Alright nerds! Hereis the second installment of Cannabinergic Pain MedicineAConcise Clinical Primer and Survey ofRandomized-controlled Trial ResultsSunil K. Aggarwal, MD, PhD
The majority of the effects of THCare mediated
through its partial agonism ofcannabinoid receptors. Of
relevance for pain management, inaddition to analgesia, the
following dose-dependentpharmacologic actions of THC
have been observed in studies:muscle relaxation, anti-inflammatory
effects, neuroprotection in ischemiaand hypoxia,
enhanced well-being, and anxiolysis.32 To understand how
this range of effects is possible,an understanding of cannabinoid
molecular biology is needed.
Cannabinoids produce analgesiathrough supraspinal,
spinal, and peripheral modes ofaction, acting on both ascending
and descending pain pathways. Theirmechanism of
action was only recently understoodwith the discovery of
the endogenous cannabinoid (orendocannabinoid) system, a
600 million-year-old signalingsystem in evolution,33,34 which
regulates neuronal excitability andinflammation35 in welldescribed
pain circuits and cascades.36–39 The endocannabinoid
system helps regulate the functionof other systems in
the body, making it an integral partof the central homeostatic
modulatory system. It has been shownto play a regulatory
role in movement, appetite, aversivememory
extinction,hypothalamic-pituitary-adrenal axis modulation,
immunomodulation, mood, bloodpressure, bone density,
tumor surveillance, neuroprotection,reproduction, inflammation,
among other actions.23,40 Studies in animals and
humans that have assessedpreexposure and postexposure
endocannabinoid levels havesuggested that the “runner’s
high,”41 the effects ofosteopathic manipulative treatment,
42,43 and the effects of electroacupuncture44 are mediated
by the endocannabinoid system.
The endocannabinoid system consistsof receptors, their
endogenous ligands, and ancillaryproteins.45 Cannabinoid
receptors, CB1 and CB2, and likely others, are transmembrane
G-protein–coupled receptors whoseactivation is negatively
coupled to adenylyl cyclase andpositively coupled to mitogenactivated
protein kinase. In neural tissue,their activation
suppresses neuronal Ca2+ conductance, activates inward rectifying
K+ conductance,and thus modulates neuronal excitability.
46 An adjective for anything that drives or stimulates
this system is “cannabinergic.”
The CB1 receptor isthe most highly expressed Gprotein–
coupled receptor in the brain and is10 times more
prevalent in the central nervoussystem as compared to the
other well-studied receptor involvedin pain: the m-opioid
receptor.47 Among many other tissues, cannabinoid receptors
have been found in abundance oncells in areas
relevant to pain: the periaqueductalgray, basal ganglia,
cerebellum, cortex, amygdala,hippocampus, dorsal primary
afferent spinal cord regions,including peripheral
nociceptors, spinal interneurons,and finally inflammatory
cytokine-releasing immune cells.46,47 In the brainstem,
cannabinoid receptor expression islow, accounting for the
lack of respiratory depression andabsence of fatal overdose
with cannabinoid drugs.48
Endocannabinoids such asarachidonylethanolamide
(anandamide) and2-arachidonylglycerol, and others, serve as
tonically active retrograde synapticneurotransmitters, meaning
that they travel “backwards” acrossthe synaptic cleft
from postsynaptic to presynapticneurons, thereby providing
feedback that, in turn, directlyupregulates or downregulates
the release of other presynapticneurotransmitters, such as
gamma-aminobutyric acid, dopamine,norepinephrine, glutamate,
and others.32 This feedback has physiological implications
for a host who may have succumb toinsult or injury
leading to pain.49 Experiments have also shown that the endocannabinoid
system is upregulated in animalmodels of
nerve damage 50 and intestinal inflammation.51 Ultimately,
while there is much that is stillpoorly understood, the known
pharmacodynamics of cannabinergicanalgesic effects have
been established through carefullydesigned experiments observing
the physiological or radiologiceffects of natural and
synthetic exogenously administeredcannabinoids in clinical
and laboratory animal models and theblockade of those
effects by genetic orpharmacological means.
The main adverse effects ofcannabinoids to focus on
presently are those that may arisewith use of these drugs in
a medical context rather than in anonmedical setting;
however, since there are far lessdata on the use of the drugs
in the former setting, the latter,though less ideal, must be
relied upon as well. Givencannabinergic drugs’ psychoactive
properties, adverse effects toconsider would include
overdose, abuse, dependence,psychomotor effects, cognitive
effects, and adverse medical andpsychiatric effects,
both short and long term. Generally,as analgesics, cannabinoids
have minimal toxicity and present norisk of lethal
overdose.48 End-organ failure secondary to medication
effect has not been described and noroutine laboratory
monitoring is required in patientstaking these medications.
With regard to cannabinoidbotanicals, the IOM concluded
after a comprehensivegovernment-commissioned review
published in 1999 that “except forthe harms associated
with smoking, the adverse effects ofmarijuana [cannabinoid
botanicals] use are within the rangeof effects tolerated
for other medications.”52
The FDA-approved product insert fordronabinol, the
THC pill, reports the followingadverse effects from overdose:
Signs and symptoms following MILD MARINOL Capsules
intoxication include drowsiness, euphoria, heightened sensory
awareness, altered time perception, reddened conjunctiva, dry
mouth and tachycardia; following MODERATE intoxication
include memory impairment, depersonalization, mood alteration,
urinary retention, and reduced bowel motility; and
following SEVERE intoxication include decreased motor
coordination, lethargy, slurred speech, and postural hypotension.
Apprehensive patients may experience panic reactions
and seizures may occur in patients with existing seizure
Regarding the dependence potentialof THC and cannabinoid
drugs, the IOM concluded that “Althoughfew
marijuana [cannabinoid botanicals]users develop dependence,
some do. Risk factorsyare similar tothose for other forms of
substance abuse. In particular,antisocial personality and
conduct disordersy” With regardto withdrawal, although
still a matter of dispute, the IOMconcluded: “A distinctive
marijuana [cannabinoid botanicals]withdrawal syndrome has
been identified, but it is mild andshort-lived. The syndrome
includes restlessness, irritability,mild agitation, insomnia,
sleep EEG disturbance, nausea, andcramping.”52
The IOM report also discussed the adverseeffects of
cognitive and psychomotor impairmentassociated with
acutely administered cannabinoidbotanicals, although it
did not take into consideration thepossibility of tolerance
Aggarwal Clin J Pain _ Volume 29, Number 2, February 2013
164 | www.clinicalpain.com r 2013Lippincott Williams & Wilkins
or preparation variability inmodifying these effects. “The
types of psychomotor functions thathave been shown to be
disrupted by the acuteadministration of marijuana [cannabinoid
botanicals] include body sway, handsteadiness,
rotary pursuit, driving and flyingsimulation, divided attention,
sustained attention, and thedigit-symbol substitution
test.” Given the concern foroccurrence these
adverse effects and that ofcognitive impairment, which has
been characterized as transientshort-term memory interruption
(see above MARINOL product insert),the panel
recommended that “no one under theinfluence of marijuana
[cannabinoid botanicals] or THCshould drive a
vehicle or operate potentiallydangerous equipment.”52
Another important source of adverseeffects data is
cannabinoid clinical trials; 2reviews are summarized below.
A 2008 review of reported adverseeffects of medical cannabinoids53
examined 31 clinical trials (23 RCTsand 8
observational studies) ofcannabinoid single-molecule
agents and cannabis-based medicinalextracts but not cannabinoid
botanicals (due to the fact thatsuch studies did
not report adverse events in thestandardized format investigators
sought) in various patientpopulations and
showed that the vast majority ofadverse events with cannabinoid
medications in clinical trials werenonserious
(96.6%). In the 23 RCTs, the medianduration of cannabinoid
exposure was 2 weeks (range, 8 h to12 mo). With
respect to the “164 serious adverseevents” that occurred,
the most common were relapse ofmultiple sclerosis (21
events [12.8%]), vomiting (16 events[9.8%]), and urinary
tract infection (15 events [9.1%]).However, investigators
reported that “there was no evidenceof a higher incidence
of serious adverse events” in thegroups assigned to cannabinoids
“compared with control [drugs] (rateratio [RR]
1.04, 95% confidence interval [CI],0.78-1.39).”53 In addition,
serious adverse events were notevenly reported in the
literature, with 99% coming fromonly 2 trials. The most
commonly reported nonserious adverseevents were dizziness
(714 events [15.5%]), followed bysomnolence (377
events [8.2%]), muscle spasm (289events [6.3%]), other
gastrointestinal tract disorder (285events [6.2%]), pain (278
events [6.0%]), dry mouth (239events [5.2%]), and bladder
disorder (222 events [4.8%]). Unlikethe serious adverse
events, the rate of nonseriousadverse events was nearly 2
times higher among participantsassigned to cannabinoids
than among controls (rate ratio [RR]1.86, 95% CI,
A more recent 2011 systematic reviewof RCTs of
cannabinergic medicines specificallyfor the treatment of
pain which pooled 18 trials ofinhaled cannabinoid botanicals,
oromucosal cannabis-based medicinalextracts, and
cannabinoid single-molecule agentsinvolving 766 patients
in total found no occurrence ofserious adverse events, with
the most serious treatment-relatedevent in the entire sample
being a subject’s fractured legrelated to a fall that was
thought to be related to dizzinessin a treatment trial with
nabilone. Nonserious adverse eventsmost frequently reported
included “sedation, dizziness, drymouth, nausea
and disturbances in concentration”and less commonly reported
adverse events included “poorcoordination, ataxia,
headache, paranoid thinking,agitation, dissociation, euphoria
and dysphoria.” Investigators noted:“Adverse effects
were generally described as welltolerated, transient or
mild to moderate and not leading towithdrawal from the
study. This is a significantdifference from the withdrawal
rates seen in studies of otheranalgesics such as opioids
where the rates of abandoningtreatment are in the range of
With regard to severe psychiatricsequalae such as
psychosis, if a very large dose ofcannabinoid botanicals is
consumed, which typically occursthrough oral ingestion of
a concentrated preparation,agitation and confusion, progressing
to sedation, generally results.55 This is self-limited
and generally disappears entirelyonce the psychoactive
components are fully metabolized andexcreted. Some have
called this an “acute cannabispsychosis,” and this generates
concern that cannabinoid use, in thelong term,
might lead to schizotypy such aschronic, debilitating psychosis.
There is some documentation of asyndrome of
acute schizophreniform reactions tocannabinoid botanicals
that may occur in young adults whoare under stress and
have other vulnerabilities toschizophreniform illness.
Furthermore, there is an associationbetween cannabinoid
botanicals use history andschizophrenia, but the causal
direction of this link has not beenestablished56,57 and
schizophrenia prevalence rates havenot changed over the
last 50 years despite increasing userates of cannabis in the
Recent preliminary work has examinedgene-environment
interactions to identify the geneticbackground of
populations at-risk for thiscannabinoid-associated psychosis
with retrospective, population-basedstudies, and
empiric cannabinoid drug exposurestudies, with candidate
genes including a commonly studiedfunctional polymorphism
in the catechol-O-methyltransferasegene (COMT
Val(15
Met)59 and a brain-derived neurotrophic factor
gene polymorphism (BDNF Val(66)Met),60 among others.
Given these risks, cannabinoidmedical use should be closely
monitored or potentially avoided inearly teens or preteens
who have preexisting symptoms ofmental illness or patients
with significant family or personalhistory of mental illness.
For physiological andpharmacological reasons,61
smoking cannabinoid herbals does notseem to have a
similar health hazard profile astobacco smoking, aside
from the potential for bronchialirritation and bronchitis.
Smoking cannabis was not associatedwith an increased risk
of developing chronic obstructivepulmonary disease
(COPD) in a random sample of 878people aged 40 years or
older living in Vancouver, Canadawho were surveyed
about their respiratory history andlifetime cannabis and
tobacco use exposure and subjectedto spirometric testing
before and after administration of200 mg ofsalbutamol, a
short-acting b2-receptor agonist. Investigators concluded
that smoking both tobacco andcannabis synergistically
increased the risk of respiratorysymptoms and COPD but
that smoking only cannabis was notassociated with an
increased risk of respiratorysymptoms or COPD.62 This
finding was also confirmed in arecently published longitudinal
study involving spriometric testingover a period of
20 years. Researchers followed morethan 5000 people in
several major American cities over 2decades and found
that the exposure equivalent ofmoderate inhalation of
cannabinoid botanical smoke dailyfor 7 years did not impair
spirometric-testing performance.63
With regard to the question of lungcancer risk, a
variety of opinions and conflictingresults are found in the
literature, likely related to studysizes, designs, and
confounding factors in existingresearch. However, the results
of 2 well-designed, large studiesconducted by senior
investigators in this field areworth noting. A recent large,
population-based retrospectivecase-control study involving
Clin J Pain _ Volume 29, Number 2, February 2013 CannabinergicPain Medicine
r 2013 LippincottWilliams & Wilkins www.clinicalpain.com | 165
1212 incident cases of lung andupper aerodigestive tract
cancer and 1040 cancer-freeage-matched and gendermatched
controls in the Los Angeles areademonstrated
significant, positive associationswith tobacco-smoking
history and the incidence suchcancers but failed to demonstrate
any significant positiveassociations or dose dependence
with cannabis-smoking history andthe incidence
of such cancers. In fact, a significant,albeit small, protective
effect was demonstrated in 1 groupof smoked cannabis
consumers.64 A second population-based case-control
study involving smoked cannabis useand head and neck
squamous cell carcinoma with 434cases and 547 agematched,
gender-matched, and geographicallymatched
controls in the greater Boston areasimilarly concluded that
moderate cannabis use is associatedwith reduced risk of
head and neck squamous cellcarcinoma.65 These 2 studies,
while large and sensitive toconfounders, need replication.
Certainly, although hundreds ofcitations can now be found
in the National Library of Medicineof studies demonstrating
antitumor properties of cannabinoidsin numerous
tissue types in mostly lab settings,some of which are also
reviewed on an online clinicalknowledge database maintained
by the National Cancer Institute,66 the inhalation of
fumes, combustion byproductparticulate matter, and polycyclic
aromatic hydrocarbons attendant withinhaled cannabinoid
botanical smoke can nevertheless benoxious for
some patients and the use ofvaporizers for lung administration
should be encouraged. Heated air canbe drawn
through cannabinoid herbal matterand, due to the volatility
of cannabinoids, which allows themto vaporize at a
temperature much lower than actualcombustion of plant
matter, active compounds willvaporize into a fine mist
which can then be dosed and inhaledwithout the generation
As to questions of overall adverseeffects of long-term
cannabinoid treatment in medicalsettings, there are essentially
no long-term controlled longitudinalstudies in such
populations, with the exception ofone 3-decade old, prospective,
federally funded inhaled cannabinoidbotanical
clinical study mentioned previouslyin the Introduction section.
Administered by the NationalInstitute on Drug Abuse
and FDA and now involving only 4chronically ill patients,
this study, now closed to newenrollment, has never systematically
collected or disseminated clinicalresponse data. One
independent comprehensive healthassessment in 2001 of 4
of the then 7 enrolled patientsshowed “mild changes in
pulmonary function” in 2 patientsand no other demonstrable
adverse outcomes or “functionallysignificant attributable
sequelae” based on a battery oftests, which included:
magnrtic resonance imaging scans ofthe brain, pulmonary
function tests, chest x-ray,neuropsychological tests, hormone
and immunological assays,electroencephalography, P300
testing, history, and neurologicalclinical examination.68
Research suggests that when THC iscoadministered
with cannabidiol, as can occur withthe usage of some strains
of herbal cannabinoid medicines andcertain cannabis-based
extractions, the anxiogenic,dysphoric, and possibly shortterm
memory interrupting effects of THCare mitigated.69,70
In addition, noncannabinoidcomponents in cannabinoid
botanicals such as terpenoids canalso help to mitigate THC
side effects.71 There is increasing evidence suggesting that
cannabinoid drugs can enhance theanalgesic activity of
opioids,72,73 and thereby their concomitant use may reduce
the dosages of opioids that chronicpain patients take.74,75
With the large number of individualswho have used
cannabinoid botanicals concomitantlywith numerous prescription
medicines, no unwanted side effectsof clinical
relevance have been described in theliterature to date. Nevertheless,
cannabinoid medicines should be usedwith caution
in patients taking other sedatingpsychotropic substances such
as alcohol and benzodiazepines.Again, from the FDAapproved
dronabinol product insert:
In studiesyMARINOL Capsules has[sic] been co-administered
with a variety of medications (e.g., cytotoxic agents,antiinfective
agents, sedatives, or opioid analgesics) without resulting
in any clinically significant drug/drug interactionsycannabinoids
may interact with other medications through both
metabolic and pharmacodynamic mechanisms. Dronabinol is
highly protein bound to plasma proteins, and therefore, might
displace other protein bound drugs. Although this displacement
hasnot been confirmed in vivoy
I tried one but it said the file was to large.
