844 VOLUME 90 NUMBER 6 | dEcEMBER 2011 | www.nature.com/cpt
nature publishing group
See commentary page 769
Selecting an appropriate treatment for chronic pain remains
problematic. Although opioids are effective analgesics, dose-
limiting side effects such as sedation, nausea and vomiting, and
fear of dependence often limit their use at higher—and possibly
more effective—doses. Of particular interest is the potential for
enhanced analgesic effect with the use of cannabinoids and opio-
ids in combination. Such a combination would allow for opioid
analgesic effects to be achieved at lower dosages than are neces-
sary when the opioids are used alone.1–4 As increasing numbers
of patients turn to medicinal cannabis to augment the effects of
opioid analgesics, the data on the potential pharmacokinetic
interactions and clinical safety of the combination need to be
Cannabinoids and opioids share several pharmacologic prop-
erties, including antinociception; a tendency to induce hypo-
thermia, sedation, and hypotension; and inhibition of intestinal
motility and locomotor activity.1,5,6 Initially, investigators postu-
lated that cannabinoids and opioids act on the same pathways to
produce their pharmacological actions.7,8 Subsequent preclinical
research conducted over the past decade has clarified the nature
of the interaction; these data suggest the existence of independ-
ent but related mechanisms of antinociception for cannabinoids
Synergy in analgesic effects between opioids and cannabinoids
has been demonstrated in animal models. The antinociceptive
effects of morphine are mediated predominantly by mu opioid
receptors but may be enhanced by delta-9-tetrahydrocannab-
inol (THC) activation of kappa and delta opiate receptors.8
It has further been suggested that the cannabinoid–opioid
interaction may occur at the level of their signal transduction
mechanisms.9,10 Receptors for both classes of drugs are cou-
pled to similar intracellular signaling mechanisms that lead to
a decrease in cyclic adenosine monophosphate production via
G protein activation.10–12 There is also some evidence that can-
nabinoids increase the synthesis and/or release of endogenous
In addition to these potential pharmacodynamic interactions,
there is the potential for pharmacokinetic interaction between
cannabinoids and other drugs. Cannabinoids have been shown
to affect the kinetics of other drugs in several ways. They inhibit
the CYP450-mediated metabolism of some drugs, slow the
absorption of others, and may also enhance penetration of some
drugs into the brain.14–16 Our prior study of oral delta-9-THC
and smoked cannabis in patients with HIV on protease inhibitor
therapies showed that oral THC had no effect on the pharma-
cokinetics of the antiviral agents.17 However, smoked cannabis
decreased the 8-h area under the plasma concentration–time
curve (AUC) of both nelfinavir (−17.4%, P = 0.46) and indi-
navir (−14.5%, P = 0.07). In a study involving 24 patients with
cancer, cannabis administered as a medicinal tea did not alter
the pharmacokinetics of the chemotherapy agents irinotecan
1division of Hematology–Oncology, San Francisco General Hospital, University of california, San Francisco, San Francisco, california, USA; 2center for AIdS Prevention
Studies, University of california, San Francisco, San Francisco, california, USA; 3division of clinical Pharmacology and Experimental Therapeutics, University of
california, San Francisco, San Francisco, california, USA. correspondence: dI Abrams (firstname.lastname@example.org)
Received 5 May 2011; accepted 12 July 2011; advance online publication 2 November 2011. doi:10.1038/clpt.2011.188
cannabinoid–Opioid Interaction in chronic Pain
DI Abrams1, P Couey1, SB Shade2, ME Kelly1 and NL Benowitz3
Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential
pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to
answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-
release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were
asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2–4, and in the morning of day
5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily.
Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration–time curves
for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95%
confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis
augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow
for opioid treatment at lower doses with fewer side effects.
ClInICal PharmaCology & TheraPeuTICs | VOLUME 90 NUMBER 6 | dEcEMBER 2011
Inhalation of vaporized cannabis delivers levels of THC and
other cannabinoids similar to those from smoked marijuana but
without exposure to combustion products.19 Here we describe
the disposition kinetics of sustained-release morphine and oxy-
codone, as well as pain ratings and other subjective responses,
before and after 4 days of treatment with vaporized cannabis.
A total of 315 potential participants were assessed for eligibility
between January 2007 and February 2009; most of them were
deemed ineligible because they either did not have pain, were
not taking the appropriate opioids, or were receiving opioids
three times a day. A total of 24 participants were enrolled, 13 of
whom were on morphine treatment and 11 on oxycodone. Of
those on morphine, 3 participants did not complete the study,
leaving 21 evaluable participants (10 on morphine, and 11 on
oxycodone) (see Table 1). Most of the participants (11 men and
10 women) were white. The average age was 42.9 (range = 33–55)
years in the morphine cohort and 47.1 (range = 28–61) years
in the oxycodone cohort. The mean morphine dose was 62 mg
twice a day (range = 10–200 mg) and the mean oxycodone dose
was 53 mg twice a day (range = 10–120 mg). The origin of the
participants’ pain was musculoskeletal (not otherwise specified)
(seven); posttraumatic (four); arthritic (two); peripheral neu-
ropathy (two); cancer, fibromyalgia, migraine, multiple sclerosis,
sickle cell disease, and thoracic outlet syndrome (one each).
Pain ratings on day 1 (before exposure to vaporized canna-
bis) and on day 5 (after exposure to vaporized cannabis) are
shown in Table 2. Participants on oxycodone had higher mean
pain scores at baseline (mean = 43.8; 95% confidence interval
(CI) = 38.6, 49.1) compared with those on morphine (mean =
34.8; 95% CI = 29.4, 40.1). Participants in both groups reported
statistically significant reductions in pain ratings on day 5 as
compared with day 1. The mean percentage change in pain was
statistically significant overall as well as for the patients on mor-
phine, but not for those on oxycodone.
opioid disposition kinetics
Mean plasma concentration–time curves for morphine and
oxycodone with and without cannabis treatment are shown in
Figure 1. There was no statistically significant change in the
AUC12 for either of these opiates (see Table 3). There was a sta-
tistically significant decrease in maximum concentration (Cmax)
of morphine sulfate during cannabis exposure. The time to Cmax
of morphine tended to be delayed during cannabis treatment,
although this effect was not statistically significant. Cannabis
had no significant effect on oxycodone kinetics. During cannabis
treatment, there were no significant changes in the AUCs of the
metabolites of either morphine or oxycodone or in the ratios of
individual metabolites to the parent drug.
Plasma tHc levels
Mean plasma THC levels were 1.8 ng/ml (SD = 1.5) at base-
line, 126.1 ng/ml (SD = 86.2) at 3 min, 33.7 ng/ml (SD = 28.9) at
10 min, 10.9 ng/ml (SD = 9.3) at 30 min, and 6.4 ng/ml (SD = 5.6)
at 60 min. The peak THC concentration occurred at 3 min in all
the participants. THC plasma levels did not vary significantly
by opioid group.
monitoring of effects
Cannabis inhalation produced a subjective “high” that was not
present with the use of opioids alone (see Figure 2). In addition,
the participants in the morphine cohort felt significantly more
stimulated and less hungry on day 5 than on day 1 (see Table 4),
whereas those in the oxycodone group were less anxious on day
5 as compared with day 1. Other than these, there were no sig-
nificant changes in the subjective effects measured. No clinically
significant adverse events were reported. Pulse oximetry moni-
toring did not reveal any episodes of lowered oxygen saturation
after cannabinoids were added to the participants’ stable opioid
Our study findings support preclinical observations that cannabis
augments the analgesic effects of opioids. We studied individuals
with chronic pain who were taking stable doses of sustained-
table 1 Participant characteristics
morphine group oxycodone group
Mean age (range)42.9 (33–55) 47.1 (28–61)
Mean opioid dose
62 Twice daily (10–200)53 Twice daily (10–120)
Mean pain score day
1 (95% cI)
34.8 (29.4, 40.1) 43.8 (38.6, 49.1)
cI, confidence interval.
table 2 Pain by study day
Day 1 Day 5 DifferencePercentage change
mean (95% CI) mean (95% CI)mean (95% CI)mean (95% CI)
Overall 21 39.6 (35.8, 43.3)29.1 (25.4, 32.8) −10.7 (−14.4, −7.3)−27.2 (−45.5, −8.9)
Morphine 1134.8 (29.4, 40.1) 24.1 (18.8, 29.4) −11.2 (−16.5, −6.0) −33.7 (−63.8, −3.5)
Oxycodone1043.8 (38.6, 49.1) 33.6 (28.5, 38.6)−10.3 (−14.8, −5.8)−21.3 (−47.0, 5.3)
cI, confidence interval.
846 VOLUME 90 NUMBER 6 | dEcEMBER 2011 | www.nature.com/cpt
release morphine or oxycodone. The participants experienced
less pain after 5 days of inhaling vaporized cannabis; when the
morphine and oxycodone groups were combined, this reduction
in pain was significant. This is the first human study to demon-
strate that inhaled cannabis safely augments the analgesic effects
of opioids. Several other studies have examined the analgesic
interaction between oral THC and opioids. Two of those studies
involved healthy volunteers exposed to experimental pain condi-
tions.14,20 THC had little effect in either of the studies, whereas
the combination of THC and morphine had synergistic effects
on affective responses to pain in one study and on response to
electrical stimulation in the other. A placebo-controlled trial in
patients taking opioids for chronic pain found that oral dronabi-
nol (delta-9-THC) decreased pain significantly.15
The mechanism by which cannabis augments the analgesic
effects of opioids could be pharmacokinetic and/or pharmaco-
dynamic. Cannabinoids have been shown to inhibit the metab-
olism of certain other drugs, both in vitro and in vivo.16,21,22
THC has been shown to slow gastrointestinal motility, result-
ing in the slowing of absorption of orally administered drugs
such as pentobarbital and ethanol. THC has also been shown
to slow the intranasal absorption of cocaine.23–25 In animals,
cannabinoids have been shown to enhance the uptake of drugs,
including cocaine and phencyclidine, into the brain; however,
the mechanisms involved are not fully understood.26
In the present study, we examined the effects of vaporized can-
nabis administered three times a day on the steady-state phar-
macokinetics of sustained-release morphine and oxycodone
administered at 12-h intervals. In the case of morphine, we
found that cannabis treatment was associated with a significant
decrease in the maximal concentration. On average, the time to
maximal morphine concentration was longer during cannabis
administration, although this effect was not significant. There
were no significant effects of cannabis treatment on the AUCs of
morphine’s metabolites or on the ratios of metabolites to parent
morphine, indicating that cannabis had no effects on metabolic
pathways. Vaporized cannabis had no significant effect on oxyco-
done kinetics or metabolite levels. The finding of a lower maximal
concentration of morphine without any accompanying changes
in metabolite levels during cannabis treatment is probably due to
delayed absorption of morphine, presumably because of slowed
gastrointestinal motility. Why such an effect was not seen for oxy-
codone is not clear. From the pharmacokinetic findings, it is clear
that the observed augmentation of analgesia by cannabis cannot
be explained on the basis of inhibition of morphine or oxycodone
metabolism leading to higher plasma levels of these drugs.
Our findings suggest that cannabis augments opioid anal-
gesia through a pharmacodynamic mechanism. However,
prior research in rodents has shown that THC and cannabid-
iol enhance the penetration of certain other drugs, including
cocaine and phencyclidine, into the brain.26 If cannabinoids
also enhance opioid penetration into the brain in humans, this
might constitute a pharmacokinetic mechanism for enhancing
the analgesic effects of opioids.
The participants reported a subjective high after inhaling can-
nabis, with little or no high after taking the oral opioids alone.
Although we do not have data on the high in these participants
in the absence of opioids (that is, with cannabis alone), the mag-
nitude and time course of the high in the participants in the
morphine group were similar to our observations in a previous
study of inhaled cannabis in healthy subjects.19 The high in the
oxycodone group after cannabis treatment appeared to be more
sustained than that in the morphine group, and also as compared
with that of our previously studied healthy subjects.
Morphine plasma level
Day 1 Day 5
Oxycodone plasma level
68 10 12
Figure 1 Plasma concentration–time curves for sustained-release (a) morphine
and (b) oxycodone before and after exposure to inhaled cannabis.
Day 1 Day 5
Day 1 Day 5
Figure 2 Subjective highs experienced when cannabis was combined with
(a) morphine and (b) oxycodone on day 5.
ClInICal PharmaCology & TheraPeuTICs | VOLUME 90 NUMBER 6 | dEcEMBER 2011
Our study has some limitations. The number of participants
was relatively small, although we were powered to detect a 25%
change in the 12-hour AUC (AUC12). With respect to pain assess-
ment, our study was not placebo-controlled, and therefore we
cannot rule out the possibility that cannabis-enhanced analgesia
was a placebo effect or a time effect of changes in activity levels
associated with confinement in the inpatient research ward setting
throughout the duration of the study. The intervention we used
was vaporized cannabis, which delivers levels of THC and other
cannabinoids similar to those of smoked cannabis without expos-
ing the user to the combustion products of cannabis cigarettes,
which could affect the metabolism and pulmonary uptake of other
drugs. Oral cannabis is commonly used to deliver medicinal THC
and results in high first-pass levels of cannabinoids in the liver,
which could have effects on opioid metabolism different from
those caused by vaporized cannabis. Therefore, further research
is needed to determine how different cannabis delivery systems
affect the metabolism of opioids and other drugs.
In conclusion, we found that vaporized cannabis augments
analgesia in individuals with chronic pain on a treatment regi-
men of stable doses of sustained-release morphine or oxyco-
done, and that the mechanism of augmentation is not explained
by elevation of plasma opioid concentrations or inhibition of
opioid metabolism. Cannabis appears to slow morphine absorp-
tion such that maximal concentrations for a dosing interval
are lower. The effect of inhaled cannabis in enhancing opiate
analgesia is most likely achieved through a pharmacodynamic
mechanism. These results suggest that further controlled studies
of the synergistic interaction between cannabinoids and opioids
table 3 morphine, oxycodone, and their metabolites: mean auc and cV by study day
Day 1 Day 5Day 5/day 1
meanCV ratio95% CI
Morphine and its metabolites
10 3.1 104.74 1.64 −1.01, 4.300.190.2
1043.6815.9510 29.6615.740.9 0.85, 0.95
10 42.0118.710 32.23 15.230.95 0.84, 1.050.17 0.23
10 1,123.94 6.89 10887.14 4.56 0.97 0.93, 1.000.060.08
10 821.399.54 10 756.73 7.411 0.92, 1.07 0.741
10 188.67 16.28 10 153.22 6.530.97 0.92, 1.010.11 0.16
10128.25 10.41 10130.45 10.941.02 0.90, 1.150.95 0.85
M3g/morphine 106.32 17.6610 6.92 6.921.060.98, 1.15 0.23 0.19
M6g/morphine 103.79 22.6910 4.13 4.131.090.98, 1.21 0.250.08
Oxycodone and its metabolites
113.63 112.52 −1.11 −3.66, 1.43 0.350.9
1164.9112.87 11 62.7416.67 0.99 0.89, 1.100.841
11 76.8613.3811 58.6719.18 0.940.84, 1.04 0.18 0.32
11 52.7214.69 11 65.1711.781.07 0.96, 1.17 0.220.46
11 38.6715.1 11 36.97 17.111.01 0.85, 1.160.860.7
111.42203.31 11 1.39 175.910.15 −1.67, 1.960.9 0.82
101.32334.96101.25302.370.630.00, 1.26 0.780.77
Noroxycodone/oxycodone112.34 18.33112.49 21.911.090.93, 1.25 0.31 0.37
Oxymorphone/oxycodone101.07 328.32 10 1.05354.88 0.7−0.01, 1.41 0.63 0.63
Statistically significant values are in bold face. AUc, area under the plasma concentration–time curve; cI, confidence interval; Cmax, maximum concentration; cV, coefficient of
variation; M3g, morphine-3-glucuronide; M6g, morphine-6-glucuronide; N-par, nonparametric; Par, parametric; Tmax, time to maximum concentration.
aTmax values are expressed as arithmetic means on each study day with standard deviation as the measure of variance. comparisons of Tmax values on day 1 and day 5 are
expressed as the paired difference in these values (day 5 − day 1).
848 VOLUME 90 NUMBER 6 | dEcEMBER 2011 | www.nature.com/cpt
table 4 Subjective effects: morphine vs. morphine/cannabis and oxycodone vs. oxycodone/cannabis
Morphine vs. morphine/cannabis
AUc 10 2.992.99
10 13.6 24.57
AUc 100.55 1.08
AUc 10 1.73 1.84
Day 5 – day 1
Oxycodone vs. oxycodone/cannabis
Statistically significant values are in bold face. AUc, area under the plasma concentration–time curve; cI, confidence interval; Cmax, maximum concentration.
ClInICal PharmaCology & TheraPeuTICs | VOLUME 90 NUMBER 6 | dEcEMBER 2011
Study participants. The participants were adults >18 years of age
who were experiencing chronic pain and receiving ongoing anal-
gesic therapy with sustained-release morphine sulfate (MS Contin)
or oxycodone hydrochloride (OxyContin) every 12 h. The partici-
pants were required to have been on a stable medication regimen for
at least 2 weeks prior to the commencement of the study. Hepatic
transaminase levels were required to be within 5 times the upper
limit of normal and serum creatinine to be <2.0 mg/dl (177 µmol/l).
A negative pregnancy test was required for female participants.
Exclusion criteria included severe coronary artery disease, uncon-
trolled hypertension, cardiac ventricular conduction abnormalities,
orthostatic mean blood pressure drop of >24 mm Hg, severe chronic
obstructive pulmonary disease, history of renal or hepatic failure,
active substance abuse, neurologic dysfunction or psychiatric dis-
order severe enough to interfere with assessment of pain, current
use of smoked tobacco products or a confirmed cotinine level, and,
in women, pregnancy, breastfeeding, or not using adequate birth
All the participants were required to have prior experience of smoking
cannabis (six or more times in their lifetime) so that they would know
how to inhale and what neuropsychologic effects to expect. Current users
were asked to discontinue cannabis use for 30 days prior to commence-
ment of the study, and such abstention was confirmed by a negative urine
THC assay prior to study enrollment.
The study was approved by the institutional review board at the Uni-
versity of California, San Francisco; the Research Advisory Panel of Cali-
fornia; the Drug Enforcement Administration; the US Food and Drug
Administration, and the National Institute on Drug Abuse. Written
informed consent was obtained from all the participants. The Clinical-
Trials.gov registration number was NCT00308555.
Study medication. The National Institute on Drug Abuse provided can-
nabis in the form of cigarettes weighing 0.9 g on average and containing
3.56% delta-9-THC. The cigarettes were kept in a locked freezer with
an alarm device attached until they were dispensed to a locked freezer
in the San Francisco General Hospital Clinical Research Center where
the inpatient study was conducted. The frozen cigarettes were thawed
and rehydrated overnight in a humidifier. The cannabis was removed
from the prerolled cigarettes and administered in a Volcano vaporizer
(Model #0100 CS; Tuttlingen, Germany), heated to 190 °C.27 The study
participants were housed in a room with a fan ventilating to the outside.
To maximize standardization of the vaporized doses, the subjects fol-
lowed a uniform puffing procedure: the cannabis was inhaled for 5 s and
then held for 10 s, with a 45-s pause before a repeat inhalation.28 The
participants were encouraged to inhale the entire vaporized dose of 0.9 g
of 3.56% delta-9-THC or as much as they could tolerate.
In a previous study we had demonstrated that this vaporization pro-
cedure results in plasma THC levels similar to those induced by smoked
marijuana but without significant exposure to carbon monoxide and
other combustion products.19
opioid disposition kinetics. Opioid pharmacokinetics were determined
on days 1 and 5 from blood samples drawn at baseline and again at 1,
2, 4, 6, 8, 10, and 12 h after oral opioid administration. Given that the
opioids were administered every 12 h, these measurements represent
plasma concentration levels at steady state. On day 5, in addition to the
opioid pharmacokinetics samples, THC plasma levels were measured
at baseline and at 3, 10, 30, and 60 min to determine THC exposure for
purposes of comparison with findings of prior and future studies. Our
previous studies had demonstrated that this time course encompasses
most of the THC AUC.19
The main outcome measure was the AUC12 for morphine and its
glucuronide metabolites, or for oxycodone and its major metabolites,
oxymorphone and noroxycodone.
Samples were shipped in a frozen state to the Center for Human
Toxicology at the University of Utah, where they were analyzed for
cannabinoids, morphine, and oxycodone using published procedures.
Briefly, morphine, morphine-3-glucuronide, and morphine-6-glucuro-
nide were measured using liquid chromatography with electrospray
ionization–tandem mass spectrometry, with lower limits of quantifica-
tion of 0.50 and 0.25 ng/ml for morphine and the glucuronides, respec-
tively.29 Oxycodone, oxymorphone, and noroxycodone were measured
using liquid chromatography with electrospray ionization–tandem mass
spectrometry, with lower limits of quantification of 0.2 ng/ml for all ana-
Cannabinoid measurements were obtained using a combination of
modifications of previously published methods. The samples under-
went liquid–liquid extraction,31 and both extracts were combined
and then derivatized and analyzed as previously described,32 except
that the method was modified to suit a different instrument (i.e., a
Hewlett Packard 5890 GC (Palo Alto, CA) equipped with a DB-5 MS,
30 m × 0.25 mm, 0.25-mm column and interfaced with a Finnigan
MAT SSQ 7000 MS (San Jose, CA) in negative chemical ionization
effects monitoring. Objective and subjective effects were meas-
ured to assess whether vaporized cannabis increases or attenuates
the side effects associated with opioid analgesics. Subjective effects
were assessed via participants’ self-reports using the Drug Effects
Questionnaire administered before the morning opioid dose and
again at 30 min and 1, 2, 4, 6, 8, 10, and 12 h after drug administration
on days 1 and 5. This questionnaire records subjective findings using
standard visual analog scales where 0 is “no effect” and 100 is “maxi-
mal effect.”33 Assessment of drug effects included pain, stimulation,
anxiety, sedation, feeling “down,” hunger, mellowness, confusion, irri-
tation, depression, feeling withdrawn, dizziness, nausea, and dryness
of the mouth. In addition, the subjects were evaluated by the nursing
staff for side effects every 4 h, recording scores for anxiety, sedation,
disorientation, paranoia, confusion, dizziness, nausea, urinary reten-
tion, constipation, emesis, headache, swollen extremities, twitching,
excitement, and level of consciousness on a scale from 0 to 4. The
participants were monitored daily for nausea and vomiting using the
Rhodes Index of Nausea, Vomiting, and Retching Questionnaire.34
Because there was a concern that enhanced opioid effects could lead
to respiratory depression, continuous pulse oximetry was performed
every night, with the results documented every 2 h on the nursing
Sample size: In a published study of individuals who took morphine on
an empty stomach, the standard deviation of the within-person change
in log (AUC10) for a morphine solution was 20% over the course of 12
months.35 Using this information, we estimated that, with a sample of
10 subjects, the study would have 80% power to detect a 25% percent
change in the AUC12 between days 1 and 5. This estimate was based on
a standardized effect size (E/S) of 1.25, using an alpha of 0.05, where E
is the within-subject effect size (25%) and S is the standard deviation
of the mean of the paired differences (20%) using a paired t-test.36,37
In prior pharmacokinetics studies, a 30% change in AUC was thought
to be clinically significant.38 Therefore, we set the target size at 25% to
ensure that we would be able to capture a clinically significant change in
AUC12. We enrolled at least 10 participants in each of the two (morphine
and oxycodone) groups.
Data analysis: We described the characteristics of the participants at
study entry overall and within each opioid group. We presented the mean
(with 95% CI) plasma levels for each opioid over the 12-h observation
period on days 1 and 5.
The primary outcome was the change in the AUC12 for morphine
or oxycodone before and after cannabis exposure. We standardized
plasma levels for each opioid to doses of 60 mg b.i.d. (observed opioid
plasma level × (60 mg/administered opioid dose)). The standardized
AUC12 was derived using the trapezoidal method over the dosing inter-
val. We estimated the geometric mean and coefficient of variation in
850 VOLUME 90 NUMBER 6 | dEcEMBER 2011 | www.nature.com/cpt
the standardized AUC on days 1 and 5. We then computed the ratio
of the geometric means (with 95% CI) for day 5/day 1. We tested the
hypothesis of a statistically significant change in standardized AUC12 of
at least 25%, using paired t-tests and nonparametric Wilcoxon signed-
rank tests. We also assessed the percentage change in the geometric
mean for Cmax and the arithmetic mean for time to maximum concen-
tration from the plasma concentration-vs.-time data for each subject.
We used similar methods to describe results and assess changes for
plasma concentrations of the metabolites of morphine (morphine-3-
glucuronide and morphine-6-glucuronide) and oxycodone (oxymor-
phone and noroxycodone). We assessed the mean THC plasma levels
(with 95% CIs) for a duration of 1 h, for the participants overall as well
as by opioid group.
We described the mean pain ratings on days 1 and 5, both overall and
within each opioid group, using mean values and 95% CIs. We assessed
the mean values (with 95% CI) of individual differences and percent-
age changes in pain between days 1 and 5, both overall and within each
opioid group, using paired t-tests.
Next, we assessed the subjective effects of vaporized marijuana among
these participants. We represented the mean perceived high over the
dosing period on days 1 and 5 for each opioid group. In addition, we
estimated the mean value (with 95% CI) of each subjective effect on days
1 and 5 and determined statistically significant changes in the mean val-
ues (with 95% CI) of individual differences, using paired t-tests for each
We are grateful to all of our study participants; to Anand dhruva for
his assistance with inpatient evaluations; and to Hector Vizoso and the
staff of the San Francisco General Hospital clinical Research center for
their excellent patient care. This publication was supported by National
Institutes of Health (NIH)/NcRR UcSF-cTSI grant UL1 RR024131 and grants
NIdA R21, dA020831-01, N01dA-3-8829, and N01dA-9-7767. Its contents
are solely the responsibility of the authors and do not necessarily represent
the official views of the NIH.
conFlict oF intereSt
The authors declared no conflict of interest.
© 2011 American Society for clinical Pharmacology and Therapeutics
1. cichewicz, d.L. Synergistic interactions between cannabinoid and opioid
analgesics. Life Sci. 74, 1317–1324 (2004).
Smith, F.L., cichewicz, d., Martin, Z.L. & Welch, S.P. The enhancement of
morphine antinociception in mice by delta9-tetrahydrocannabinol.
Pharmacol. Biochem. Behav. 60, 559–566 (1998).
cichewicz, d.L., Martin, Z.L., Smith, F.L. & Welch, S.P. Enhancement mu opioid
antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis
and receptor identification. J. Pharmacol. Exp. Ther. 289, 859–867 (1999).
cichewicz, d.L. & Mccarthy, E.A. Antinociceptive synergy between delta(9)-
tetrahydrocannabinol and opioids after oral administration. J. Pharmacol. Exp.
Ther. 304, 1010–1015 (2003).
Manzanares, J., corchero, J., Romero, J., Fernández-Ruiz, J.J., Ramos, J.A. &
Fuentes, J.A. Pharmacological and biochemical interactions between opioids
and cannabinoids. Trends Pharmacol. Sci. 20, 287–294 (1999).
Massi, P., Vaccani, A., Romorini, S. & Parolaro, d. comparative characterization
in the rat of the interaction between cannabinoids and opiates for their
immunosuppressive and analgesic effects. J. Neuroimmunol. 117,
Johnson, M.R., Melvin, L.S. & Milne, G.M. Prototype cannabinoid analgetics,
prostaglandins and opiates–a search for points of mechanistic interaction.
Life Sci. 31, 1703–1706 (1982).
Pugh, G. Jr, Smith, P.B., dombrowski, d.S. & Welch, S.P. The role of endogenous
opioids in enhancing the antinociception produced by the combination of
delta 9-tetrahydrocannabinol and morphine in the spinal cord. J. Pharmacol.
Exp. Ther. 279, 608–616 (1996).
Welch, S.P. & Stevens, d.L. Antinociceptive activity of intrathecally
administered cannabinoids alone, and in combination with morphine, in
mice. J. Pharmacol. Exp. Ther. 262, 10–18 (1992).
10. Welch, S.P. & Eads, M. Synergistic interactions of endogenous opioids and
cannabinoid systems. Brain Res. 848, 183–190 (1999).
11. Welch, S.P., Thomas, c. & Patrick, G.S. Modulation of cannabinoid-
induced antinociception after intracerebroventricular versus intrathecal
administration to mice: possible mechanisms for interaction with morphine. J.
Pharmacol. Exp. Ther. 272, 310–321 (1995).
12. Pugh, G. Jr, Welch, S.P. & Bass, P.P. Modulation of free intracellular calcium
and cAMP by morphine and cannabinoids, alone and in combination in
mouse brain and spinal cord synaptosomes. Pharmacol. Biochem. Behav. 49,
13. Kaymakçalan, S. Pharmacological similarities and interactions between
cannabis and opioids. Adv. Biosci. 22-23, 591–604 (1978).
14. Roberts, J.d., Gennings, c. & Shih, M. Synergistic affective analgesic interaction
between delta-9-tetrahydrocannabinol and morphine. Eur. J. Pharmacol. 530,
15. Narang, S. et al. Efficacy of dronabinol as an adjuvant treatment for chronic
pain patients on opioid therapy. J. Pain 9, 254–264 (2008).
16. Mitra, G., Poddar, M.K. & Ghosh, J.J. In vivo and in vitro effects of delta-9-
tetrahydrocannabinol on rats liver microsomal drug-metabolizing enzymes.
Toxicol. Appl. Pharmacol. 35, 523–530 (1976).
17. Abrams, d.I. et al. Short-term safety of cannabinoids in HIV infection:
results of a randomized, controlled clinical trial. Annals. Intern. Med. 139,
18. Engels, F.K. et al. Medicinal cannabis does not influence the clinical
pharmacokinetics of irinotecan and docetaxel. Oncologist 12,
19. Abrams, d.I., Vizoso, H.P., Shade, S.B., Jay, c., Kelly, M.E. & Benowitz, N.L.
Vaporization as a smokeless cannabis delivery system: a pilot study. Clin.
Pharmacol. Ther. 82, 572–578 (2007).
20. Naef, M., curatolo, M., Petersen-Felix, S., Arendt-Nielsen, L., Zbinden, A. &
Brenneisen, R. The analgesic effect of oral delta-9-tetrahydrocannabinol
(THc), morphine, and a THc-morphine combination in healthy subjects under
experimental pain conditions. Pain 105, 79–88 (2003).
21. Fernandes, M., Warning, N., christ, W. & Hill, R. Interactions of several
cannabinoids with the hepatic drug metabolizing system. Biochem.
Pharmacol. 22, 2981–2987 (1973).
22. Benowitz, N.L. & Jones, R.T. Effects of delta-9-tetrahydrocannabinol on drug
distribution and metabolism. Antipyrine, pentobarbital, and ethanol. Clin.
Pharmacol. Ther. 22, 259–268 (1977).
23. chesher, G.B., dahl, c.J., Everingham, M., Jackson, d.M., Marchant-Williams,
H. & Starmer, G.A. The effect of cannabinoids on intestinal motility and their
antinociceptive effect in mice. Br. J. Pharmacol. 49, 588–594 (1973).
24. Lukas, S.E., Sholar, M., Kouri, E., Fukuzako, H. & Mendelson, J.H. Marihuana
smoking increases plasma cocaine levels and subjective reports of euphoria
in male volunteers. Pharmacol. Biochem. Behav. 48, 715–721 (1994).
25. Lukas, S.E., Benedikt, R., Mendelson, J.H., Kouri, E., Sholar, M. & Amass, L.
Marihuana attenuates the rise in plasma ethanol levels in human subjects.
Neuropsychopharmacology 7, 77–81 (1992).
26. Reid, M.J. & Bornheim, L.M. cannabinoid-induced alterations in brain
disposition of drugs of abuse. Biochem. Pharmacol. 61, 1357–1367 (2001).
27. Hazekamp, A., Ruhaak, R., Zuurman, L., van Gerven, J. & Verpoorte, R.
Evaluation of a vaporizing device (Volcano®) for the pulmonary
administration of tetrahydrocannabinol. J. Pharm. Sci. 95, 1308–1317 (2006).
28. Foltin, R.W., Fischman, M.W. & Byrne, M.F. Effects of smoked marijuana on food
intake and body weight of humans living in a residential laboratory. Appetite
11, 1–14 (1988).
29. Slawson, M.H., crouch, d.J., Andrenyak, d.M., Rollins, d.E., Lu, J.K. & Bailey,
P.L. determination of morphine, morphine-3-glucuronide, and morphine-
6-glucuronide in plasma after intravenous and intrathecal morphine
administration using HPLc with electrospray ionization and tandem mass
spectrometry. J. Anal. Toxicol. 23, 468–473 (1999).
30. Fang, W.B. & Moody, d.E. determination of oxycodone and metabolites by
high performance liquid chromatography-electrospray ionization-tandem
mass spectrometry. Presented at the Society of Forensic Toxicologists Annual
Meeting (durham, Nc, 2007).
31. Foltz, R.L., McGinnis, K.M. & chinn, d.M. Quantitative measurement of
delta 9-tetrahydrocannabinol and two major metabolites in physiological
specimens using capillary column gas chromatography negative ion chemical
ionization mass spectrometry. Biomed. Mass Spectrom. 10,316–323 (1983).
32. Huang, W. et al. Simultaneous determination of Δ9-tetrahydrocannabinol and
11-nor-9-carboxy-Δ9-tetrahydrocannabinol in human plasma by solid-phase
extraction and gas chromatography–negative ion chemical ionization-mass
spectrometry. J. Anal. Toxicol. 25, 531–537 (2001).
ClInICal PharmaCology & TheraPeuTICs | VOLUME 90 NUMBER 6 | dEcEMBER 2011 Download full-text
33. Wewers, M.E. & Lowe, N.K. A critical review of visual analogue scales in
the measurement of clinical phenomena. Res. Nurs. Health 13, 227–236 (1990).
34. Rhodes, V.A., Watson, P.M. & Johnson, M.H. development of a reliable
and valid measures of nausea and vomiting. Cancer Nursing 7, 33–41 (1984).
35. Gourlay, G.K., Plummer, J.L., cherry, d.A. & Purser, T. The reproducibility
of bioavailability of oral morphine from solution under fed and fasted
conditions. J. Pain Symptom Manage. 6, 431–436 (1991).
36. dupont, W.d. & Plummer, W.d. Jr. Power and sample size calculations. A
review and computer program. Control. Clin. Trials 11, 116–128 (1990).
37. Hulley, S.B., cummings, S.R. & Browner, W.S. Designing Clinical Research: An
Epidemiologic Approach (Williams & Wilkins, Baltimore, Md, 1988).
38. davis, M.P., Varga, J., dickerson, d., Walsh, d., LeGrand, S.B. & Lagman, R.
Normal-release and controlled-release oxycodone: pharmacokinetics,
pharmacodynamics, and controversy. Support. Care Cancer 11, 84–92 (2003).