orally, the bioavailability of C. sativa is relatively low compared to inhalation due to a high first pass metabolism in the liver (25–30 %). The onset of psychoactive effects (initial and peak response) depends on the route of administration and varies between 30 min to 4 hours [7–9]. The duration of the effect after oral administration is prolonged due to continued slow reabsorption from the gut [10] and could be, for a single dose administered orally, 4–6 hours [7, 8]. The effects as an appetite stimulant as well as psychomotoric

* These authors contributed equally to the work.

nabinol) in a double-blind, randomized, single center, three-period cross-over study involving 9 healthy male volunteers. The pharmacokinetics of the cannabinoids was highly variable. The metabolic pattern was significantly different after administration of the different forms: the heated extract showed a lower median THC plasma AUC24 h than the unheated extract of 2.84 vs. 6.59 pmol h/mL, respectively. The later was slightly higher than that of dronabinol (4.58 pmol h/mL). On the other hand, the median sum of the metabolites (THC, 11-OH‑THC, THCCOOH, CBN) plasma AUC24 h was higher for the heated than for the unheated extract. The median CBD plasma AUC24 h was almost 2-fold higher for the unheated than for the heated extract. These results indicate that use of unheated extracts may lead to a beneficial change in metabolic pattern and possibly better tolerability.

and cognitive effects endure for 24 hours or even longer periods, respectively [11, 12]. The most important cannabinoids in C. sativa plants are Δ9-tetrahydrocannabinol (THC), Δ8-tetrahydrocannabinol, cannabinol (CBN), cannabidiol (CBD), Δ9-tetrahydrocannabinolic acid A (THCA‑A) " Fig. 1) [13] and cannabidiolic acid (CBDA). (l THC is preferentially taken up by fatty tissues reaching peak concentrations in 4–5 days [11], from where it is slowly released back into the bloodstream [14, 15]. Due to accumulation in fatty tissue, terminal elimination half-life of THC is up to 7 days, and complete elimination of a single dose can take up to 30 days [16]. Metabolism of THC takes place in the liver and potentially in the gut wall. Because of the sequestration in fatty tissue there is a poor relationship between plasma or urine concentrations and degree of cannabinoidinduced effects. Following oral administration, THC is rapidly hydroxylated to its major metabo-

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Original Papers

Fig. 1

Main metabolic pathways of THC.

Structural formulas of important herbal cannabinoids.

lite, 11-OH-Δ9tetrahydrocannabinol (11-OH‑THC), which is more potent than THC and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) [17]. The latter two metabolites are further conju" Fig. 2) and excreted into feces and urine [18, 19]. The acgated (l id derivatives of THC are devoid of psychotropic effects and do not bind to cannabis CB1 and CB2 receptors, although they possess some anti-inflammatory action [20]. In naturally grown C. sativa, up to 95 % of the occurring cannabinoids are in the form of THCA‑A and CBDA. By heating to 200– 210 °C for 5 minutes, they are quantitatively decarboxylized to phenolic THC [21] and CBD, respectively. Although THCA‑A is described as pharmacologically inactive [22], reports of popular medicinal use of unheated cannabis or cannabis preparations show pharmacological effects often accompanied with a lower rate of adverse effects (anecdotal reports). It also possesses some anti-inflammatory and analgesic effects [20]. Recently, it was shown that unheated cannabis extract was able to inhibit tumor necrosis factor alpha in macrophage culture and peripheral macrophages after LPS stimulation [23]. Although CBD is devoid of psychotropic activities, it may have some beneficial effects (such as sedating, anticonvulsant, anti-inflammatory, and neuroprotective properties [24–28]). Due to possible beneficial effects of other cannabinoids, plant extracts may be superior to administration of synthetic THC for treating medical diseases. Therefore, in the present clinical study, the pharmacokinetics and effects of two different C. sativa extracts were compared to the oral administration of synthetic THC. To assess the potentially beneficial effect of THCA‑A and CBDA, one extract was unheated and the other one was heated.

Materials and Methods !

Ten healthy male subjects were enrolled and 9 completed the study.

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The study protocol and the informed consent form were submitted to the local State Ethics Committee of both cantons of Basel (EKBB) for review and approval (#63/04; Oct 14, 2005). Exceptional permit for scientific use of cannabinoids was obtained from the Federal Office for Public Health (AB 8/5-BetmG‑05.000 236). The study was notified to the Swiss health agency (Swissmedic, #2005DR1311). All subjects (age: 21–45 years) gave their written informed consent prior to entry into the study. As assessed by screening examination, subjects were healthy and fulfilled all inclusion criteria. In particular, they had to be non-smokers. Special exclusion criteria were: a known hypersensitivity to drugs and in particular to cannabinoids, need of any concomitant medication and positive findings in the pre-study urinary drug screening (opioids, cannabinoids, ecstasy, benzodiazepines), as well as history or indication of drug abuse. Driving of any vehicles and operating potentially dangerous machines after administrations was not allowed until the first of repetitive determinations of urinary THC-COOH was negative. Main objective of the study was to assess the relative bioavailability of THC. Secondary study endpoints were to assess the tolerability and safety of the treatments. A double-blind, randomized, three-period cross-over experiment was performed. A wash-out phase between two consecutive treatments of at least 2 weeks was used. Seventy-two hours after each administration, urinary THC-COOH concentration had to be determined using the fluorescence polarization immunoassay technique (FPIA) (Abbott). If this test was positive for THC-COOH (cut-off 1 ng/mL), it had to be repeated in weekly intervals until one test was negative before the next administration of study drug was allowed, but at least 2 weeks after the preceding administration. Dronabinol (Marinol®, Unimed Pharmaceuticals, Inc., Marietta, GA, USA) was obtained from DiaMo Narcotics Ltd. C. sativa drug was produced in Switzerland; a voucher sample is deposited at Cannapharm AG. Plant extracts were manufactured by Cannapharm AG. Cannabis extracts were prepared by ethanol 70 % m/ m (DER 4.5) and contained per capsule 10 mg THCtot (THC + THCA‑A) and 10–15 mg CBDtot (CBD + CBDA). Galenical formula-

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Fig. 2

Original Papers

Table 1 Content of the galenical forms of Marinol® and heated and unheated C. sativa extract. Forms Form A – Marinol™1) Form B – heated extract Form C – unheated extract

CBDA

CBDtot

CBN

THC

THCA‑A

THCtot

mg

mg

mg

mg

mg

mg

– 27.8 14.8

–

– 28.6 25.6

– 1.6 0.6

20 17.6 10.4

– 2.2 7.6

20 19.8 18.0

0.8 10.8

Ratio CBDtot/THCtot NA 1.44 1.42

Nominal content. CBDA = CBD acid; CBDtot = CBD + CBDA; THCA‑A = THC acid A; THCtot = THCA‑A + THC

tion of extracts was done by the Hospital Pharmacy, University Clinic Basel according to GMP regulations (Prof. C. Surber). The content of cannabinoids was controlled prior to the start of the study at Frutarom Ltd. by HPLC analysis using UV detection (210 nm for THC and CBD and 224 nm for THCA, CBDA, and CBN). Extraction: methanol/chloroform 9 : 1 (V/V). Stationary phase was Spherisorb 80-3 2 × 250, and the mobile phase a gradient of ortho-phosphoric acid/acetonitril. Run time was 65 min. Limit of quantification was 0.2 mg/capsule and intra-assay variability was 0.13–0.25%. The following treatments were given: A) 20 mg dronabinol (reference medication), B) 2 capsules containing cannabis extract from heated Herba Cannabis (140 °C for 12 min), and C) 2 capsules containing cannabis extract from unheated Herba Cannabis. The " Table 1). ratios of CBDtot/THCtot of both extracts were 1.4 (l For each subject, drug input was to be applied in the morning at about 8 a. m. after at least 12 hours fasting.

Determination of THC, 11-OH‑THC, THC-COOH, CBN, and CBD in plasma Plasma concentrations of THC and metabolites (11-hydroxyΔ9 THC and 11-nor-9-carboxy-Δ9 THC), CBN, and CBD metabolites have been measured in plasma and urine by a sensitive LC/MS/ MS method [29] under GLP-conditions in the Clinical Chemistry Laboratory, University Hospital Basel (Dr. A. Scholer). The concentrations of the analytes were calculated by comparing the peak area (%) of an analyte with the corresponding area (%) on the standard curve. System variations were adjusted by comparing the area (%) of the internal standards. The internal standards were THC‑d3 for EDTA-plasma and THC-COOH‑d3 for urine. Run time was 25 min. Lower limit of quantification in EDTA-plasma was 0.2 ng/mL for CBN, THC, THC-COOH, CBD, and 11-OH‑THC, in urine 3 ng/mL for CBN, 1 ng/mL for CBD, THC, and THC-COOH and 2 ng/mL for 11-OH‑THC. The coefficients of variation of all interand intra-assay determinations were between 1.3–15.5 %.

Pharmacokinetics Blood samples (10 mL) for LC/MS/MS analysis were drawn in heparin-coated tubes through indwelling catheter placed into the cubital vein of the forearm. Samples were drawn immediately before administrations (baseline) and 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after drug administration. Blood samples were centrifuged at 3000 rpm to separate plasma which was instantly deep-frozen and stored in polystyrene tubes at − 20 °C until analysis.

Pharmacokinetic analysis Maximum plasma concentration (Cmax) and the time of its occurrence (Tmax) were determined by inspection of raw data. Plasma profiles were evaluated by nonparametric analysis using WinNonlin nonlinear regression software (version 5.0) to estimate

the area under the plasma concentration/time curve (AUC) over the first 24 hours after drug administration.

Assessment of psychotropic effects Psychotropic effects were assessed after administration of all treatments immediately before administrations (baseline) and 2 h, 4 h, 8 h, 12 h, and 24 h after administrations by visual analog scales (VAS) measurements (for relaxation, concentration, tiredness, euphoria, dysphoria, anxiety, tension, disorientation, illusion and derealization, hallucination, changed emotions, nausea, abdominal discomfort, and vertigo). The VAS for items was a horizontal line of 100 mm length. The left-most end should state “totally disagree” (0%), the other end ”agree very much” (100 %).

Statistical analysis Data were analyzed by analysis of variance and subsequently the Tukey multicomparison test (normally distributed data) or the Friedman test with subsequent multiple Wilcoxon signed ranks test with Bonferroniʼs correction (not normally distributed data), as appropriate, using SPSS for windows software (version 15.0) as two-sided comparisons. The level of significance was p < 0.05.

Results !

Ten healthy male subjects [mean age 27.0 (range 23–40) years; mean weight 75.5 (range 66–95) kg; mean height 179.5 (range 174–188) cm] entered the study and received at least one administration of a study drug. Nine subjects completed the study. One subject after administration of dronabinol discontinued his participation due to mild paresthesia, warm feeling, conjunctional injection, vertigo, visual disturbances, abdominal discomfort, dry mouth, tremor, and paleness as well as moderate short-lasting anxiety. Since the symptoms were in the vast majority of mild severity, this subject was replaced. Data are given as means ± SEM (median), unless stated otherwise. " Table 2 and disPharmacokinetic parameters are summarized in l " played in l Fig. 3 A to F for (A) THC, its metabolites (B) 11-OH‑THC, (C) THC-COOH, as well as for (D) CBN, (E) CBD, and (F) the total plasma concentrations of THC, 11‑OH‑THC, THC-COOH, and CBN. Although there were for THC some slight differences in AUC, Cmax, and Tmax values, and for 11-OH‑THC and THC-COOH in AUC and Cmax values, due to the high intersubject variability, no statistically significant differences could be observed. However, after administration of the unheated extract, significantly (p = 0.042) lower or, after the heated extract, higher (p = 0.05) Tmax values were observed than after administration of dronabinol. As expected, no CBD could be detected in plasma after administration of the synthetic THC (dronabinol). After administration of the unheated extract, the AUC of CBD was about 2-fold higher [7.67 ± 2.06 (4.63) pmol h/mL] than after administration of the

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CBD mg

Original Papers

Table 2 Summary of pharmacokinetic parameters. Dronabinol 20 mg

(1) THC AUC(0–24 h) (pmol h/mL) Cmax (pmol/mL) Tmax (h) (2) 11-OH‑THC AUC(0–24 h) (pmol h/mL) Cmax (pmol/mL) Tmax (h) (3) THC-COOH AUC(0–24 h) (pmol h/mL) Cmax (pmol/mL) Tmax (h) (4) CBN AUC(0–24 h) (pmol h/mL) Cmax (pmol/mL) Tmax (h) (5) CBD AUC(0–24 h) (pmol h/mL) Cmax (pmol/mL) Tmax (h) 6) Sum [(1)–(4)] AUC(0–24 h) (pmol h/mL) Cmax (pmol/mL) Tmax (h) Relative Bioavailability (%)

Heated extract

Unheated Extract

8.43 ± 4.23 (4.58) 3.26 ± 1.74 (1.53) 1.06 ± 0.19 (1.0)

3.48 ± 0.84 (2.84) 1.33 ± 0.42 (0.8) 0.78 ± 0.09 (1.0)

9.75 ± 2.95 (6.59) 3.24 ± 0.83 (2.26) 1.17 ± 0.22 (1.0)

9.51 ± 2.07 (6.86) 2.99 ± 0.65 (2.53) 1.67 ± 0.17 (2.0)

10.61 ± 3.83 (7.24) 2.22 ± 0.69 (1.51) 1.44 ± 0.23 (2.0)

7.52 ± 2.15 (7.27) 1.72 ± 0.41 (1.5) 1.00 ± 0.14 (1.0)

121.94 ± 39.91 (84.32) 20.71 ± 5.47 (22.11) 1.78 ± 0.32 (2.0)

157.80 ± 85.16 (70.68) 16.88 ± 7.34 (10.04) 2.89 ± 0.35 (2.0)

39.03 ± 10.44 (45.14) 5.62 ± 1.06 (6.62) 2.11 ± 0.26 (2.0)

10.66 ± 4.70 (7.14) 2.05 ± 0.78 (1.19) 1.06 ± 0.19 (1.0)

9.25 ± 1.91 (8.41) 1.94 ± 0.40 (1.82) 0.94 ± 0.15 (1.0)

6.23 ± 2.23 (3.77) 1.74 ± 0.31 (1.88) 1.00 ± 0.14 (1.0)

0.00 ± 0.00 (0.0) 0.00 ± 0.00 (0.0) NA

3.68 ± 1.34 (2.53) 0.94 ± 0.22 (0.87) 0.83 ± 0.17 (0.5)

7.67 ± 2.06 (4.63) 3.95 ± 0.92 (3.06) 1.17 ± 0.39 (1.0)

149.13 ± 44.24 (99.98) 26.90 ± 6.53 (27.47) 1.44 ± 0.18 (1.0) 100

181.15 ± 90.54 (90.57) 19.73 ± 8.03 (12.29) 2.67 ± 0.33 (2.0) 345.7 ± 180.5 (83.3)

62.53 ± 14.04 (60.36) 10.47 ± 1.86 (12.29) 1.22 ± 0.21 (1.0) 57.4 ± 12.6 (60.4)

Fig. 3 Plasma concentration of THC (panel A) and metabolites (panels B–F) after oral administration of 20 mg dronabinol (reference medication). –■–, 2 capsules containing cannabis extract from heated Herba Cannabis; –●–, 2 capsules containing cannabis extract from unheated Herba Cannabis; –▲–, mean ± SEM (n = 9): A THC, B 11-OH‑THC, C THC-COOH, D CBN, E CBD, and F total plasma concentrations of THC and metabolites (11‑OH‑THC, THC-COOH, CBN).

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Means ± SEM (Median)

Original Papers

Table 3 Percentage of total AUC(0–24 h) of different metabolites. Administration

THC

11-OH‑THC

THC-COOH

CBD

CBN

A) Dronabinol B) Heated extract C) Unheated extract

5.45 ± 1.04 (5.13) 3.39 ± 1.05 (2.46) 15.82 ± 3.32 (11.37) A: P = 0.005 B: P = 0.001

9.70 ± 2.03 (8.79) 7.53 ± 1.54 (6.14) 10.42 ± 1.69 (12.30)

76.44 ± 3.50 (80.83) 77.02 ± 4.08 (77.16) 48.55 ± 6.82 (55.34) A: P = 0.002 B: P = 0.001

0.0 ± 0.0 (0.0) 3.02 ± 1.09 (1.50) 14.85 ± 4.40 (12.56) A: P = 0.001 B: P = 0.01

8.41 ± 2.66 (6.98) 9.04 ± 2.43 (7.68) 10.35 ± 3.00 (5.67)

A: significantly different from administration A); B: significantly different from administration B)

(p = 0.01) from 14.85 % for the unheated to 3.02 % for the heated extract.

Discussion

Fig. 4 Relative bioavailabilities of different THC and metabolites (AUC0–24 h, means).

heated extract [3.68 ± 1.34 (2.53) pmol h/mL]; this difference was not statistically significant. Cmax values were different between the treatments (p = 0.002): Cmax of the unheated extract was 3.95 ± 0.92 (3.06) pmol/mL and of the heated extract 0.94 ± 0.22 (0.87) pmol/mL. Tmax values were not different. For CBN, no significant differences could be detected for AUC, Cmax, and Tmax between the treatments. Overall the oral absorption was estimated as the sum of AUC(0–24 h) values of THC, 11-OH‑THC, THC-COOH, and CBN. Although mean values indicated large differences, median values were comparable between the treatments. Likewise, no significant differences could be detected for Cmax values. Tmax values were significantly (p = 0.001) higher after administration of the heated extract than after administration of dronabinol or the unheated extract. On the other hand, after administration of cannabis extracts, a " Table 3 and different metabolic pattern was detected (see l Fig. 4): for the unheated extract, the highest proportion of THC AUC of all cannabinoids was observed (15.82 %). It was significantly higher than after administration of dronabinol (5.45%, p = 0.005) and after the heated extract (3.39 %; p = 0.001). The proportions of 11-OH‑THC and CBN were virtually unchanged between the different treatments. For THC-COOH the unheated extract showed the lowest proportion (48.55%), which was significantly (p = 0.001) lower than that after administration of the heated extract (77.02%) and also lower (p = 0.002) than after administration of dronabinol (76.44 %). After administration of dronabinol, no plasma concentrations of CBD could be detected. This was as expected, since THC is not converted to CBD in vivo and is found only in C. sativa plants. Heating of extracts decreased the proportion of CBD significantly

The pharmacokinetics of cannabinoid metabolites showed a high intersubject variability. The median relative oral bioavailabilities of the heated and unheated extract (versus synthetic dronabinol) were 83.3 % and 60.4 %, respectively. The metabolic pattern was significantly different after administration of the different forms: the unheated extract, the heated extract, and dronabinol showed a median THC plasma AUC24 h of 6.59, 2.84, and 4.58 pmol h/mL, respectively, whereas the median sum of the metabolites (THC, 11-OH‑THC, THC-COOH, CBN) plasma AUC24 h were 60.36, 90.57, and 99.98 pmol h/mL, respectively. The median plasma AUC24 h values for the inactive metabolite THC-COOH were highest after administration of dronabinol (84.32 pmol h/mL) and almost 2-fold lower after administration of the unheated extract (45.14 pmol h/mL). After administration of the heated extract, intermediate values were observed (70.68). The highest median THC plasma AUC24 h for the unheated extract is even more surprising when the lower amount of applied THCtot (18 versus 20 mg) with only 10.4 mg in the phenolic form is considered. This could be the result of changes in the absorption of the applied cannabinoids and cannabinoid metabolites, of changes in metabolic activity or elimination processes. With this experimental design, the cause(s) of the change(s) could not be identified. There were psychotropic effects after administration of all treatments as assessed by VAS measurements. However, the intensity of these effects was weak, and no statistically significant difference between the treatments could be detected (data not shown). This is partly in contrast to reports of strong effects after smoking 20 mg THC. However, compared to smoking after oral administration, the relative bioavailability of THC is about 30 % [9]. With dronabinol, slightly more psychotropic adverse effects were observed. This might be explained by the higher relative bioavailability of cannabinoids after dronabinol administration and/or protective effects of some constituents of the extracts. It is known that CBD and TCHA‑A have some (neuro)protective effects [20, 23–28]. The administration of Cannabis sativa extracts in the doses applied in this study was well tolerated. These extracts have a slightly lower total relative bioavailability than after administration of dronabinol. The potentially better tolerability should be investigated in further clinical trials.

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Conflict of Interest !

J. D. has received a research grant of Cannapharm Ltd. M. L. is an employee of Cannapharm Ltd.

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