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

Abstract

The most important psychoactive constituent of CANNABIS SATIVA L. is Δ (9)-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 (dronabinol) 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 AUC (24 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, THC-COOH, CBN) plasma AUC (24 h) was higher for the heated than for the unheated extract. The median CBD plasma AUC (24 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.

Full text

Introduction
!
The use of cannabinoids in several clinical indica-
tions is currently under evaluation [1–6]. The
most active agent of Cannabis sativa L. (Cannaba-
ceae) is Δ9-tetrahydrocannabinol (THC).
When ingested orally, thebioavailability of C. sati-
va is relativelylow 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
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-tetrahy-
drocannabinol, cannabinol (CBN), cannabidiol
(CBD), Δ9-tetrahydrocannabinolic acid A (THCA‑A)
(l
"Fig. 1) [13] and cannabidiolic acid (CBDA).
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 sin-
gle dose can take up to 30 days [16]. Metabolism
of THC takes place in the liverand potentially in the
gut wall. Because of the sequestration in fatty tis-
sue there is a poor relationship between plasma or
urine concentrations and degree of cannabinoid-
induced effects. Following oral administration,
THC is rapidly hydroxylated to its major metabo-
Abstract
!
The most important psychoactive constituent of
Cannabis sativa L. is Δ9-tetrahydrocannabinol
(THC). Cannabidiol (CBD), another important con-
stituent, is able to modulate the distinc t unwanted
psychotropic effect of THC. In natural plant ex-
tracts 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 trans-
formed to THC and CBD by heating. Previous re-
ports 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 accompa-
nied with a lower rate of adverse effects. There-
fore, 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-
nabinol) in a double-blind, randomized, single
center, three-period cross-over study involving
9 healthy male volunteers. The pharmacoki-
netics 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, THC-
COOH, CBN) plasma AUC24h 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 pat-
tern and possibly better tolerability.
* These authors contributed equally to the work.
Heat Exposure of Cannabis sativa Extracts
Affects the Pharmacokinetic and Metabolic Profile
in Healthy Male Subjects
Authors Martin Eichler1*, Luca Spinedi1*, Sandra Unfer-Grauwiler1, Michael Bodmer 1, Christian Surber2, Markus Luedi3,
Juergen Drewe1
Affiliations 1Departments of Clinical Pharmacology and Gastroenterology & Hepatology, University Hospital Basel, Basel, Switzerland
2Institute for Hospital Pharmacy, University Hospital Basel, Basel, Switzerland
3Cannapharm Ltd., Burgdorf, Switzerland
Key words
l
"Cannabis sativa L.
l
"Cannabaceae
l
"tetrahydrocannabinol
l
"THC
l
"THC metabolites
l
"CBD
l
"pharmacokinetics
received January 2, 2012
revised February 6, 2012
accepted 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 Gastro-
enterology & Hepatology
University Hospital Basel
Petersgraben 4
4031 Basel
Switzerland
Phone: +41 7 89 23 27 44
Fax: + 4161 2 65 85 81
juergen.drewe@unibas.ch
Eichler M et al. Heat Exposure of …Planta Med
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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-
gated (l
"Fig. 2) and excreted into feces and urine [18,19]. The ac-
id derivatives of THC are devoid of psychotropic effects and do
not bind to cannabis CB1and CB2receptors, although they pos-
sess some anti-inflammatory action [20].
In naturally grown C. sativa, up to 95 % of the occurring cannabi-
noids 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]. Re-
cently, 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-in-
flammatory, and neuroprotective properties [24–28]).
Due to possible beneficial effects of other cannabinoids, plant ex-
tracts 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 ex-
tracts were compared to the oral administration of synthetic
THC. To assess the potentially beneficial effect of THCA‑Aand
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.
The study protocol and the informed consent form were submit-
ted to the local State Ethics Committee of both cantons of Basel
(EKBB) for review and approval (#63/04; Oct 14, 2005). Exception-
al 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 con-
sent prior to ent ry into the study. As assessed by screening exami-
nation, 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 can-
nabinoids, need of any concomitant medication and positive
findings in the pre-study urinary drug screening (opioids, canna-
binoids, ecstasy, benzodiazepines), as well as history or indica-
tion 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 bioavailabil-
ity of THC. Secondary study endpoints were to assess the toler-
ability 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 ad-
ministration.
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 Canna-
pharm AG. Cannabis extracts were prepared by ethanol 70% m/
m (DER 4.5) and contained per capsule 10 mg THCtot (THC +
THCA‑A) an d 10 –15 mg CBDtot (CBD + CBDA). Galenical formula-
Fig. 1 Structural formulas of important herbal cannabinoids.
Fig. 2 Main metabolic pathways of THC.
Eichler M et al. Heat Exposure of …Planta Med
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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 gra-
dient of ortho-phosphoric acid/acetonitril. Run time was 65 min.
Limit of quantification was 0.2 mg/capsule and intra-assay vari-
ability was 0.13–0.25%.
The following treatments were given: A) 20 mg dronabinol (refer-
ence 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
ratios of CBDtot/THCtot of both extracts were 1.4 (l
"Table 1).
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-hydroxy-
Δ9THC and 11-nor-9-carboxy-Δ9THC), 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 con-
centrations 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 compar-
ing 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 inter-
and 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 centri-
fuged at 3000 rpm to separate plasma which was instantly
deep-frozen and stored in polystyrene tubes at −20 °C until anal-
ysis.
Pharmacokinetic analysis
Maximum plasma concentration (Cmax) and the time of its occur-
rence (Tmax) were determined by inspection of raw data. Plasma
profiles were evaluated by nonparametric analysis using Win-
Nonlin 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, 4h, 8 h, 12h, and 24 h after administrations by visual analog
scales (VAS) measurements (for relaxation, concentration, tired-
ness, euphoria, dysphoria, anxiety, tension, disorientation, illu-
sion and derealization, hallucination, changed emotions, nausea,
abdominal discomfort, and vertigo). The VAS for items was a hori-
zontal 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 admin-
istration of a study drug. Nine subjects completed the study. One
subject after administration of dronabinol discontinued his par-
ticipation due to mild paresthesia, warm feeling, conjunctional
injection, vertigo, visual disturbances, abdominal discomfort,
dry mouth, tremor, and paleness as well as moderate short-last-
ing 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.
Pharmacokinetic parameters are summarized in l
"Table 2 and dis-
played in l
"Fig. 3 A to Ffor (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 statistical-
ly significant differences could be observed. However, after ad-
ministration of the unheated extrac t, 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 adminis-
tration 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
Table 1 Content of the galenical forms of Marinol®and heated and unheated C. sativa extract.
Forms CBD CBDA CBDtot CBN THC THCA‑A THCtot Ratio CBDtot/THCtot
mg mg mg mg mg mg mg
Form A –Marinol™1) ––––20 –20 NA
Form B –heated extract 27.8 0.8 28.6 1.6 17.6 2.2 19.8 1.44
Form C –unheated extract 14.8 10.8 25.6 0.6 10.4 7.6 18.0 1.42
1) Nominal content. CBDA = CBD acid; CBDtot = CBD + CBDA; THCA‑A = THC acid A; THCtot =THCA‑A+THC
Eichler M et al. Heat Exposure of …Planta Med
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Table 2 Summary of pharmacokinetic parameters.
Means ± SEM (Median) Dronabinol 20 mg Heated extract Unheated Extract
(1) THC
AUC(0–24 h) (pmol h/mL) 8.43 ± 4.23 (4.58) 3.48 ± 0.84 (2.84) 9.75 ± 2.95 (6.59)
Cmax (pmol/mL) 3.26 ± 1.74 (1.53) 1.33 ± 0.42 (0.8) 3.24 ± 0.83 (2.26)
Tmax (h) 1.06 ± 0.19 (1.0) 0.78 ± 0.09 (1.0) 1.17 ± 0.22 (1.0)
(2) 11-OH‑THC
AUC(0–24 h) (pmol h/mL) 9.51 ± 2.07 (6.86) 10.61 ± 3.83 (7.24) 7.52 ± 2.15 (7.27)
Cmax (pmol/mL) 2.99 ± 0.65 (2.53) 2.22 ± 0.69 (1.51) 1.72 ± 0.41 (1.5)
Tmax (h) 1.67 ± 0.17 (2.0) 1.44 ± 0.23 (2.0) 1.00 ± 0.14 (1.0)
(3) THC-COOH
AUC(0–24 h) (pmol h/mL) 121.94 ± 39.91 (84.32) 157.80 ± 85.16 (70.68) 39.03 ± 10.44 (45.14)
Cmax (pmol/mL) 20.71 ± 5.47 (22.11) 16.88 ± 7.34 (10.04) 5.62 ± 1.06 (6.62)
Tmax (h) 1.78 ± 0.32 (2.0) 2.89 ± 0.35 (2.0) 2.11 ± 0.26 (2.0)
(4) CBN
AUC(0–24 h) (pmol h/mL) 10.66 ± 4.70 (7.14) 9.25 ± 1.91 (8.41) 6.23 ± 2.23 (3.77)
Cmax (pmol/mL) 2.05 ± 0.78 (1.19) 1.94 ± 0.40 (1.82) 1.74 ± 0.31 (1.88)
Tmax (h) 1.06 ± 0.19 (1.0) 0.94 ± 0.15 (1.0) 1.00 ± 0.14 (1.0)
(5) CBD
AUC(0–24 h) (pmol h/mL) 0.00 ± 0.00 (0.0) 3.68 ± 1.34 (2.53) 7.67 ± 2.06 (4.63)
Cmax (pmol/mL) 0.00 ± 0.00 (0.0) 0.94 ± 0.22 (0.87) 3.95 ± 0.92 (3.06)
Tmax (h) NA 0.83 ± 0.17 (0.5) 1.17 ± 0.39 (1.0)
6) Sum [(1)–(4)]
AUC(0–24 h) (pmol h/mL) 149.13 ± 44.24 (99.98) 181.15 ± 90.54 (90.57) 62.53 ± 14.04 (60.36)
Cmax (pmol/mL) 26.90 ± 6.53 (27.47) 19.73 ± 8.03 (12.29) 10.47 ± 1.86 (12.29)
Tmax (h) 1.44 ± 0.18 (1.0) 2.67 ± 0.33 (2.0) 1.22 ± 0.21 (1.0)
Relative Bioavailability (%) 100 345.7 ± 180.5 (83.3) 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): ATHC, B11-OH‑THC,
CTHC-COOH, DCBN, ECBD, and Ftotal plasma
concentrations of THC and metabolites (11‑OH‑THC,
THC-COOH, CBN).
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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,andT
max between the treatments.
Overall the oral absorption was estimatedas 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 compara-
ble 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 extrac t than
after administration of dronabinol or the unheated extract.
On the other hand, after administration of cannabis extracts, a
different metabolic pattern was detected (see l
"Table 3 and
Fig. 4): for the unheated extract, the highest proportion of THC
AUC of all cannabinoids was observed (15.82 %). It was signifi-
cantly 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 sig-
nificantly (p = 0.001) lower than that after administ ration of the
heated extract (77.02 %) and also lower (p = 0.002) than after ad-
ministration 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
(p = 0.01) from 14.85% for the unheated to 3.02% for the heated
extract.
Discussion
!
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 adminis-
tration 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) plas-
ma 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 con-
sidered.
This could be the result of changes in the absorption of the ap-
plied cannabinoids and cannabinoid metabolites, of changes in
metabolic activity or elimination processes. With this experi-
mental design, the cause(s) of the change(s) could not be identi-
fied.
There were psychotropic effects after administration of all treat-
ments as assessed by VAS measurements. However, the intensity
of these effects was weak, and no statistically significant differ-
ence 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 ef-
fects [20, 2 3–28].
The administration of Cannabis sativa extracts in the doses ap-
plied in this study was well tolerated. These extracts have a
slightly lower total relative bioavailability than after administra-
tion of dronabinol. The potentially better tolerability should be
investigated in further clinical trials.
Fig. 4 Relative bioavailabilities of different THC and metabolites
(AUC0–24 h, means).
Table 3 Percentage of total AUC(0–24 h) of different metabolites.
Administration THC 11-OH‑THC THC-COOH CBD CBN
A) Dronabinol 5.45± 1.04 (5.13) 9.70 ± 2.03 (8.79) 76.44 ± 3.50 (80.83) 0.0 ± 0.0 (0.0) 8.41 ± 2.66 (6.98)
B) Heated extract 3.39 ± 1.05 (2.46) 7.53± 1.54 (6.14) 77.02 ± 4.08 (77.16) 3.02 ± 1.09 (1.50) 9.04 ± 2.43 (7.68)
C) Unheated extract 15.82 ± 3.32 (11.37)
A: P = 0.005
B: P = 0.001
10.42 ± 1.69 (12.30) 48.55 ± 6.82 (55.34)
A: P = 0.002
B: P = 0.001
14.85 ± 4.40 (12.56)
A: P = 0.001
B: P = 0.01
10.35 ± 3.00 (5.67)
A: significantly different from administration A); B: significantly different from administration B)
Eichler M et al. Heat Exposure of …Planta Med
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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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