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

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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.
Introduction
!
The use of cannabinoids in several clinical indica-
tions is currently under evaluation [16]. 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 (2530%).
The onset of psychoactive effects (initial and peak
response) depends on the route of administration
and varies between 30 min to 4 hours [79]. 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, 46 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 (THCAA)
(l
"Fig. 1) [13] and cannabidiolic acid (CBDA).
THC is preferentially taken up by fatty tissues
reaching peak concentrations in 45 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 THCAA (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-OHTHC, 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 00320943
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
Original Papers
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lite, 11-OH-Δ9tetrahydrocannabinol (11-OHTHC), 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 THCAA and CBDA. By heating to 200
210 °C for 5 minutes, they are quantitatively decarboxylized to
phenolic THC [21] and CBD, respectively.
Although THCAA 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 [2428]).
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 THCAAand
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-BetmG05.000 236). The
study was notified to the Swiss health agency (Swissmedic,
#2005DR1311).
All subjects (age: 2145 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 +
THCAA) 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
Original Papers
Downloaded by: Universität Basel. Copyrighted material.
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 0.130.25%.
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-OHTHC, 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 THCd3 for EDTA-plasma and THC-COOHd3 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-OHTHC, in
urine 3 ng/mL for CBN, 1 ng/mL for CBD, THC, and THC-COOH and
2 ng/mL for 11-OHTHC. The coefficients of variation of all inter-
and intra-assay determinations were between 1.315.5 %.
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 2340) years;
mean weight 75.5 (range 6695) kg; mean height 179.5 (range
174188) 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-OHTHC,
(C) THC-COOH, as well as for (D) CBN, (E) CBD, and (F) the total
plasma concentrations of THC, 11OHTHC, THC-COOH, and CBN.
Although there were for THC some slight differences in AUC, Cmax,
and Tmax values, and for 11-OHTHC 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 THCAA THCtot Ratio CBDtot/THCtot
mg mg mg mg mg mg mg
Form A Marinol1) ––––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; THCAA = THC acid A; THCtot =THCAA+THC
Eichler M et al. Heat Exposure of Planta Med
Original Papers
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Table 2 Summary of pharmacokinetic parameters.
Means ± SEM (Median) Dronabinol 20 mg Heated extract Unheated Extract
(1) THC
AUC(024 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-OHTHC
AUC(024 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(024 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(024 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(024 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(024 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 BF) 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-OHTHC,
CTHC-COOH, DCBN, ECBD, and Ftotal plasma
concentrations of THC and metabolites (11OHTHC,
THC-COOH, CBN).
Eichler M et al. Heat Exposure of Planta Med
Original Papers
Downloaded by: Universität Basel. Copyrighted material.
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(024 h)
values of THC, 11-OHTHC, 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-OHTHC 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-OHTHC, 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 TCHAA have some (neuro)protective ef-
fects [20, 2 328].
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
(AUC024 h, means).
Table 3 Percentage of total AUC(024 h) of different metabolites.
Administration THC 11-OHTHC 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
Original Papers
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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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Original Papers
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... The CBDA compound is thermally unstable and can be decarboxylated to CBD. The decarboxylation process starts from 80 to 230 °C, depending on the duration of the exposure time [12]. ...
... The CBDA compound is thermally unstable and can be decarboxylated to CBD. The decarboxylation process starts from 80 to 230 • C, depending on the duration of the exposure time [12]. ...
... The biosynthesis of CBD occurs through CBDA synthase, which catalyzes the stereoselective oxidocyclization of cannabigerolic acid into CBDA [20]. It has been proven that the biosynthesis of CBDA/THCA is accelerated and decarboxylated to CBD and THC, respectively, after heating to 200-210 • C for 5 min [12], 120 • C for 20 min [20], or 80-145 • C for 5 to 10 min in a vacuum oven [10]. It has been shown that the decarboxylation of CBDA and THCA is accelerated by the heating process. ...
Article
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Cannabidiol (CBD) is a non-psychoactive cannabinoid compound found in hemp plants that has recently sparked interest in the biomedical and food industries. CBD is a natural decarboxylated product of cannabidiolic acid (CBDA). In this study, processing parameters were developed to enhance the decarboxylation process of CBDA in hemp leaves using hot-melt extrusion (HME). The hemp leaves were formulated with two different acid-based polymers, namely ascorbic acid (AA) and ascorbyl palmitate (AP), before the HME. The results showed that the carboxylation process of CBDA was increased by at least 2.5 times in the extrudate leaves and the content of the CBD was four times higher when formulated with AP (2800 µg/g) compared with the raw leaves (736 µg/g). The total phenolic and total flavonoid content, as well as the DPPH antioxidant capacity, were higher in the AP formulated extrudate. At the same time, the Δ9-tetrahydrocannabinol (THC) content was reduced by half in the extrudate compared with the raw leaves. It was also observed that double HME processing did not increase the decarboxylation process. It was concluded that the HME process significantly improved the conversion rate of CBDA to CBD in formulated hemp leaves with a reduced THC content.
... With the measurement of serum CBD now published in canines conjures a presumption that CBDA may undergo biotransformation to CBD based on a single human study (6). In-vitro systems of gastric absorption suggest that CBDA might become CBD in the gastrointestinal tract and that CBD has the potential to become 9-tetrahydrocannabinol (THC) through either gastric or hepatic conversion (7,8). ...
... Currently, there is little evidence of this occurrence in vivo, but in general it is thought that CBD does not become THC in vivo (9). Conversely, literature has shown that providing oral CBDA rather than CBD, actually results in a 3-fold higher Cmax of CBD in the bloodstream of people (6). This has led to the idea that CBDA may be a more bioavailable cannabinoid that becomes CBD in vivo or that it might help with the absorption of CBD, allowing for higher serum concentrations with lower dosing (6). ...
... Conversely, literature has shown that providing oral CBDA rather than CBD, actually results in a 3-fold higher Cmax of CBD in the bloodstream of people (6). This has led to the idea that CBDA may be a more bioavailable cannabinoid that becomes CBD in vivo or that it might help with the absorption of CBD, allowing for higher serum concentrations with lower dosing (6). To date, there has been little examination of serum CBDA in any species to prove this postulation. ...
Article
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Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.
... Following inhalation, 9 -THC is detectable in plasma within seconds after the first puff and the peak plasma concentration is attained within 3-10 minutes (Russo and Marcu, 2017). Oral 9 -THC formulations exhibit variable absorption and undergo extensive hepatic firstpass metabolism (Eichler et al., 2012). This results in lower peak plasma concentration relative to inhalation and a longer delay (120 minutes) to reach peak concentration (McPartland and Guy, 2017). ...
... There was a highly significant difference regarding duration of hospital stay among three groups of PSS in acute cannabis intoxicated pre-school children. These findings were similar to study in France of Le Garrec et al. (2014) .Oral 9-THC formulations exhibit variable absorption and undergo extensive hepatic first-pass metabolism (Eichler et al., 2012) and this resulting in lower peak plasma 9-THC concentration relative to inhalation and a longer delay (120 minutes) to reach peak concentration. The elimination half-life of 9-THC vary from approximately 6 minutes to 22 hours, so that most of acute cannabis intoxicated children should better observed for 24 hours (McPartland and Guy, 2017). ...
... As unheated extracts are rich in acids, the in vitro potency of cannabidiolic acid (CBDA) and/or tetrahydrocannabinolic acid (THCA), which may increase the bioavailability of CBD or THC, respectively [41], is also of interest. The potency of CBD was higher than that of CBDA in all 14 cell lines investigated to date [5,42]. ...
Article
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Preclinical models provided ample evidence that cannabinoids are cytotoxic against cancer cells. Among the best studied phytocannabinoids, cannabidiol (CBD) is most promising for the treatment of cancer as it lacks the psychotomimetic properties of delta-9-tetrahydrocannabinol (THC). In vitro studies and animal experiments point to a concentration- (dose-)dependent anticancer effect. The effectiveness of pure compounds versus extracts is the subject of an ongoing debate. Actual results demonstrate that CBD-rich hemp extracts must be distinguished from THC-rich cannabis preparations. Whereas pure CBD was superior to CBD-rich extracts in most in vitro experiments, the opposite was observed for pure THC and THC-rich extracts, although exceptions were noted. The cytotoxic effects of CBD, THC and extracts seem to depend not only on the nature of cannabinoids and the presence of other phytochemicals but also largely on the nature of cell lines and test conditions. Neither CBD nor THC are universally efficacious in reducing cancer cell viability. The combination of pure cannabinoids may have advantages over single agents, although the optimal ratio seems to depend on the nature of cancer cells; the existence of a 'one size fits all' ratio is very unlikely. As cannabinoids interfere with the endocannabinoid system (ECS), a better understanding of the circadian rhythmicity of the ECS, particularly endocannabinoids and receptors, as well as of the rhythmicity of biological processes related to the growth of cancer cells, could enhance the efficacy of a therapy with cannabinoids by optimization of the timing of the administration, as has already been reported for some of the canonical chemotherapeutics. Theoretically, a CBD dose administered at noon could increase the peak of anandamide and therefore the effects triggered by this agent. Despite the abundance of preclinical articles published over the last 2 decades, well-designed controlled clinical trials on CBD in cancer are still missing. The number of observations in cancer patients, paired with the anticancer activity repeatedly reported in preclinical in vitro and in vivo studies warrants serious scientific exploration moving forward.
... The most economically relevant cannabinoids (i.e., 9 -THC and CBD) are predominantly found in their acid forms in mature female inflorescence tissues, which are converted to the psychoactive and medicinal neutral forms through decarboxylation (Eichler et al., 2012;Zou and Kumar, 2018). The neutral forms also exist in relatively low quantities in the fresh inflorescences and tend to increase in proportion to the acid forms as the inflorescences mature (Aizpurua-Olaizola et al., 2016). ...
Article
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Before ultraviolet (UV) radiation can be used as a horticultural management tool in commercial Cannabis sativa (cannabis) production, the effects of UV on cannabis should be vetted scientifically. In this study we investigated the effects of UV exposure level on photosynthesis, growth, inflorescence yield, and secondary metabolite composition of two indoor-grown cannabis cultivars: ‘Low Tide’ (LT) and ‘Breaking Wave’ (BW). After growing vegetatively for 2 weeks under a canopy-level photosynthetic photon flux density (PPFD) of ≈225 μmol⋅m–2⋅s–1 in an 18-h light/6-h dark photoperiod, plants were grown for 9 weeks in a 12-h light/12-h dark “flowering” photoperiod under a canopy-level PPFD of ≈400 μmol⋅m–2⋅s–1. Supplemental UV radiation was provided daily for 3.5 h at UV photon flux densities ranging from 0.01 to 0.8 μmol⋅m–2⋅s–1 provided by light-emitting diodes (LEDs) with a peak wavelength of 287 nm (i.e., biologically-effective UV doses of 0.16 to 13 kJ⋅m–2⋅d–1). The severity of UV-induced morphology (e.g., whole-plant size and leaf size reductions, leaf malformations, and stigma browning) and physiology (e.g., reduced leaf photosynthetic rate and reduced Fv/Fm) symptoms intensified as UV exposure level increased. While the proportion of the total dry inflorescence yield that was derived from apical tissues decreased in both cultivars with increasing UV exposure level, total dry inflorescence yield only decreased in LT. The total equivalent Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) concentrations also decreased in LT inflorescences with increasing UV exposure level. While the total terpene content in inflorescences decreased with increasing UV exposure level in both cultivars, the relative concentrations of individual terpenes varied by cultivar. The present study suggests that using UV radiation as a production tool did not lead to any commercially relevant benefits to cannabis yield or inflorescence secondary metabolite composition.
... The most economically relevant cannabinoids (i.e., Δ 9 -THC and CBD) are predominantly found in their acid forms in mature female inflorescence tissues, which are converted to the psychoactive and medicinal neutral forms through decarboxylation (Eichler et al., 2012;Zou and Kumar, 2018). The neutral forms also exist in relatively low quantities in the fresh inflorescences and tend to increase in proportion to the acid forms as the inflorescences mature (Aizpurua-Olaizola et al., 2016). ...
Preprint
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It is commonly believed that exposing Cannabis sativa (cannabis) plants to ultraviolet (UV) radiation can enhance Δ9-tetrahydrocannabinol (Δ9-THC) concentrations in female inflorescences and associated foliar tissues. However, a lack of published scientific studies has left knowledge-gaps in the effects of UV on cannabis that must be elucidated before UV can be utilized as a horticultural management tool in commercial cannabis production. In this study we investigated the effects of UV exposure level on photosynthesis, growth, inflorescence yield, and secondary metabolite composition of two indoor-grown cannabis cultivars: ‘Low Tide’ (LT) and ‘Breaking Wave’ (BW). After growing vegetatively for 2 weeks under a canopy-level photosynthetic photon flux density (PPFD) of ≈225 μmol·m–2·s–1 in an 18-h light/6-h dark photoperiod, plants were grown for 9 weeks in a 12-h light/12-h dark “flowering” photoperiod under a canopy-level PPFD of ≈400 µmol·m–2·s–1 and 3.5 h·d–1 of supplemental UV radiation with UV photon flux densities (UV-PFD) ranging from 0.01 to 0.8 μmol·m–2·s–1 provided by light-emitting diodes (LEDs) with a peak wavelength of 287 nm (i.e., biologically-effective UV doses of 0.16 to 13 kJ·m–2·d–1). The severity of UV-induced morphology (e.g., whole-plant size and leaf size reductions, leaf malformations, and stigma browning) and physiology (e.g., reduced leaf photosynthetic rate and reduced Fv/Fm) symptoms worsened as UV exposure level increased. While the proportion of dry inflorescence yield that was derived from apical tissues decreased in both cultivars with increasing UV exposure level, total dry inflorescence yield only decreased in LT. The equivalent Δ9-THC and cannabidiol (CBD) concentrations also decreased in LT inflorescences with increasing UV exposure level. While the total terpene content in inflorescences decreased with increasing UV exposure level in both cultivars, the relative concentrations of individual terpenes varied by cultivar. The potential for using UV to enhance cannabis quality must still be confirmed before it can be used as a production tool for modern, indoor-grown cannabis cultivars.
... An important consideration for the cannabinoid analysis is that cannabinoids from plants are effectively in a "prodrug" form, existing as cannabinolic acids that must be decarboxylated to their respective cannabinol form to have pharmacological effects. 2 This decarboxylation, for example, occurs while smoking; however, upon oral consumption, no CBDA or THCA present is converted to CBD or THC by enzymatic or other processes. 37,38 If the production and processing of CBD oils does not remove all THCA and CBDA, some THCA and CBDA might still be present in the final CBD oil products. To evaluate whether THCA and CBDA would decarboxylate to their respective cannabinol forms during the AgPS-MS analysis and would thus interfere with the quantification of the THC/ CBD ratio, standard solutions of THCA and CBDA were analyzed with AgPS-MS (Supporting Information, Figure S9), Analytical Chemistry pubs.acs.org/ac ...
Article
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The control over the amount of psychoactive THC (Δ-9-tetrahydrocannabinol) in commercial cannabidiol (CBD) products has to be strict. A fast and simple semiquantitative Ag(I)-impregnated paper spray mass spectrometric method for differentiating between THC and CBD, which show no difference in standard single-stage or tandem MS, was established. Because of a different binding affinity to Ag(I) ions, quasi-molecular Ag(I) adducts [THC + Ag]⁺ and [CBD + Ag]⁺ at m/z 421 and 423 give different fragmentation patterns. The product ions at m/z 313 for THC and m/z 353 and 355 for CBD can be used to distinguish THC and CBD and to determine their ratio. Quantification of THC/CBD ratios in commercial CBD oils was accomplished with a low matrix effect (−2.2 ± 0.4% for THC and −2.0 ± 0.3% for CBD). After simple methanol extraction (recovery of 87.3 ± 1.2% for THC and 92.3 ± 1.4% for CBD), Ag(I)-impregnated paper spray analysis was employed to determine this ratio. A single run can be completed in a few minutes. This method was benchmarked against the UHPLC-UV method. Ag(I)-impregnated paper spray MS had the same working range (THC/CBD = 0.001–1) as UHPLC-UV analysis (R² = 0.9896 and R² = 0.9998, respectively), as well as comparable accuracy (−2.7 to 14%) and precision (RSD 1.7–11%). The method was further validated by the analysis of 10 commercial oils by Ag(I)-impregnated paper spray MS and UHPLC-UV analysis. Based on the determined relative concentration ratios of THC/CBD and the declared CBD concentration, 6 out of 10 CBD oils appear to contain more THC than the Dutch legal limit of 0.05%.
Article
The use of cannabinoids in veterinary medicine has been increasing exponentially recently and there is little information regarding the pharmacokinetics of cannabinoids except for cannabidiol (CBD) and tetrahydrocannabinol (THC), with even more sparse information related to their native acid forms found in cannabis. Cannabigerol (CBG) is the precursor molecule to cannabinoid formation in the cannabis plant which may have medicinal properties as well, yet there are no publications related to CBG or the native cannabigerolic acid (CBGA) in companion animal species. The aim of this study was to investigate similar dosing of CBG and CBGA from hemp plants that have been used for cannabidiol pharmacokinetic studies. Administration in the fed and fasted state was performed to better understand absorption and retention of these unique hemp‐derived cannabinoids in dogs. Results suggest that when providing a hemp‐derived CBG/CBGA formulation in equal quantities, CBGA is absorbed approximately 40‐fold better than CBG regardless of being given to fed or fasted dogs. After twice daily dosing for two weeks at 2 mg/kg in the fasted and then fed state, no differences in the mean serum CBG (5 ng/ml) or CBGA (250 ng/ml) serum concentrations were observed between states. Importantly, physical examination, complete blood counts, and serum chemistry evaluations over the two weeks suggest no adverse events during this short‐term dosing trial.
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Cannabis users typically smoke or vape cannabis or ingest it in edibles, whereas cannabinoids are typically administered via injection in rodent research. The present study examined the effects of route of administration (ROA) of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Adult female and male Long Evans rats were trained to discriminate intraperitoneal (i.p.) THC from vehicle in a drug discrimination procedure. Following acquisition, dose-effect curves were determined with THC using i.p., oral (p.o.), and subcutaneous (s.c.) injection in both sexes and aerosol exposure in males only, followed by a time course with one dose for each ROA. Both sexes acquired THC discrimination in a similar number of sessions, although baseline response rates were significantly lower in females than males. THC fully substituted for the 3 mg/kg i.p. training dose across all ROA. While potencies were similar for ROA involving first-pass metabolism (i.p. and p.o.), THC potency was lower with s.c. administration. During the time course analysis, aerosol administration had the shortest latency to onset of discriminative stimulus effects and the shortest duration of effect, whereas s.c. administration had the longest duration. The results of this examination of the effects of ROA on an abuse-related effect of THC provide an empirical foundation to facilitate choice of ROA for mechanistic investigation of THC's pharmacology. Further, animal models using translationally relevant ROA may facilitate more accurate predictions of their effects in humans.
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Frustration at the restrictions to access prescribed cannabinoids in New Zealand has resulted in a black market of home-made cannabis-based products for medicinal use. These products are being made, and marketed illegally, by individuals calling themselves ‘Green Fairies’. The products take many forms and are being used to treat a range of illnesses and symptoms including pain, insomnia, anxiety, and seizures. Analytical extraction methods were developed to determine the cannabinoid content in a variety of matrices, principally those that are soluble in methanol and those that are soluble in hexane. An LC-MS/MS method was developed that detected THC, THCA, CBD, CBDA, CBG, CBGA, CBN, THCV, and CBC with lower detection limits around 0.001mg of cannabinoid per gram (mgg−1) of product. One hundred ‘Green Fairy’ samples have been analysed to determine the cannabinoid content, including 12 fully extracted cannabis oil (FECO) samples, 12 ethanolic tinctures, 6 vape juices, 39 oily liquids with olive oil, hemp seed oil, or medium chain triglycerides (MCT) as a base, and 31 waxy solids made using coconut oil. Nine named cannabis plant cultivars purported to be used to make these products have also been analysed. The results of the analyses show that these Green Fairy products contain a wide range of cannabinoid concentrations and the claim that a product was high in CBD was often not correct. The proposed dose size was not specified for these products, but few would provide what is considered an effective dose when compared with the administration of commercially purified cannabinoid products available by prescription. For many products the manufacturer had specified which cannabis cultivar had been used but a comparison of cannabinoid ratios showed a lack of consistency within products said to be made from the same strain. Analysis of named cannabis cultivars available showed little variation in the relative amounts of THC and CBD.
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Objective: To quantify the antiemetic efficacy and adverse effects of cannabis used for sickness induced by chemotherapy. Design: Systematic review. Data sources: Systematic search (Medline, Embase, Cochrane library, bibliographies), any language, to August 2000. Studies: 30 randomised comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available (1366 patients). Oral nabilone, oral dronabinol (tetrahydrocannabinol), and intramuscular levonantradol were tested. No cannabis was smoked. Follow up lasted 24 hours. Results: Cannabinoids were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride: relative risk 1.38 (95% confidence interval 1.18 to 1.62), number needed to treat 6 for complete control of nausea; 1.28 (1.08 to 1.51), NNT 8 for complete control of vomiting. Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles: 2.39 (2.05 to 2.78), NNT 3. Some potentially beneficial side effects occurred more often with cannabinoids: “high” 10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness 1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to 52.1), NNT 7. Harmful side effects also occurred more often with cannabinoids: dizziness 2.97 (2.31 to 3.83), NNT 3; dysphoria or depression 8.06 (3.38 to 19.2), NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17; paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given cannabinoids were more likely to withdraw due to side effects 4.67 (3.07 to 7.09), NNT 11. Conclusions: In selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness. Potentially serious adverse effects, even when taken short term orally or intramuscularly, are likely to limit their widespread use. What is already known on this topic What is already known on this topic Requests have been made for legalisation of cannabis (marijuana) for medical use Long term smoking of cannabis can have physical and neuropsychiatric adverse effects Cannabis may be useful in the control of chemotherapy related sickness
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The discovery of carboxylic acid metabolites of the cannabinoids (CBs) dates back more than three decades. Their lack of psychotropic activity was noted early on, and this resulted in a total absence of further research on their possible role in the actions of the CBs. More recent studies have revealed that the acids possess both analgesic and anti-inflammatory properties and may contribute to the actions of the parent drug. A synthetic analog showed similar actions at considerably lower doses. In this review, a brief survey of the extensive literature on metabolism of Δ9-tetrahydrocannabinol to the acids is presented, while more emphasis is given to the recent findings on the biological actions of this class of CBs. A possible mechanism involving effects on eicosanoids for some of these actions is also suggested. Finally, an analogy with a putative metabolite of anandamide, an endogenous CB, is discussed.
Article
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The pharmacokinetics of intravenously administered 14C-Δ9-tetrahydrocannabinol and derived radiolabeled metabolites were studied in three dogs at two doses each at 0.1 or 0.5 and 2.0 mg/kg. Two dogs were biliary cannulated; total bile was collected in one and sampled in the other. The time course for the fraction of the dose per milliliter of plasma was best fit by a sum of five exponentials, and there was no dose dependency. No drug was excreted unchanged. The mean apparent volume of distribution of the central compartment referenced to total drug concentration in the plasma was 1.31 ± 0.07 liters, approximately the plasma volume, due to the high protein binding of 97%. The mean metabolic clearance of drug in the plasma was 124 ± 3.8 ml/min, half of the hepatic plasma flow, but was 4131 ± 690 ml/min referenced to unbound drug concentration in the plasma, 16.5 times the hepatic plasma flow, indicating that net metabolism of both bound and unbound drug occurs. Apparent parallel production of several metabolites occurred, but the pharmacokinetics of their appearance were undoubtedly due to their sequential production during liver passage. The apparent half-life of the metabolic process was 6.9 M-1 0.3 min. The terminal half-life of Δ9-tetrahydrocannabinol in the pseudo-steady state after equilibration in an apparent overall volume of distribution of 2170 ± 555 liters referenced to total plasma concentration was 8.2 ± 0.23 days, based on the consistency of all pharmacokinetic data. The best estimate of the terminal half-life, based only on the 7000 min that plasma levels could be monitored with the existing analytical sensitivity, was 1.24 days. However, this value was inconsistent with the metabolite production and excretion of 40–45% of dose in feces, 14–16.5% in urine, and 55% in bile within 5 days when 24% of the dose was unmetabolized and in the tissue at that time. These data were consistent with an enterohepatic recirculation of 10–15% of the metabolites. Intravenously administered radiolabeled metabolites were totally and rapidly eliminated in both bile and urine: 88% of the dose in 300 min with an apparent overall volume of distribution of 6 liters. These facts supported the proposition that the return of Δ9-tetrahy-drocannabinol from tissue was the rate-determining process of drug elimination after initial fast distribution and metabolism and was inconsistent with the capability of enzyme induction to change the terminal half-life.
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1. Chemical content, assay procedures, and pharmacokinetics of cannabis sativa are discussed briefly.2. Cannabinoid cellular effects relating to chromosomes and immunity including cellular metabolism and allergic reactions are presented.3. Gross and microscopic brain pathology due to cannabis use is reviewed involving EEG alterations, psychopathology including aggressive behaviour as well as properties of psychomotor impairment, tolerance and dependence.4. Cardiopulmonary effects of marihuana are recorded under pulmonary pharmacological effects including the macrophage defense system and effects of smoke constituents; under cardiovascular effects cardiac toxicity and possible mechanism of action are discussed.5. Alterations of reproductive hormonal production and maturation of reproductive cells by marihuana in males and females with attendant impairment of reproductive function or fertility including reproductive outcome are reported.6. Field studies with healthy chronic cannabis users in Jamaica, Greece and Costa Rica are related as to observed medical alterations.7. Potential clinical effects are summarized in point form.
1. Single doses of an aqueous suspension of [14C]-Δ9-tetrahydrocannabinol (Δ9-THC) were administered by intraperitoneal injection to groups of male and female CBA strain mice.2. Experimental groups were sacrificed from 2 min to 6 hr following injection, and levels of Δ9-THC and its more polar metabolites determined in several tissues.3. High levels of Δ9-THC were found in several fat bodies, along with liver and lung. Moreover, there was a large difference in the levels of cannabinoid accumulation in the fat organs studied, with significantly higher concentrations as well as absolute amounts of cannabinoid being found in gonadal fat.4. The high Δ9-THC concentrations persisted in fat over several hours without significant metabolism, while in liver, lung and several other tissues, the level of Δ9-THC declined as substantial metabolism occurred during the same period.5. The relative levels of cannabinoid found in various tissues were also examined after intravenous administration of the drug and a differential uptake of Δ9-THC and its metabolites by gonadal fat was again observed.
Article
The pharmacokinetics of intravenously administered 14C-delta9-tetrahydrocannabinol and derived radiolabeled metabolites were studied in three dogs at two doses each at 0.1 or 0.5 and 2.0 mg/kg. Two dogs were biliary cannulated; total bile was collected in one and sampled in the other. The time course for the fraction of the dose per milliliter of plasma was best fit by a sum of five exponentials, and there was no dose dependency. No drug was excreted unchanged. The mean apparent volume of distribution of the central compartment referenced to total drug concentration in the plasma was 1.31 +/- 0.07 liters, approximately the plasma volume, due to the high protein binding of 97%. The mean metabolic clearance of drug in the plasma was 124 +/- 3.8 ml/min, half of the hepatic plasma flow, but was 4131 +/- 690 ml/min referenced to unbound drug concentration in the plasma, 16.5 times the hepatic plasma flow, indicating that net metabolism of both bound and unbound drug occurs. Apparent parallel production of several metabolites occurred, but the pharmacokinetics of their appearance were undoubtedly due to their sequential production during liver passage. The apparent half-life of the metabolic process was 6.9 +/- 0.3 min. The terminal half-life of delta9-tetrahydrocannabinol in the pseudo-steady state after equilibration in an apparent overall volume of distribtuion of 2170 +/- 555 liters referenced to total plasma concentration was 8.2 +/- 0.23 days, based on the consistency of all pharmacokinetic data. The best estimate of the terminal half-life, based only on the 7000 min that plasma levels could be monitored with the existing analytical sensitivity, was 1.24 days. However, this value was inconsistent with the metabolite production and excretion of 40-45% of dose in feces, 14-16.5% in urine, and 55% in bile within 5 days when 24% of the dose was unmetabolized and in the tissue at that time. These data were consistent with an enterohepatic recirculation of 10-15% of the metabolites. Intravenously administered radiolabeled metabolites were totally and rapidly eliminated in both bile and urine; 88% of the dose in 300 min with an apparent overall volume of distribution of 6 liters. These facts supported the proposition that the return of delta9-tetrahydrocannabinol from tissue was the rate-determining process of drug elimination after initial fast distribution and metabolism and was inconsistent with the capability of enzyme induction to change the terminal half-life.
Article
A knowledge of pharmacokinetic data is particularly important with drugs that have a narrow margin of safety. Exhaustive pre-marketing pharmacokinetic investigations and pharmacokinetic studies in populations are the two principal means of acquiring such knowledge. Although popular, the concept of half-life which decreases with age for many drugs is insufficient to calculate dosage in elderly people. Measurements of creatinine clearance provide an almost mathematical approach to the dosage of drugs that are excreted exclusively by the kidneys. In contrast, changes in hepatic metabolism with age and pathology are difficult to evaluate, and their consequences are often vaguely perceived. Our knowledge of relationships between age and pharmacodynamics is still in infancy. Owing to the wide consumption of medicine by elderly people, drug interactions are frequent at all stages, including absorption, metabolization, transport and site of action.
Article
14C-delta-tetrahydrocannabinol (14C-Δ9THC) was administered to 12 long-term marihuana smokers intravenously, orally or by inhalation, and the drug's disposition, excretion and psychologic effects compared. Over 90 per cent of the dose was absorbed after oral administration; the psychologic effects and plasma levels of metabolites of Δ9,-THC peaked at three hours. After inhalation, the peak psychologic "high" ranged from 10 to 140 minutes (average peak "high" of 70 minutes), correlating well with the peak plasma levels of metabolites of Δ9-THC. The percentage of administered radioactive dose excreted in urine during the first day was similar after oral and intravenous routes, but the proportion of radioactivity recovered from feces (seven days) exceeded that in the one-day urine output. The fact that the psychologic effects in response to pharmacologic doses of ingested or inhaled 14C-Δ9-THC were temporally correlated with plasma levels of the metabolites of the drug supports the hypothesis that t...
Article
Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.