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An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia

Authors:
  • Bedrocan International

Abstract and Figures

In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their [INCREMENT]-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, <1-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4-mg CBD, <1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30% decrease in pain scores compared to placebo (90% vs 55% of patients, P = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = -0.5, P < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (P < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions, and the role of psychotropic symptoms on pain relief.
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Research Paper
An experimental randomized study on the analgesic
effects of pharmaceutical-grade cannabis in
chronic pain patients with fibromyalgia
Tine van de Donk
a
, Marieke Niesters
a
, Mikael A. Kowal
b
, Erik Olofsen
a
, Albert Dahan
a,
*, Monique van Velzen
a
Abstract
In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled
pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact
knowledge on their Δ
9
-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, ,1-mg CBD;
Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV,
Veendam, the Netherlands), Bedrolite (18.4-mg CBD, ,1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and
a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and
electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect
greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30%
decrease in pain scores compared to placebo (90% vs 55% of patients, P50.01), with spontaneous pain scores correlating with the
magnitude of drug high (r520.5, P,0.001). Cannabis varieties containing THC caused a significant increase in pressure pain
threshold relative to placebo (P,0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced
analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This
experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses
after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores,
THC–CBD interactions, and the role of psychotropic symptoms on pain relief.
Keywords: Cannabis, Chronic pain, Fibromyalgia, Pharmacokinetics, THC, CBD, Placebo cannabis, Pain models
1. Introduction
In the current opioid epidemic, there is the need for pharmaceutical
alternatives to opioid treatment in patients with chronic pain. An
alternative may be found in the chemicals of the cannabis plant
(Cannabis sativa L.), which contains over 500 chemical compo-
nents, with more than 100 of them being cannabinoids.
8
Cannabinoids, or more specifically phytocannabinoids, are the
main active chemical components of the cannabis plant. They
exhibit most of their pharmacological effects via cannabinoid type 1
(CB
1
)andtype2(CB
2
) G-protein-coupled receptors.CB
1
receptors
are located mainly in the central nervous system, whereas CB
2
receptors are mostly found on immune cells.
21
These receptors
form part of the endocannabinoid system, a modulatory biological
system that influences the activity of different neurotransmitters with
their own ligands, the endocannabinoids, such as anandamide and
2-arachidonoylglycerol.
22
As for cannabis, its major cannabinoid is
Δ
9
-tetrahydrocannabinol (THC), a partial CB
1
-receptor agonist, that
produces a variety of effects including altered cognition and motor
function, analgesia, and psychotropic effects (eg, drug high).
3
Another key component of cannabis is cannabidiol (CBD) that,
while nonintoxicating, does affect mood and cognition.
16
It is a CB
2
receptor antagonist and additionally has agonist activity at the 5HT-
receptor and stimulates the vanilloid receptor type 1 with similar
efficacy as capsaicin.
2,7,11,29
In this experimental trial, we explored the effect of
pharmaceutical-grade cannabis in patients with chronic pain caused
bythefibromyalgia(FM)syndrome.Fibromyalgia is characterized by
chronic widespread pain, often accompanied by secondary
symptoms including sleep disturbance, tiredness, and cognitive
symptoms such as memory deficits.
10
This condition predominantly
affects women, with a worldwide prevalence of 2% to 8% and
conventional pharmacologic treatment is considered only mildly
effective.
5,8,17
We explored the analgesic effects of inhaled pharmaceutical-
grade cannabis using the cannabis plant with all its natural
components. We tested 4 different varieties with exact knowledge
on their THC and CBD content. The varieties used were Bedrocan
with a high THC/low CBD content, Bedrolite with a high CBD/low
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Department of Anesthesiology, Leiden University Medical Center, Leiden, the
Netherlands,
b
Bedrocan International BV, Veendam, the Netherlands
*Corresponding author. Address: Anesthesia and Pain Research Unit, Department
of Anesthesiology, Leiden University Medical Center, H5-022, 2300 RC Leiden, the
Netherlands. Tel: 131 71 526 9111. E-mail address: a.dahan@lumc.nl (A. Dahan).
Supplemental digital content is available for this article. Direct URL citations appear
in the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.painjournalonline.com).
PAIN 160 (2019) 860–869
Copyright ©2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf
of the International Association for the Study of Pain. This is an open-access article
distributed under the terms of the Creative Commons Attribution-Non Commercial-
No Derivatives License 4.0 (CCBY-NC-ND), where it is permissib le to download and
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860 T. van de Donk et al.·160 (2019) 860–869 PAIN
®
THC content, Bediol with a combined high THC/high CBD content,
and a placebo variety without any THC or CBD content. This
approach enabled exploration of cannabis effects on pain relief
relative to placebo cannabis that was similar in smell, appearance,
and handling compared with the other varieties. We assessed relief
of experimental pressure pain, electrical pain, and spontaneous
pain (primary endpoints), as well as the subjective and psychotropic
effects. We hypothesized that compared with placebo treatment, all
THC-containing treatments would cause greater analgesic
responses for both spontaneous pain and evoked pain models.
2. Methods
2.1. Ethics and trial registration
This single-center, double-blind, placebo-controlled, 4-way
crossover study, with acronym Spirocan, was performed at the
Anesthesia and Pain Research Unit of the Department of
Anesthesiology at LUMC. The protocol was approved by the
local institutional review board and the Central Committee on
Research Involving Human Subjects in The Hague. The study
was registered at trialregister.nl under identifier NTR6091 and in
the European Union Drug Regulating Authorities Clinical Trials
(EUDRACT) database under identifier 201500381139. Before
enrollment, all patients gave written informed consent.
2.2. Patients: inclusion and exclusion criteria
Female patients diagnosed with FM were approached to
participate in the study through announcements in local
newspapers and the web site of the association of patients
with FM. When patients indicated interest in the study and were
diagnosed with FM by a rheumatologist, they were queried for
inclusion and exclusion criteria. Inclusion criteria were: a pain
score $5 for most of the day (on a verbal pain scale from 0 5no
pain to 10 5most pain imaginable) and positive diagnostic
criteria of the 2010 American College of Rheumatology.
28
These
criteria include a widespread pain index (WPI) $7 (on a scale
from 0 to 19) and a symptom severity (SyS) score $5 (on a scale
from 0 to 12) or a WPI of 3 to 6 and a SyS score $9. The WPI
defines the number of body areas in which a patient experi-
enced pain during the past week; the SyS score indicates the
level of other main symptoms of FM such as fatigue, non-
refreshing sleep, and cognitive symptoms. The presence of
autonomic complaints such as diarrhea or obstipation, dizzi-
ness, dry mouth/eyes, etc. was not a reason for exclusion, as we
consider these symptoms consistent with the FM syndrome.
Exclusion criteria included age ,18 years, any medical,
neurological, or psychiatric illness, use of strong opioids or
other painkillers except paracetamol and/or ibuprofen, benzo-
diazepine use, any known allergies to study medication, illicit
drug or alcohol use, recent use of cannabis, pregnancy, breast
feeding, and the presence of pain syndromes other than FM. On
the day of screening and on the morning of each of the 4 study
days, the urine of the patient was tested for illicit drug use using
a dipstick (Alere Toxicology Plc, Oxfordshire, United Kingdom;
the stick tests for cocaine, amphetamine, cannabinoids,
phencyclidine, methadone, benzodiazepines, tricyclic antide-
pressants, and barbiturates). In case of a positive test, the
subject was excluded from the study. Subjects were instructed
not to eat for at least 6 hours and drink for at least 2 hours before
the study visit. Any foods or beverages containing caffeine such
as coffee, tea, or chocolate were not allowed for 24 hours before
the study visit.
2.3. Study design: drugs, inhalation, and blood sampling
Patients visited the research unit on 5 occasions. On their first
visit, the patients were screened (medical history, physical
examination, and urinalysis) and familiarized with the experimen-
tal setup (they were, for example, trained in the inhalation
process). On each of their next visits, the patients received 1 of 4
possible cannabis treatments (in random order) with at least 2
weeks between visits.
The active cannabis substances were composed of the dried,
milled, and homogenized flowers of the plant Cannabis sativa L.,
which were cultivated under standardized conditions in line with
the requirements of good manufacturing practices (GMP). We
used 4 distinct pharmaceutical-grade cannabis varieties, all
obtained from Bedrocan International BV (Veendam, the Nether-
lands) and all prepared by Proxy Laboratories BV (Leiden, the
Netherlands) under GMP conditions:
(1) Bedrocan: The Bedrocan cannabis variety contains 22% THC
(220 mg per gram) and less than 1% CBD. It was developed in the
Netherlands out of a requirement by the Dutch Health Ministry to
have a “high THC” variety available to patients. We used 100 mg
that contained 22.4-mg THC and less than 1-mg CBD.
(2) Bediol: The Bediol cannabis variety is characterized by the
combination of 6.3% THC (63 mg per gram) and 8% CBD (80
mg per gram). We used 200 mg that contained 13.4-mg THC
and 17.8-mg CBD.
(3) Bedrolite: This variety is composed of 9% CBD (90 mg per
gram) and less than 1% THC. We used 200 mg that contained
18.4-mg CBD and less than 1-mg THC.
(4) Placebo: The placebo was derived from the Bedrocan
cannabis variety after selective removal of the cannabinoids
by solvent extraction by Proxy Laboratories BV under GMP
conditions. After removal of the cannabinoids, the specific
terpene profile (responsible for smell and taste) was restored in
a subsequent manufacturing step. Consequently, the placebo
had a moisture content and terpenoid profile matching the
active drug (Bedrocan).
Study medication was analyzed for cannabinoid content,
terpene profile, and water content by an independent quality
control laboratory. In addition, tests were performed to ensure
that unwanted elements were absent such as adulterants,
microbes, heavy metals, and pesticides. The pharmacy and
ethics committee reviewed and approved the products’ quality
certificates before dispensing the cannabis to the research team.
During the study, all varieties were refrigerated at 2 to 8 ˚C in triple-
layer laminated foil pouches.
Patients were dosed with cannabis vapor. All cannabinoids
are mostly present in the plant in their acid form. Application of
heat is needed for decarboxylation of the cannabinoid acids
into their active forms (eg, THC acid into THC).
9
All 4 cannabis
varieties were vaporized using the Volcano Medic vaporizer
(Storz & Bickel GmbH & Co, Tuttlingen, Germany)—a safe and
reliable method of intrapulmonary administration of cannabi-
noids.
13,30
The Volcano heated the homogenized plant material
to 210 ˚C to allow for conversion of the THC acid and CBD acid
into THC and CBD vapor for inhalation. The vapor was collected
in an 8-L plastic balloon that, after inflation, was detached from
the vaporizer and subsequently equipped with a mouthpiece
for inhalation. For the purpose of blinding, the balloon was
covered with an opaque plastic bag so that no variation in
density of the vapor was visible between visits. The evaporation
process was performed by a member of the research team not
involved in the study proceedings. Before and after each
evaporation, the device was cleaned with alcohol. The
April 2019·Volume 160 ·Number 4 www.painjournalonline.com 861
complete content of the balloon was inhaled through the mouth
within 3 to 7 minutes, and each breath was held for 5 seconds
after each inhalation.
On each occasion, an arterial line was placed in the left or right
radial artery for blood sampling. Five milliliter of blood was
obtained at t50 (control sample, before inhalation), 5, 10, 20, 30,
40, 50, 60, 90, 120, and 180 minutes after the start of inhalation.
Blood was collected in EDTA tubes (covered with an aluminum
foil), centrifuged at 2000gat 4˚C; separated plasma was stored at
280˚C until analysis. The samples were analyzed by Analytical
Biochemical Laboratory BV, Assen, the Netherlands. All handlingof
the samples was done in a darkened room to prevent the cannabis
molecules from disintegrating. Determinationof the CBD, THC, and
its active metabolite 11hydroxyTHC (11-OH-THC) plasma con-
centrations was performed using liquid chromatography with
tandem mass spectrometer detection (LCMS/MS). In Supple-
mental Materials 1 to 3, the analysis specifications including
chromatograms of the 3 cannabis varieties are given for 2 (low and
high) concentrations (available at http://links.lww.com/PAIN/A705).
2.4. Study design: pain tests, questionnaires, and safety
All subjects rated their FM pain on an 11-point visual analogue
scale (from 0 5no pain to 10 5most severe pain imaginable) at
baseline (before cannabis inhalation) and at 1, 2, and 3 hours after
inhalation.
Two experimental pain tests were performed:
(1) Pressure pain test
18
: A pressure algometer (FDN 100; Wagner
Instruments Inc, Greenwich, CT) was used to deliver pressure
pain on a skin area of 1 cm
2
between the thumb and index
finger; the affected area overlays the adductor pollicis muscle.
The algometer has a force capacity (6accuracy) of 100 62N
(10 60.2 kgf) and graduation of 1 N (100 gf), respectively. A
gradually increasing pressure was manually applied, and the
subjects were asked to indicate when the procedure became
painful (pressure pain threshold). All measurements were
obtained in triplicate at t50 (baseline), 12, 22, 32, 42, 62, 92,
122, 152, and 182 minutes after the start of inhalation. The 3
measurements were averaged for further analysis.
(2) Electrical pain test
20
: Electrical pain was induced using a locally
designed computer interfaced electrical currents stimulator
(CICS, Leiden University Medical Center, Leiden, the Nether-
lands). The stimulator was connected to 2 electrodes (surface
area 0.8 cm
2
) placed on the tibial surface of the right leg,
approximately 10 cm above th e medial malleolus. The stimulator
produced a stimulus train (stimulus duration 0.2 ms at 10 Hz)
that increased from 0 mA at 0.5 mA/second (cutoff 128 mA).
The subjects were instructed to press a control button when
pain was first felt (pain threshold) and when the pain became
unbearable (pain tolerance; this ended the stimulus train).
Measurements were obtained at t50, 10, 20, 30, 40, 60, 90,
120, 150, and 180 minutes after the start of cannabis inhalation.
Two questionnaires were taken to assess the effect of drug
treatment on mental and psychoactive cannabis effects:
(1) Bowdle questionnaire
4,30
: This questionnaire evaluates 3
psychedelic effects (drug high, alterations in internal perception,
and alterations in external perception) from 13 questions scored
on a 100-mm visual analogue scale (from 0, no effect, to 100,
maximum effect). Internal perception reflects inner feelings that
do not correspond with the reality and is derived from questions
regarding the hearing of unrealistic voices or sounds and having
unrealistic thoughts and paranoid or anxious feelings. The
external perception indicates a misperception of an external
stimulus or change in the awareness of the subject’s
surroundings and is derived from questions regarding the
perceptual change of body parts, the change of surroundings,
the altered passing of time, the difficulty of controlling thoughts,
and the change in color and sound intensity.
(2) Bond and Lader questionnaire
3,30
: The Bond and Lader
scales are calculated from sixteen 100-mm visual analogue
scales. The endpoints are set at antonymous word pairs such
as “alert–drowsy,” “well coordinated–clumsy,” “mentally
slow–quick witted,” and “incompetent–proficient.” The study
participant’s task is to make a mark on each scale at the point
that best describes how they currently feel considering that the
2 anchors reflect the greatest extent they experience each
state. Responses from these 16 scales are then scored to yield
3 main factors of alertness (alert, strong, clearheaded,
coordinated, energetic, quickwitted, attentive, proficient,
and interested), contentment (contented, happy, amicable,
gregarious, and tranquil), and calmness (calm and relaxed). A
high score indicates impairment.
The subjects were queried before drug inhalation and at 30-
min intervals after the start of inhalation. Adverse events and
serious adverse events were collected in the case record form. In
case of a serious adverse event, the event was treated, and no
further measurements were obtained. In case of an adverse event
(eg, nausea, vomiting, headache, and dizziness), no further action
was taken apart from supportive care.
2.5. Randomization, allocation, and blinding
Randomization was performed by the pharmacy using a computer-
generated randomization list. A distinct randomization sequence
was created for each subject; randomization sequence was
controlled withjust 2 subjects with an identical treatment sequence.
On the day before the experiment, the subject was allocated to
treatment by the pharmacy after receiving a fax message from the
investigators with the participant’s identifier code and study visit
number. Treatment was prepared on the day of the study and
collected by a technician from the pharmacy in a closed opaque
canister labeled with the patient’s identifier code and study visit
number; the contents of the canister were emptied in the vaporizer.
The study team was next presented with the filled opaque balloon
just before the actual cannabis inhalation. The investigators (and
patients) remained blinded until data analysis was complete (June
2018). The study was independently monitored ensuring that all
good clinical practice requirements were met.
2.6. Statistical analysis: sample size and assessment of
treatment effects
Considering the data from Wallace et al.,
25
we calculated the
need for 20 subjects to allow for a significant separation between
treatments with a power .0.9 and alpha 50.05. In case of
dropout after one visit, the data were discarded, and a new
subject was recruited. Before the data analyses, all variables were
screened for missing data, homoscedasticity, distribution abnor-
malities, and outliers. For both primary and secondary endpoints,
the effect of active treatment (Bedrocan, Bedrolite, or Bediol) on
the change in effect was compared between treatments using
a mixed model. Treatment was set as a fixed effect, a random
effect for the subject was added to account for repeated
measurements over time, and treatment order was added as
a covariate. For spontaneous pain, the responder rate was
determined for each treatment and compared with placebo
responder rates using a x
2
test. A responder was defined as
having a reduction in spontaneous pain score of at least 30% or
50% at one or more measurements. In addition, the change in
862 T. van de Donk et al.·160 (2019) 860–869 PAIN
®
spontaneous pain score relative to baseline was related to the
drug high score by Spearman’s r. The number of adverse events
between the 3 active treatments and placebo was analyzed using
ax
2
test. SPSS (IBM Corp Released 2017; IBM SPSS Statistics
for Windows, Version 25.0, Armonk, NY: IBM Corp) was used for
all analyses with Pvalues ,0.05 considered significant. All data
are reported as mean 6SD, unless otherwise stated.
3. Results
Twenty-five patients were recruited for participation. Five patients
ended their participation after their first study visit for unknown
reasons (n 51), side effects such as dizziness and nausea (n 53),
and fear of needles (n 51) (Fig. 1). All were replaced by another
patient according to the protocol. The 20 patients who completed
the trial were on average 39 613 years with an average weight of 82
620 kg and height of 169 67 cm (body mass index 29 67kg/m
2
).
At screening, patients reported an average verbal pain score of 7.20
61.24 units and were all diagnosed with FM with a WPI of 13.9 6
2.6, SyS of 9.2 61.3, and 14.9 62.9 of positive tender points.
Cannabis inhalation was achieved in (minutes:seconds) 5:03 6
2:54 (21 611 inhalations; Bedrocan), 6:57 64:05 (23 611
inhalations; Bediol), 5:30 62:37 (22 610 inhalations; Bedrolite),
and 2:48 61:40 (14 66 inhalations; Placebo). The complete
content of the balloon was inhaled by all subjects. All 3 active
treatments, but not placebo, were associated with several
adverse effects (Table 1), with frequent effects related to the
inhalation of cannabis (coughing during inhalation in 65%-70%,
sore throat and bad taste during inhalation in 25%-35% of
participants). Most adverse effects unrelated to the inhalation
process were drug high in 40% to 80%, dizziness in 15% to 20%,
and nausea in 5% to 30% of participants. Two patients reported
feelings of drug high after placebo treatment. There were no
differences in frequency of adverse effects between active
treatments (P.0.05). No serious adverse events occurred.
After inhalation of all 3 active treatments, THC, its metabolite
11-OH-THC, and CBD, were detectable with the following CMAX
and TMAX values (Fig. 2). Bedrocan: THC 82 620 ng/mL at t55
minutes, 11-OH-THC 5 63 ng/mL at 10 minutes, and CBD 0.2 6
0.3 ng/mL at 5 minutes; Bediol: THC 76 635 ng/mL at t55
minutes, 11-OH-THC 5 63 ng/mL at 10 minutes, and CBD 80 6
029 ng/mL at 5 minutes; and Bedrolite: THC 13 65 ng/mL at t5
5 minutes, 11-OH-THC 0.9 60.5 ng/mL at 10 minutes, and CBD
155 657 ng/mL at 5 minutes. No cannabinoids were detectable
after placebo inhalations.
None of the treatments had an effect greater than placebo on
spontaneous pain scores or electrical pain responses (Fig. 3 and
Table 2). By contrast, both Bedrocan and Bediol caused
a significant increase in tolerance to the pressure applied to the
skin over the adductor pollicis muscle for the duration of the
study. The largest effect was observed for the cannabis variety
that contained high doses of both THC and CBD (Bediol) with an
increase in tolerated pressure of 9 to 11 kgf from t520 to 90
minutes (P,0.001 vs placebo; t50 minutes is the start of
cannabis inhalation). Over this same time range, Bedrocan
increased the tolerated pressure by 7 to 9 kgf (P50.006 vs
placebo). With respect to spontaneous pain scores and tolerance
to pressure pain, Bediol had significantly greater effects than
Bedrolite (P50.04 for both endpoints, Table 2 and Fig. 3).
After placebo treatment, 11 and 6 patients had 30% and 50%
reduction in pain scores on at least one measurement period,
respectively. Comparing these responder rates to active treat-
ment, significantly more patients responded to Bediol with
a decrease in spontaneous pain by 30% (n 518, P50.01;
Fig. 4) but not with a decrease by 50% (n 59, P50.052). At both
responder rates, all other treatments had response profiles not
different from placebo (Fig. 4). Spontaneous pain scores were
strongly correlated with the magnitude of drug high for Bedrocan
(r520.5, P,0.001) and for Bediol (r520.5, P,0.001).
Psychoactive effects of treatment, as measured by the Bowdle
questionnaire, are given in Table 3. Bedrocan and Bediol caused
moderate drug high responses, on average just below 50% of the
maximum possible response (Fig. 3B), but significantly greater
than placebo (P,0.001). Bedrolite had less intense drug high
responses compared with either Bedrocan (P50.003) or Bediol
(P,0.001). Small effects were seen for changes in internal
perception (Bediol vs placebo, max. mean difference with
placebo 7 mm, P50.009, Table 3) and external perception
(Bedrocan and Bediol vs placebo, max. mean difference with
placebo 17 mm, P,0.001), indicative of limited psychosis-like
effects after Bedrocan and Bediol treatment. Bedrolite caused
smaller changes in internal perception than Bediol (P50.04) and
smaller changes in external perception than both Bediol (P5
0.004) and Bedrocan (P50.01). The responses to the Bond and
Lader questionnaire indicate mild deterioration in mood observed
during Bediol treatment (max. mean difference with placebo
Figure 1. Consort flow diagram. FM, fibromyalgia.
Table 1
Incidence of adverse events.
Bedrocan Bediol Bedrolite Placebo
Drug high, n (%) 16 (80) 16 (80) 8 (40) 2 (10)
Coughing, n (%) 14 (70) 14 (70) 13 (65) 0 (0)
Sore throat, n (%) 2 (10) 7 (35) 1 (5) 0 (0)
Bad taste, n (%) 5 (25) 6 (30) 5 (25) 0 (0)
Dyspnoea, n (%) 0 (0) 1 (5) 0 (0) 0 (0)
Dizzy, n (%) 3 (15) 4 (20) 2 (10) 0 (0)
Headache, n (%) 1 (5) 2 (10) 3 (15) 1 (5)
Nausea, n (%) 3 (15) 6 (30) 1 (5) 0 (0)
Vomiting, n (%) 0 (0) 0 (0) 1 (5) 0 (0)
Sleepy, n (%) 1 (5) 0 (0) 1 (5) 0 (0)
n, number of patients affected.
April 2019·Volume 160 ·Number 4 www.painjournalonline.com 863
11 mm, P50.02, Table 3) and mild deterioration in alertness
during Bedrocan (max. mean difference with placebo 21 mm, P5
0.02). Some small differences in mood and alertness were
observed among the 3 active treatments (Table 3).
To assess whether blinding of active vs placebo treatment was
successful, we calculated Bang’s blinding index (Bang’s BI),
1,26
which translates correct vs random guessing into a single
number. Bang’s BI ranges between 21 and 1 with 0 a perfect
blinding and values .0.5 or ,20.5 indicative of failure of blinding
above random guessing in the majority of subjects. Bang’s BI
values were between 0.3 and 0.4 just after inhalation for the 3
active treatments (40% of patients correctly guessed that they
received active treatment, whereas 50% of patients were unable
to determine what treatment they received). At the end of the
experiment, more subjects correctly guessed that they received
active treatment after Bedrocan (Bang’s BI 0.85) or Bediol
(Bang’s BI 0.90) inhalation. After placebo treatment, Bang’s BI
was 20.05 just after inhalation and 0.45 at the end of the study.
Assessment of a possible order effect on the measured pain-
related endpoints did not show a significant effect (P.0.05),
indicating that starting with placebo or with active treatment had
no significant effect on outcome.
In Figure 5A, the plasma THC concentration vs Dpressure pain
for the 3 active cannabis varieties is plotted showing loops with
counterclockwise direction. Using a nonparametric collapsing
approach, we closed the loops to give the relationship between
the estimated THC effect-site (or steady-state) concentration and
Dpressure pain (Fig. 5B)
19
(Using ke0obj, written and kindly
provided by Dr. S.L. Shafer [Stanford University, Palo Alto, CA]).
The effect of Bedrocan (blue dots) is derived from just THC
(reference drug). The effect of Bediol (red dots) is lower than
expected from its steady-state THC concentration range,
indicative of an antagonist effect of CBD (when combined with
THC) on the pressure pain response. By contrast, when CBD is
administered without relevant THC content (Bedrolite, green
dots), a small THC-independent analgesic effect is apparent.
4. Discussion
The main findings of this experimental study in chronic pain
patients with FM are that:
(1) none of the treatments had an effect greater than placebo on
spontaneous pain scores; (2) compared to placebo responder
rates, significantly more patients responded to Bediol (contain-
ing high doses of THC and CBD) with a decrease in
spontaneous pain by 30%; the 2 other active treatments had
response profiles not different from placebo; (3) the reduction in
spontaneous pain scores was correlated with the magnitude of
drug high; (4) pressure pain threshold increased significantly in
patients treated with Bedrocan and Bediol, 2 cannabis varieties
with a high THC content; (5) Bedrolite, a cannabis variety with
a high CBD content was devoid of analgesic activity in any of
the spontaneous or evoked pain models; and (6) CBD
increased plasma concentrations of THC but had an antago-
nistic effect on analgesia when combined with THC.
Major strengths of our study are the measurement of plasma
concentrations of the inhaled cannabinoids enabling the corre-
lation of plasma concentration rather than dose to effect, the use
of a placebo cannabis variety exempt from THC and CBD but with
the original terpene profile of the Bedrocan variety, and the testing
of well-defined cannabis varieties in a group of patients with
a well-defined chronic pain condition. Limitations of the study are
the short treatment period and lack of validation of the
experimental measures in FM.
Figure 2. Plasma concentrations of Δ
9
-tetrahydrocannabinol (THC), its metabolite 11-hydroxy-THC (11-OH-THC), and cannabidiol (CBD) after inhalation of 3
cannabis varieties, Bedrocan (A), Bediol (B), and Bedrolite (C). Data are mean 695% confidence interval.
Figure 3. Effect of cannabis varieties Bedrocan, Bediol, Bedrolite, and placebo cannabis on spontaneous pain scores (A), pressure pain threshold (B), and drug
high (C). Data are mean 6SEM and are relative to baseline. NRS, numerical rating score; VAS, visual analogue scale.
864 T. van de Donk et al.·160 (2019) 860–869 PAIN
®
Table 2
Effect of treatment on experimental pain and spontaneous pain responses.
Treatment Measurement time since the start of cannabis inhalation (minutes)
10 20 30 40 60 90 120 150 180 Pvs placebo
Pressure pain (Dkgf) Bedrocan 4.28 68.6 7.18 68.7 9.64 69.7 8.83 69.9 9.46 611.8 6.81 69.9 5.88 610.4 2.24 69.0 3.83 68.3 0.006
Bediol 7.72 67.1 10.67 612.0 11.23 613.2 10.13 611.3 9.83 612.7 9.14 69.9 5.88 69.2 6.24 68.6 4.24 610.6 <0.001
Bedrolite* 2.69 65.6 5.27 67.4 4.64 67.5 5.42 68.5 4.11 69.5 2.49 68.1 1.99 68.6 2.01 69.5 3.24 69.7 0.095
Placebo 1.68 63.5 2.04 64.6 2.56 66.5 1.49 67.3 0.36 66.7 20.87 66.8 21.12 67.6 21.96 68.8 22.67 67.6
Electrical pain threshold (DmA) Bedrocan 20.15 62.6 0.55 62.7 0.39 62.5 1.3 62.7 0.9 62.9 0.38 62.9 20.1 62.8 20.43 63.5 20.35 63.6 0.383
Bediol 0.18 61.8 20.31 64.8 0.32 63.0 1.02 63.4 1.09 62.6 1.94 64.5 0.52 62.7 1.19 63.5 0.82 62.5 0.825
Bedrolite 0.92 62.7 0.99 62.8 1.42 63.3 1.32 63.1 0.69 62.6 0.47 63.31 0.47 63.0 0.27 64.2 0.72 63.5 0.954
Placebo 20.2 62.2 0.58 61.8 1.1 61.8 1.63 62.8 1.13 62.9 1.1 62.6 1.15 62.5 0.8 62.4 0.98 63.3
Electrical pain tolerance (DmA) Bedrocan 20.95 63.8 0.58 63.3 0.33 63.3 0.83 63.7 20.1 63.3 20.4 63.6 20.77 64.2 21.17 64.7 20.92 65.0 0.809
Bediol 20.71 (3.2) 20.44 (3.0) 20.6 (4.2) 20.48 (3.5) 20.68 (3.3) 21.13 (3.4) 22.18 (4.1) 21.65 (4.0) 22.13 (4.3) 0.581
Bedrolite 20.41 (3.2) 20.68 (2.5) 0.14 (3.1) 20.18 (4.3) 20.48 (3.7) 20.43 (3.2) 21.11 (4.0) 20.68 (4.2) 20.88 (4.2) 0.900
Placebo 20.37 (2.3) 21.07 (2.5) 20.2 (2.6) 20.05 (2.4) 0.03 (3.5) 20.9 (2.43) 20.72 (2.1) 21.47 (1.9) 21.12 (2.6)
Spontaneous pain score (Dcm) Bedrocan 21.56 61.6 21.81 62.1 21.50 61.6 0.678
Bediol 22.06 61.6 22.00 61.9 21.59 61.4 0.293
Bedrolite* 21.29 61.4 21.12 61.2 21.53 61.6 0.351
Placebo 21.35 61.1 21.41 61.3 21.53 61.6
Data are relative to baseline values.
Values are mean 6SD.
Bold values represent significant
P
value.
*
P
50.04 vs Bediol.
April 2019·Volume 160 ·Number 4 www.painjournalonline.com 865
Over the past years, cannabis has become increasingly
popular for medical use. Currently, an increasing number of
countries legalized or are planning to legalize cannabis for
medicinal purposes. For instance, in the Netherlands, stan-
dardized cannabis has been available in pharmacies on
prescription since 2003. However, cannabinoids typically have
modest effects with small effect sizes and numbers needed to
treat .20.
24
In addition, the effect of cannabinoids in relieving
chronic pain seems to diminish over time.
24
Still, many patients
report using cannabis for the treatment of chronic pain with
promising results.
23
We performed a small experimental study to
explore the acute analgesic effects on experimental measures of
3 cannabis varieties that ranged in THC and CBD content after
a single inhalation.
Our experimental study was not designed to provide direct
evidence for the clinical use of cannabis in FM but may be used
to design future clinical trials. In addition, our approach allows
to link the observed effect with THC and CBD plasma
concentrations and to detect possible pharmacokinetic and/
or pharmacodynamic interactions. Here, we discuss the
performance and outcome of the study with focus on the use
of placebo cannabis, pharmacokinetics, potential analgesic
efficacy of THC and CBD, and adverse effects.
4.1. Placebo cannabis
We used a placebo cannabis variety (ie, a cannabis plant devoid
of THC or CBD but with the full terpene profile) as a comparator
to ensure blinding of treatment. Cannabis placebo varieties
without cannabinoids have been used before.
27
Our placebo
plant material had a similar smell and appearance as the other
cannabis varieties. The importance of successful blinding in
clinical trials on cannabis analgesia has recently been
highlighted.
26
Although our approach theoretically allows for
blinding of treatment during inhalation, we cannot exclude that
lack of psychoactive symptoms from placebo inhalation during
the course of the study had some influence on the outcome in
some of the pain models. This is especially relevant given the
study crossover design. Indeed, at the end of the study, 13/20
(65%) patients guessed correctly that they had received
Table 3
Effect of treatment on subjective feelings derived from the Bowdle questionnaire and Bond and Lader questionnaire.
Treatment Measurement time since the start of cannabis inhalation (minutes)
0 30 60 90 120 150 180 Pvs placebo
Bowdle drug high (mm) Bedrocan 0 43 637 34 630 27 627 19 626 10 615 4 66<0.001
Bediol 0 45 637 45 633 40 634 24 627 14 621 5 69<0.001
Bedrolite* 0.1 60.2 13 621 9 616 6 611 4 68264164 0.240
Placebo 0.2 60.5 0 613680610612061060
Bowdle internal perception (mm) Bedrocan 1 63467368266164162060 0.272
Bediol 0 616697619 7 617 7 617 3 681640.009
Bedrolite† 0 61061061061060061061 0.903
Placebo 0 61060060060060060061
Bowdle external perception (mm) Bedrocan 1 6618624 15 619 10 617 7 614 4 619 2 640.001
Bediol 1 6318618 16 618 13 620 9 617 6 613 2 64<0.001
Bedrolite* 1 62262162262162161061 0.765
Placebo 1 64162061061061060060
Bond and Lader calmness (mm) Bedrocan 18 619 9 613 8 612 9 614 7 698612 12 615 0.289
Bediol 24 621 13 623 14 625 14 626 14 622 16 621 13 619 0.562
Bedrolite 18 619 7 696698611 8 610 8 611 11 614 0.226
Placebo 18 622 12 617 14 619 13 619 14 621 12 619 14 629
Bond and Lader mood (mm) Bedrocan 8 612 12 613 13 6912691269968767 0.875
Bediol‡ 12 613 20 622 18 622 18 624 17 622 15 621 12 616 0.020
Bedrolite 11 612 8 67968967868868868 0.996
Placebo 11 611 9 6910698
69869869969
Bond and Lader alertness (mm) Bedrocan 14 617 45 627 47 622 45 621 40 624 30 621 23 620 0.026
Bediol 19 618 46 626 47 623 43 623 40 623 34 626 25 622 0.010
Bedrolite* 16 617 25 618 27 616 25 618 25 619 23 619 19 617 0.399
Placebo 16 617 16 614 16 614 17 614 19 618 17 618 15 616
Values are mean 6SD.
Bold values represent significant
P
value.
*
P
,0.01 vs Bedrocan and Bediol.
P
,0.05 vs Bediol.
P
,0.05 vs Bedrocan and Bedrolite.
Figure 4. Cannabis responder rates: (A) Percentage responders with
a decrease of at least 30% in spontaneous pain scores on at least one
measurement. (B) Percentage responders with a decrease of at least 50% in
spontaneous pain scores on at least one measurement.
866 T. van de Donk et al.·160 (2019) 860–869 PAIN
®
placebo treatment. On the other hand, the terpenes present in
the placebo plant may have exerted some effects. Terpenes are
assumed to interact with cannabinoids (entourage effect),
improving their pharmacodynamic effects (eg, by increasing
pulmonary uptake and change binding of cannabinoids to their
receptors), but also have effects of their own, including anti-
inflammatory, antidepressant, and analgesic effects.
12,22
This
then suggests that the placebo cannabis variety used in our
study is best considered an active placebo. Hence, the
observation of an appreciable placebo effect in the relief of
spontaneous pain is not surprising.
4.2. Pharmacokinetics
The pharmacokinetic analysis showed that peak THC con-
centrations were similar after Bedrocan and Bediol inhalation,
whereas the peak THC concentration after Bedrolite inhalation
was about one-sixth of that of the other 2 varieties (Fig. 2).
These are important observations and indicate that magnitude
of THC plasma concentrations was partly dependent on the
presence of CBD in the inhalant. In Bedrocan, 24-mg inhaled
THC (and ,1-mg CBD) produced a mean THC peak plasma
concentration of 82 ng/mL. In the other 2 cannabis varieties
with CBD contents of about 18 mg, THC plasma concen-
trations were at least 50% higher than expected from the
Bedrocan pharmacokinetic data. The THC–CBD pharmaco-
kinetic interaction may be explained by (1) a possible CBD-
induced increase in pulmonary THC uptake, for example, due
to an increase in pulmonary blood flow. We are unaware of any
data that support this mechanism; (2) CBD-induced inhibition
of THC metabolism. Although CBD potently inhibits THC
metabolism in the rat,
14
our data do not support any inhibition
of THC conversion to 11-OH-THC (Fig. 2); and (3) cyclizing of
CBD into THC. Because both compounds are chemically
related, CBD can convert into THC; this has been observed
after subcutaneous administration of CBD in the rat.
14
To
further improve our understanding of the pharmacokinetic
behavior of THC under different CBD conditions, we plan
a compartmental pharmacokinetic analysis of our data.
4.3. Outcome of the acute experimental pain tests
Two cannabis varieties, Bedrocan and Bediol, were analgesic in
the pressure pain model but had no effect in the electrical pain
model or on relief of spontaneous pain. The pressure pain test
seems especially suited for exploring treatment effects in FM pain,
as it elicits mechanical muscle stimulation through Ad- and C-
fiber activation and better reflects the symptoms of patients with
FM than electrical pain, which produces direct sensory nerve
stimulation.
19
We previously used electrical noxious stimulation
as a model of acute pain and showed high sensitivity of opioids in
alleviating transcutaneous electrical pain.
20
The current data
suggest that cannabis may have limited use in acute pain
treatment.
Interestingly, when CBD and THC were combined (in Bediol),
CBD had antagonistic pharmacodynamic effects (Fig. 5B),
possibly because of an antagonistic or negative modulatory
action at the CB
1
receptor.
6
Despite this pharmacodynamic
antagonism, the analgesic responses exceeded those of
Bedrocan, possibly because of the CBD-induced increase in
THC concentrations. The opposed direction of the pharmaco-
kinetic and pharmacodynamic CBD–THC interactions is an
indication of the complex pharmacological behavior of canna-
binoids in humans. When CBD is given without relevant THC
content (ie, Bedrolite, containing predominantly CBD), just
small analgesic effects not different from placebo became
apparent. This is somewhat surprising, as it is our experience
and that of others that patients with chronic pain report
beneficial effects from CBD treatment.
23
Possibly, such effects
are related to improvement of insomnia, anxiety, cognition,
and/or mood. In addition, it may well be that a single CBD
administration may be insufficienttoelicitanalgesicresponses,
or that the dose was too low.
4.4. Side effects
Some side effects of active treatment were observed. One-third
of patients reported sore throat and bad taste, whereas two-
thirds coughed during the 5- to 7-minute inhalation of the active
treatments. In the course of the study, one-third of patients
experienced nausea without vomiting. All symptoms were rated
Figure 5. (A) Plasma THC concentration (C
P
) vs the change in pressure pain threshold after treatment with Bedrocan (blue dots), Bediol (red dots), and Bedrolite
(green dots). The arrows indicate the direction of effect, starting at the large yellow circle. (B) Estimated steady-state or effect-site (C
E
) concentration vs the change
in pressure pain threshold for the 3 active cannabis varieties. THC, tetrahydrocannabinol.
April 2019·Volume 160 ·Number 4 www.painjournalonline.com 867
as mild. An important observation was that most patients disliked
the feeling of drug high after inhalation, although the intensity was
rated as moderate (Fig. 3C). Because this is a general
observation in chronic pain patients treated with psychedelic
medication, we recently studied the ability to temper the feeling of
drug high induced by racemic ketamine. We observed that drug
high intensity was reduced by 30% during administration of the
nitric oxide donor sodium nitroprusside.
15
Because cannabis and
ketamine produce their psychotropic effects through separate
pathways (N-methyl-D-aspartate receptor antagonism vs CB
1
-
receptor agonism), further studies are needed to discover viable
options to reduce THC-related drug high without reducing
analgesia. Still, it may be that this may have a negative effect on
analgesic efficacy because we observed that relief of spontane-
ous pain was correlated with drug high scores. This suggests that
some level of intoxication is required for an analgesic cannabis
effect, or that the lack of complete blinding due to the occurrence
of psychotropic side effects (or symptoms during inhalation)
influenced pain scoring to some extent.
In conclusion, in this experimental and highly controlled
study, we explored the pharmacokinetics and pharmacody-
namics of 3 active cannabis varieties in chronic pain patients
with FM. The most important observation is that when
simultaneously inhaled, THC and CBD interact in complex
fashions with synergistic pharmacokinetic but antagonistic
pharmacodynamic interactions. The analgesic efficacy of
active treatment was limited to varieties that contained THC
and was observed exclusively in the evoked pressure pain
model. None of the active treatments were effective in reducing
spontaneous pain scores more than placebo. Further studies
are needed to assess efficacy and safety (including addictive
behavior) in clinical trials with prolonged treatment periods and
explore the role of psychotropic effects in the development of
analgesia.
Conflict of interest statement
This investigator-initiated trial was performed in collaboration with
Bedrocan International BV (Veendam, the Netherlands). Bed-
rocan International BV was responsible for the production and
delivery of the cannabis products and the Volcano device for
cannabis inhalation. M.A. Kowal is an employee of Bedrocan
International BV, the Netherlands. He commented on the
protocol and final version of the paper. The other authors have
no conflict of interest to declare.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be
found online at http://links.lww.com/PAIN/A705.
Article history:
Received 15 August 2018
Received in revised form 29 November 2018
Accepted 6 December 2018
Available online 20 December 2018
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... Notably though, THC has shown promising analgesic efficacy (Abrams et al., 2007;Ellis et al., 2009;Ware et al., 2010;Wilsey et al., 2013;Wallace et al., 2015;Wilsey et al., 2016;van de Donk et al., 2019). This analgesic effect of THC is still under investigation but likely mirrors THC's concentration and thus cannabis' intoxication potential (Wilsey et al., 2013;Andreae et al., 2015;Wallace et al., 2015;van de Donk et al., 2019). ...
... Notably though, THC has shown promising analgesic efficacy (Abrams et al., 2007;Ellis et al., 2009;Ware et al., 2010;Wilsey et al., 2013;Wallace et al., 2015;Wilsey et al., 2016;van de Donk et al., 2019). This analgesic effect of THC is still under investigation but likely mirrors THC's concentration and thus cannabis' intoxication potential (Wilsey et al., 2013;Andreae et al., 2015;Wallace et al., 2015;van de Donk et al., 2019). In clinical trials studying the analgesic efficacy for cannabis, the THC concentrations utilized are consistently <10% (Abrams et al., 2007;Ellis et al., 2009;Ware et al., 2010;Wilsey et al., 2013;Wallace et al., 2015;Wilsey et al., 2016). ...
... Literature suggests that different concentrations of THC and CBD and different ratios of THC:CBD induce variances in experienced subjective effects (Pennypacker and Romero-Sandoval, 2020). In fact, it appears that certain lower ratios of THC:CBD are more apt to produce an attenuation of THC induced effects (Dalton et al., 1976;Englund et al., 2013;van de Donk et al., 2019) while higher ratios are more likely to enhance THC induced effects (Arkell et al., 2019;Solowij et al., 2019;van de Donk et al., 2019). For instance, one study found that inhaled cannabis at a 2:1 THC:CBD ratio (8 mg THC (1.6%)/4 mg CBD (0.8%)) enhanced the subjects' intoxication when compared with THC alone (8 mg), but a 1:20 THC:CBD ratio (8 mg THC (1.6%)/400 mg CBD (80%)) reduced the subjects' intoxication when compared with THC alone (8 mg) (van de Donk et al., 2019). ...
Article
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Background and aims: The effects exuded by cannabis are a result of the cannabinoids trans-Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and is dependent upon their pharmacological interaction and linked to the two cannabinoids’ concentrations and ratios. Based on current literature and trends of increasing cannabis potency, we postulate that most medical cannabis products with THC and CBD have ratios capable of producing significant acute intoxication and are similar to recreational products. We will test this by organizing products into clinically distinct categories according to TCH:CBD ratios, evaluating the data in terms of therapeutic potential, and comparing the data obtained from medical and recreational programs and from states with differing market policies. Methods: We utilized data encompassing online herbal dispensary product offerings from nine U.S. states. The products were analyzed after being divided into four clinically significant THC:CBD ratio categories identified based on the literature: CBD can enhance THC effects (THC:CBD ratios ≥1:1), CBD has no significant effect on THC effects (ratios ∼ 1:2), CBD can either have no effect or can mitigate THC effects (ratios 1:>2 < 6), or CBD is protective against THC effects (ratios ≤1:6). Results: A significant number of products (58.5%) did not contain any information on CBD content. Across all states sampled, the majority (72–100%) of both medical and recreational products with CBD (>0%) fall into the most intoxicating ratio category (≥1:1 THC:CBD), with CBD likely enhancing THC’s acute effects. The least intoxicating categories (1:>2 < 6 and ≤1:6 THC:CBD) provided the smallest number of products. Similarly, the majority of products without CBD (0%) contained highly potent amounts of THC (>15%). These results were consistent, regardless of differing market policies in place. Conclusions: Despite the distinct goals of medical and recreational cannabis users, medical and recreational program product offerings are nearly identical. Patients seeking therapeutic benefits from herbal cannabis products are therefore at a substantial risk of unwanted side effects, regardless of whether they obtain products from medical or recreational programs. Efforts are needed to better inform patients of the risks associated with high potency cannabis and the interaction between THC and CBD, and to help shape policies that promote more therapeutic options.
... Patients with chronic pain (CP) often describe their everyday bodily sensations as a knife being stabbed into the back, a bad sunburn that won't go away, metal filings under the skin, an open wound, or an electric shock. CP is the debilitating side-effect of numerous diseases and conditions, including cancer 1 , peripheral neuropathy [2][3][4][12][13][14] , and fibromyalgia [3][4][5] . CP affects more than 1.5 billion people around the world 6 and 64% of American adults over the age of 30 7 . ...
... Medical cannabinoids have shown to have some analgesic effects [2][3][4][5]8,13,14 and the potential to help individuals with CP reduce their opioid intake 9,11 . However, cannabis's history as a recreational drug has led to concerns about its efficacy and safety from physicians, patients, and the public, making its implementation as an established treatment option slow. ...
... The cannabis plant (Cannabis sativa) contains hundreds of cannabinoids that interact with CB1 receptors in the central nervous system 5,13,14 and CB2 receptors on immune cells throughout the body 5,13 . The major cannabinoid is ∆ 9tetrahydrocannabinol (THC), which is responsible for the "drug high" associated with cannabis use 5 . ...
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This paper is an examination of the existing literature on the use of medical cannabinoids for the treatment of adults with chronic pain (CP). The use of medical cannabinoids in the treatment of CP has been a controversial topic due to societal associations with the recreational use of cannabis and the lack of information as to their analgesic effects. This paper analyzes trends in how medical cannabinoids perform as an analgesic treatment for adults with CP, especially in comparison to opioids. Additionally, this paper explores any secondary effects participants may experience as a result of treatment with medical cannabinoids. It will be shown that, while medical cannabinoids have the potential to reduce pain in those suffering from CP, there are numerous factors that must be considered before they become an acceptable treatment option. In addition, there is evidence that the analgesic effects of medical cannabinoids may be primarily due to their intoxicating effect rather than their interaction with neural pain pathways. This review of existing literature acts to guide future research on the use of medical cannabinoids for the treatment of CP.
... Twenty patients were randomly divided into groups: bedrocan (22% THC, <1% CBD), bediol (6.3% THC, 8% CBD), bedrolite (<1% THC, 9% CBD), or placebo. Vaporized cannabis or placebo was administered on four occasions with a 2-week washout between treatments [34]. Spontaneous pain NRS scores were not significantly different between groups, but 18 patients receiving bediol reported a 30% reduction in spontaneous pain (p = 0.01) [34]. ...
... Vaporized cannabis or placebo was administered on four occasions with a 2-week washout between treatments [34]. Spontaneous pain NRS scores were not significantly different between groups, but 18 patients receiving bediol reported a 30% reduction in spontaneous pain (p = 0.01) [34]. Using an algometer to quantify pressure tolerance over the adductor pollicis muscle, bediol, and bedrocan enhanced the pressure threshold (bediol: increase from 9 to 11 kgf, p < 0.001; bedrocan: increase from 7 to 9 kgf, p = 0.006) [34,35]. ...
... Spontaneous pain NRS scores were not significantly different between groups, but 18 patients receiving bediol reported a 30% reduction in spontaneous pain (p = 0.01) [34]. Using an algometer to quantify pressure tolerance over the adductor pollicis muscle, bediol, and bedrocan enhanced the pressure threshold (bediol: increase from 9 to 11 kgf, p < 0.001; bedrocan: increase from 7 to 9 kgf, p = 0.006) [34,35]. The electrical pain test, assessed using two electrodes superior to the right medial malleolus, showed no effect of bedrocan or bediol electrical pain threshold [34,36]. ...
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With emerging information about the potential for morbidity and reduced life expectancy with long-term use of opioids, it is logical to evaluate nonopioid analgesic treatments to manage pain states. Combinations of drugs can provide additive and/or synergistic effects that can benefit the management of pain states. In this regard, tetrahydrocannabinol (THC) and cannabidiol (CBD) modulate nociceptive signals and have been studied for chronic pain treatment. Psilocybin, commonly known as “magic mushrooms”, works at the serotonin receptor, 5-HT2A. Psilocybin has been found in current studies to help with migraines since it has a tryptamine structure and works similarly to triptans. Psilocybin also has the potential for use in chronic pain treatment. However, the studies that have looked at alternative plant-based medications such as THC, CBD, and psilocybin have been small in terms of their sample size and may not consider the demographic or genetic differences in the population because of their small sample sizes. At present, it is unclear whether the effects reported in these studies translate to the general population or even are significant. In summary, additional studies are warranted to evaluate chronic pain management with alternative and combinations of medications in the treatment of chronic pain.
... Fibromyalgia One clinical trial investigated CBD among people with fibromyalgia. Inhaled cannabis with varying concentrations of THC and CBD was administered to 20 women with fibromyalgia to assess pain responses [28]. Following a single inhalation of three cannabis products (22% THC, ˂1% CBD; 6.3% THC, 8% CBD; 9% CBD, ˂ 1% THC; and placebo without THC or CBD), none of the active treatments had an effect that was greater than placebo on spontaneous pain or electrical pain response. ...
... CBD is a substrate for CYP2C19 and CYP3A4 with potential to increase serum concentrations of antidepressants, tofacitinib, and reduce concentrations of clopidogrel. Inhaled CBD can boost serum THC concentration, potentially resulting in increased psychoactive effects [28]. In a recent study of CBD administered to 120 frontline healthcare professionals who experienced burnout related to COVID-19, adverse events of increased liver function tests were observed in 4 of the 59 subjects receiving CBD 150 mg twice daily over a period of 28 days [53]. ...
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Purpose of Review This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence. Recent Findings CBD has potential for relief of symptoms of pain, sleep, and mood disturbance in rheumatology patients, but sound clinical evidence is lacking. CBD is safe when accessed from a regulated source, whereas wellness products are less reliable regarding content and contaminants. Dosing for symptom relief has not yet been established. Summary As many rheumatology patients are trying CBD as a self-management strategy, the healthcare community must urgently accrue sound evidence for effect.
... In 1 trial, different types of inflorescences were administered to evaluate the most efficacious ratio of THC to CBD concentrations against pain. (Pretzsch, et al., 2019b;Solowij, et al., 2019;Van de Donk, et al., 2019;Abrams, et al., 2020;Farokhnia, et al., 2020;Liu, et al., 2020;Lopez, et al., 2020;Thompson, et al., 2020;Naftali, et al., 2021a;Anderson, et al., 2021;Aran, et al., 2021;Naftali, et al., 2021b) ...
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Cannabis has long been regarded as a recreational substance in the Western world. The recent marketing authorization of some medicinal products of industrial origin and the introduction onto the market of inflorescences for medical use mean that medical doctors can now prescribe Cannabis-based medicines in those countries which allow it. Nevertheless, there is still considerable controversy on this topic in the scientific community. In particular, this controversy concerns: the plant species to be used; the pathologies that can be treated and consequently the efficacy and safety of use; the routes of administration; the methods of preparation; the type and dosage of cannabinoids to be used; and, the active molecules of interest. As such, although medical Cannabis has been historically used, the results of currently completed and internationally published studies are inconclusive and often discordant. In light of these considerations, the aim of this work is to analyse the current legislation in countries that allow the use of medical Cannabis, in relation to the impact that this legislation has had on clinical trials. First of all, a literature search has been performed (PubMed and SciFinder) on clinical trials which involved the administration of Cannabis for medical use over the last 3 years. Of the numerous studies extrapolated from the literature, only about 43 reported data on clinical trials on medical Cannabis, with these mainly being performed in Australia, Brazil, Canada, Denmark, Germany, Israel, Netherlands, Switzerland, the United Kingdom and the United States of America. Once the reference countries were identified, an evaluation of the legislation in relation to Cannabis for medical use in each was carried out via the consultation of the pertinent scientific literature, but also of official government documentation and that of local regulatory authorities. This analysis provided us with an overview of the different legislation in these countries and, consequently, allowed us to analyse, with greater awareness, the results of the clinical trials published in the last 3 years in order to obtain general interest indications in the prosecution of scientific research in this area.
... 4 Although the AE rates of sublingual or smoked or vaped MC declined from 40% after a month of treatment to 30% a year later, 4 in the current study, AEs declined from 34% during the titration phase to almost none during the maintenance phase, which ranged from 3 to 15 months. In a study on patients with fibromyalgia treated by a single vaporizer session of MC from the Bedrocan cultivar, which is the cultivar used for the VCs of the inhaler, 80% of the treated patients reported psychoactive effects, 11 whereas in our study, only 10% reported psychoactive AEs, such as anxiety and restlessness. Hence, MC treatment using the inhaler seems similar to traditional MC for effectiveness, but superior regarding safety, while exposing the patients to very low doses of aerosolized D 9 -THC. ...
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Introduction: Preliminary clinical studies on medical cannabis (MC) treatment using the Syqe Inhaler showed short-term effectiveness and safety at very low and precise doses of MC. Objectives: Here, we retrospectively analyzed "real-life" long-term data collected in real time on the potential effectiveness and safety of MC administered with this device. Methods: Patients were monitored by Syqe's patient support program. (-)-Δ9-trans-Tetrahydrocannabinol (Δ9-THC) served as a dosage marker for full-spectrum MC. Pain intensity was evaluated using a numeric pain scale (NPS) from baseline to 120 days after treatment initiation. The change in quality of life (QoL) from baseline was evaluated. Adverse events (AEs) were followed up continuously for 15 months. Results: Of the 143 patients (mean age 62 ± 17 years; 54% males) included in the analysis, most (72%) were diagnosed with chronic neuropathic pain. The stable daily dose, after a mean 26 ± 10 days of titration was 1,500 ± 688 μg aerosolized Δ9-THC. Significant pain reduction, ranging from 22.8% in the intent-to-treat population to 28.4% in the population that reported baseline pain intensity ≥8 points on the NPS (P < 0.001), was observed. Ninety-two percent of patients reported improved QoL. Adverse events were reported mostly during the titration phase (34% of patients) and declined to ≤4% at 3 to 15 months. Only 7% of patients reported psychoactive AEs (anxiety and restlessness). Conclusions: Medical cannabis treatment with the Syqe Inhaler demonstrated overall long-term pain reduction, QoL improvement, and a superior AE profile compared with administration of MC by conventional routes. Additional follow-up in a larger population is warranted.
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Characterised by chronic widespread musculoskeletal pain, generalised hyperalgesia, and psychological distress, fibromyalgia (FM) is a significant unmet clinical need. The endogenous cannabinoid system plays an important role in modulating both pain and the stress response. Here, we appraise the evidence, from preclinical and clinical studies, for a role of the endocannabinoid system in FM and the therapeutic potential of targeting the endocannabinoid system. While many animal models have been used to study FM, the reserpine-induced myalgia model has emerged as the most translatable to the clinical phenotype. Inhibition of fatty acid amide hydrolase (FAAH) has shown promise in preclinical studies, ameliorating pain- and anxiety-related behaviour, and not associated with the development of tolerance. Clinically, there is evidence for alterations in the endocannabinoid system in patients with FM, including single nucleotide polymorphisms and increased levels of circulating endocannabinoids and related N-acylethanolamines. Single entity cannabinoids, cannabis, and cannabis-based medicines in patients with FM show promise therapeutically but limitations in methodology and lack of longitudinal studies to assess efficacy and tolerability preclude the current recommendation for their use in patients with FM. Gaps in the literature that warrant further investigation are discussed, particularly the need for further development of animal models with high validity for the multifaceted nature of FM, balanced studies to eliminate sex-bias in preclinical research, and ultimately, better translation between preclinical and clinical research.
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
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Introduction: Fibromyalgia (FM) is a chronic pain syndrome associated with fatigue, insomnia, dyscognition, and emotional distress. Critical illness mechanisms include central sensitization to nociceptive and non-nociceptive stimuli often resulting in hypersensitivity to all sensory input. Areas covered: The clinical presentation of FM can vary widely and therefore requires therapies tailored to each patient's set of symptoms. This manuscript examines currently prescribed therapeutic approaches supported by empirical evidence as well as promising novel treatments. Although pharmacological therapy until now has been only moderately effective for FM symptoms, it represents a critical component of every treatment plan. Expert opinion: Currently approved pharmacological therapies for FM symptoms have limited but proven effectiveness. Novel therapies with cannabinoids and naltrexone appear promising. Recent functional imaging studies of FM have discovered multiple brain network abnormalities that may provide novel targets for mechanism-based therapies. Future treatment approaches, however, need to improve more than clinical pain but also other FM domains like fatigue, insomnia, and distress.
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This review examines evidence cannabinoids in chronic non-cancer pain (CNCP), and addresses gaps in the literature by: considering differences in outcomes based on cannabinoid type and specific CNCP condition; including all study designs; and following IMMPACT guidelines. MEDLINE, Embase, PsycINFO, CENTRAL and clinicaltrials.gov were searched in July 2017. Analyses were conducted using Revman 5.3 and Stata 15.0. A total of 91 publications containing 104 studies were eligible (n = 9958 participants), including 47 RCTs and 57 observational studies. Forty-eight studies examined neuropathic pain, seven studies examined fibromyalgia, one rheumatoid arthritis, and 48 other CNCP (13 MS-related pain, 6 visceral pain, and 29 samples with mixed or undefined CNCP). Across RCTs, PERs for 30% reduction in pain were 29.0% (cannabinoids) vs 25.9% (placebo), significant effect for cannabinoids, number needed to treat to benefit (NNTB): 24 (95%CI 15-61); for 50% reduction in pain, PERs were 18.2% vs. 14.4%; no significant difference. Pooled change in pain intensity (standardised mean difference: -0.14, 95%CI -0.20, -0.08) was equivalent to 3mm on a 100mm visual analogue scale greater than placebo. In RCTs, PERs for all-cause AEs were 81.2% vs. 66.2%; number needed to treat to harm (NNTH): 6 (95%CI 5-8). There were no significant impacts upon physical or emotional functioning, and low-quality evidence of improved sleep and patient global impression of change. Evidence for effectiveness of cannabinoids in CNCP is limited. Effects suggest NNTB are high, and NNTH low, with limited impact on other domains. It appears unlikely that cannabinoids are highly effective medicines for CNCP.
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Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24 h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, given the increasing medical use of CBD-only products, has important legal and forensic ramifications.
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Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here.
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The design of analgesic clinical trials invariably involves a comparison between placebo and active study medication. An assumption is made that treatment effects can be approximated by subtracting the response to placebo from that attained with the use of active study medication. However, the psychoactivity of cannabinoids may unmask their presence and lead to an expectation and/or conditioning of pain relief. For example, study participants biased toward the belief that cannabis is beneficial for their condition might be more inclined to report positive effects if they were to accurately identify the active treatment because of its psychoactivity. This may lead to incorrect assumptions regarding the efficacy of a cannabinoid. Methodologies designed to counteract unmasking need to be implemented in the design phase of a study. During the clinical trial, it is also important to query participants as to which treatment they believe they have received. Blinding can be considered to be preserved when the accuracy of treatment guesses is not considerably different than random guessing, which is estimated to be correct 50% of the time. After a study has been completed, the use of statistical methodologies such as regression and mediation analysis are worthy of consideration to see whether psychoactive effects biased the results.
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Background: The political climate around Cannabis as a medicine is rapidly changing. Legislators are adopting policies regarding appropriate medical applications, while the paucity of research may make policy decisions around conditions for which Cannabis is an effective medicine difficult. Methods: An anonymous online survey was developed to query medical Cannabis users about the conditions they use Cannabis to treat, their use patterns, perception of efficacy, and physical and mental health. Participants were recruited through social media and Cannabis dispensaries in Washington State. Results: A total of 1429 participants identified as medical Cannabis users. The most frequently reported conditions for which they used Cannabis were pain (61.2%), anxiety (58.1%), depression (50.3%), headache/migraine (35.5%), nausea (27.4%), and muscle spasticity (18.4%). On average, participants reported an 86% reduction in symptoms as a result of Cannabis use; 59.8% of medical users reported using Cannabis as an alternative to pharmaceutical prescriptions. Global health scores were on par with the general population for mental health and physical health. Conclusions: While patient-reported outcomes favor strong efficacy for a broad range of symptoms, many medical users are using Cannabis without physician supervision and for conditions for which there is no formal research to support the use of Cannabis (e.g., depression and anxiety). Future research and public policy should attempt to reduce the incongruence between approved and actual use.
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Was ist neu? Die Therapie des Fibromyalgie-Syndroms (FMS) fußt auf einer Stärkung des Patienten hinsichtlich körperlicher Bewegung, physiotherapeutischen Maßnahmen und Krankheitsbewältigungsstrategien. Dieser Artikel thematisiert neben den aktuellen, leitliniengestützten Konzepten auch neue therapeutische Ansätze und pathophysiologische Überlegungen. Pathophysiologische Aspekte Das biopsychosoziale Krankheitsmodell hat weiterhin Gültigkeit. Das FMS wird als „Endzustand“ infolge verschiedener ätiologischer Faktoren und pathophysiologischer Mechanismen verstanden. In den letzten Jahren wurde eine „small fiber“-Pathologie diskutiert, ebenso wie der potenziell negative Einfluss eines hohen Fruktose-Konsums auf den Serotoninstoffwechsel. Diagnostik Die Diagnosekriterien wurden 2016 leicht modifiziert, die deutsche Leitlinie erfuhr ihr letztes Update 2017. Kernsymptome sind ein generalisierter Schmerz sowie Schlafstörungen und Fatigue. Das FMS kann begleitend zu anderen Erkrankungen vorkommen. Wichtig ist dennoch ein Ausschluss organischer Ursachen. Therapie Im Vordergrund stehen körperliche Aktivierung und symptomorientierte Maßnahmen. Eine primäre medikamentöse Therapie wird nicht empfohlen, insbesondere NSAR oder Opiate sollten nicht zum Einsatz kommen. Bei schweren Verläufen sollte eine multimodale Behandlung erfolgen. Neue medikamentöse Therapien sind noch weit vom klinischen Einsatz entfernt.
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Background: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer. Methods: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg-1 min-1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. Results: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. Conclusions: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. Clinical trial registration: NTR 5359.
Article
Unlabelled: Using 8-hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, most of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta 9-THC on 3 separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was used to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (eg, good drug effect, feeling high, etc) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all P < .0004). Psychoactive and subjective effects were dose-dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. Because the 2 active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. Perspective: A crossover, randomized, placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease. This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain.