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Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.
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European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
Review Article
Practical considerations in medical cannabis administration and dosing
Caroline A. MacCallum
a,
, Ethan B. Russo
b
a
Faculty of Medicine, University of British Columbia, BC, Canada
b
International Cannabis and Cannabinoids Institute, Prague, Czech Republic
ARTICLE INFO
Keywords:
Cannabis
Cannabinoids
Marijuana
Drug abuse
Psychopharmacology
Adverse events
ABSTRACT
Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical
complexity and variability, quality control issues, previous dearth of appropriately powered randomised con-
trolled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise
patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/na-
biximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology
and therapeutics has become untenable. In this article, the authors endeavour to present concise data on can-
nabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration
(smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain pri-
marily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or less, preferably in
conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is
less potent, and may require much higher doses for its adjunctive benets on pain, inammation, and at-
tenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and
titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks.
Suggestions are oered on cannabis-drug interactions, patient monitoring, and standards of care, while special
cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain,
use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and
hazardous activities.
1. Introduction
Cannabis has a history of medical application likely exceeding that
of the written word, including mainstream usage in Europe and North
America for a century between 1840 and 1940 [1,2]. It is only in the
last century that quality control issues, the lack of a dened chemistry,
and above all, politically and ideologically motivated prohibition re-
legated it planta non grata. The discovery and elucidation of the en-
docannabinoid system [3], coupled with a popular tidal wave of an-
ecdotal accounts and renaissance of therapeutic clinical trials renders
that status quo ante untenable.
One preparation, Sativex®(USAN: nabiximols), an oromucosal
cannabis-based medicine with 2.7 mg of THC and 2.5 mg CBD plus
terpenoids per spray has attained regulatory approval in 29 countries
for treatment of spasticity in multiple sclerosis, having met the
standards of safety, ecacy and consistency required of any pharma-
ceutical. The problem for physicians with respect to treatment with
herbal cannabis remains acute, however: How does the responsible
healer and medical scientist approach the desperate patient for whom
conventional medicine has failed and wishes to avail themselves of a
purportedly healing herb that has been an international societal outlaw
for decades? The answer is simple: educational and scientic standards
apply to the cannabis controversy equally with that of any other pu-
tative therapy.
Unfortunately, physicians of the world remain profoundly un-
educated with respect to cannabis and the endocannabinoid system
(ECS) that underlies much of its activity. A recent USA study [4]
documented that 89.5% of surveyed residents and fellows felt un-
prepared to prescribe, while only 35.3% even felt ready to answer
cannabis questions. Additionally, only 9% of American medical schools
https://doi.org/10.1016/j.ejim.2018.01.004
Received 27 October 2017; Accepted 1 January 2018
Corresponding author.
E-mail addresses: info@drcarolinemaccallum.com (C.A. MacCallum), ethan.russo@icci.science (E.B. Russo).
Abbreviations: 5-HT
1A
, serotonin 1A receptor; AE, adverse events; AIDS, acquired immunodeciency syndrome; CB
1
, cannabinoid-one receptor; CB
2
, cannabinoid-two receptor; CBD,
cannabidiol; CBDA, cannabidiolic acid; CRISP-R, Clustered Regularly Interspaced Short Palindromic Repeats; ECS, endocannabinoid system; GAP, Good Agricultural Practice; GCP, Good
Clinical Practice; GMP, Good Manufacturing Practice; HIV, human immunodeciency virus; MS, multiple sclerosis; PAH, polycyclic aromatic hydrocarbon; RCT, randomised controlled
trial; THC, Δ
9
-tetrahydrocannabinol; THCA, tetrahydrocannabinolic acid; TRPV1, transient receptor potential cation channel vanilloid subfamily receptor 1; USAN, United States Adopted
Name
European Journal of Internal Medicine 49 (2018) 12–19
Available online 04 January 2018
0953-6205/ © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
T
documented pertinent clinical cannabis content in their curricula.
While it remains a common complaint that cannabis therapeutics
lacks adequate documentation, according to a recent publication [5],
scientist and clinicians are recognising the limitations of randomised
controlled studies in their generalisability to populations vs. customi-
sation of best evidence based practices for individual patients. In-
dividualized evidence based medicine may be delivered to a patient
using an N-of-1, or single clinical trial, whereby the patient is the sole
unit of observation for ecacy and side eects of various interventions.
This method can be applied to a medical cannabis patient to nd an
optimal intervention or sweet spotcombination of plant varieties and
dosage forms that provide superior symptom control.
In this article, two experienced clinicians, internist and neurologist,
respectively, oer their review of the literature and personal observa-
tions that might serve as an initial guide to suggested Good Clinical
Practice (GCP) as applied to cannabis. These include our opinion that
cannabis medicines, whether prescription or over-the-counter, should
be ideally cultivated organically according to Mendelian selective
breeding techniques without the necessity of genetic modication or
CRISPR technology according to Good Agricultural Practice (GAP), be
extracted and processed under Good Manufacturing Practice (GMP) [6],
and be made available to consumers with full information as to can-
nabinoid and terpenoid proles, and certication that the material is
free of pesticide [7], microbial or heavy metal contamination.
2. Cannabis pharmacology in brief
Cannabis produces phytocannabinoids (plant cannabinoids) in
greatest abundance in the unfertilised female owers in acid form, most
abundantly tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic
acid (CBDA), which are most frequently utilised after heating either by
smoking, vaporisation, or baking in confections to produce decarbox-
ylation of the more familiar neutral cannabinoids, tetra-
hydrocannabinol (THC) and cannabidiol (CBD) (see graphical abstract)
[8].
THC is the primary psychoactive component of cannabis, working
primarily as a weak partial agonist on CB
1
and CB
2
receptors with well-
known eects on pain, appetite, digestion, emotions and thought pro-
cesses mediated through the endocannabinoid system, a homeostatic
regulator of myriad physiological functions [9], found in all chordates.
THC can cause psychoactive adverse events depending on dose and
patient previous tolerance. Its use is applicable for many symptoms and
conditions including; pain, nausea, spasticity/spasms, appetite stimu-
lation, anxiety, depression, post-traumatic stress disorder (PTSD), in-
somnia et al.
CBD, in contrast, has little anity for these receptors directly, but
rather is a negative allosteric modulator of CB
1
[10], with protean
pharmacological eects on various other receptor systems including
TRPV1, 5-HT
1A
, adenosine A2A and non-receptor mechanisms (re-
viewed [11]), productive of analgesic, anti-inammatory, anti-anxiety,
and anti-psychotic eects among many others. CBD is non-intoxicating,
and has been shown to help with similar symptoms, with added benet
as an anticonvulsant, anti-psychotic, neuroprotectant, and anti-in-
ammatory (including autoimmune conditions). Cannabis is a multi-
modal treatment. It can be used to treat multiple symptoms and con-
ditions concurrently, which can therefore help to reduce polypharmacy
burden.
There are thousands of individual cannabis types, which patients
and purveyors may erroneously refer to as strains, whereas the pre-
ferred term is chemical variety or chemovar[12]. Each chemovar
contains varying concentrations of cannabinoids and other components
with important pharmacological and modulatory eects include the
monoterpenoids [8,11] myrcene (analgesic, sedating), limonene (anti-
depressant and immune-stimulating), pinene (acetylcholinesterase in-
hibitor alleviating short-term memory impairment from THC) and the
sesquiterpenoid beta-caryophyllene (anti-inammatory analgesic and
selective full agonist at the CB
2
receptor). The relative proportions of
these and other components are the primary determinants of the
pharmacological eects and adverse events associated with a particular
cannabis chemovar, and is critical information that should be available
to patients and physicians recommending such treatment. Until recent
years, the vast majority of chemovars in Europe [13] and North
America [14] were THC-predominant (Type I cannabis). Con-
temporaneously, there has been greater interest in mixed THC:CBD
(Type II) and CBD-predominant (Type III cannabis) chemovars with
broader mechanisms of action and improved therapeutic indexes [12].
The acid cannabinoids have received much less research interest,
but possess fascinating pharmacological properties. THCA has been
noted to produce anti-inammatory eects via antagonism of tumour
necrosis factor-alpha (TNF-α)[15], to be a strong anti-emetic [16] and
was recently demonstrated to be an agonist of the PPAR-γnuclear re-
ceptor with neuroprotective eects [17], as well as anticonvulsant ef-
cacy [18]. CBDA is also a powerful anti-emetic [19] and anti-anxiety
agent [20] in rodents, and both acid cannabinoids have prominent
anecdotal reports of benet on skin and other tumors.
3. Pharmacokinetic considerations
Absorption, distribution, and metabolism determine the onset and
duration of action of each dosage form. Absorption has the most
variability, and is aected by product lipophilicity, bioavailability as
well as the inherent organ tissue dierences (i.e., alveolar, dermal vs.
gastric). Cannabinoids are lipophilic and have low water solubility.
Therefore, for topical or oral routes, they are best absorbed in the
presence of fat, oils or polar solvents, such as ethanol. There is sug-
gestion that newer technology such as using nano- or ionized particles
or the use omega fats in carrier oil can enhance absorption; or for to-
picals preparations, using ingredients to mildly disrupt the skin barrier
may allow greater absorption of active ingredient. Factors such as re-
cent meals, depth of inhalation, duration of breath holding, tempera-
ture of vaporizer all aect cannabis absorption, which can vary from
20%30% orally, up to 1060% for inhalation [21]. Clinicians will
benet from an understanding of these factors to prescribe or re-
commend cannabis to enable estimation of a target quantity of dried
product for their patients. See Dosing strategies and clinical pearls
section for more details.
4. Modes of administration
This information is summarised (Table 1,Table 2)[7,2127].
5. Therapeutic uses
Cannabis can be a useful tool in the treatment of many complex
diseases or rare conditions which lack eective conventional ther-
apeutic options, or where the side eects burden of such treatments
outweigh the benets, for example, central sensitivity syndromes (-
bromyalgia, chronic fatigue syndrome, migraines, irritable bowel), or
multiple sclerosis, neuropathic pain, and refractory nausea. An assess-
ment of current evidence in various indications is summarised (Table 3)
[2833].
6. Dosing strategies and clinical pearls
There is insucient evidence to support the necessity of a trial of
synthetic cannabinoids prior to initiating cannabis-based medicine
treatment, unless legal availability is not an option.
General approach to cannabis initiation is start low, go slow, and
stay low.
For cannabis inhalation, patients should start with 1 inhalation and
wait 15 min. Then, they may increase by 1 inhalation every
1530 min until desired symptom control has been achieved.
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19
13
Higher THC concentrations of herbal cannabis may allow utilization
of lower amounts. Patients should titrate accordingly to avoid ad-
verse events.
THC-mediated side eects such as fatigue, tachycardia and dizziness
are avoidable when starting dose is low and titration is slow.
Slow upward dose titration promotes tolerance to psychoactive se-
quelae of THC, which is especially important for naïve users.
Medical cannabis patients, in contrast to recreational users, fre-
quently use CBD-predominant chemovars with the smallest amount
of THC to get the greatest improvement in symptom control, func-
tion, and quality of life, with fewest adverse events.
Attainment of euphoric eects is not required to attain symptom
control.
For chronic conditions and symptoms, long acting oral preparations
are the mainstay of treatment.
Vaporisation can be utilised as an add-on prn technique for episodic
exacerbations of symptoms.
CBD can balance THC side eects, especially in daytime use, or
when driving is required.
Cannabis should be stored in a safe place, or lock box in the home.
Physicians must clearly communicate the potential risks and safety
of cannabis, no dierently than with any psychoactive medication.
We suggest documentation in a standard treatment agreementform
for medical-legal purposes. (See https://www.drcarolinemaccallum.
com/cannabis-resources/.)
Patients should keep a symptom inventorychart indicating re-
sponse or ecacy for each cannabis product for each symptom as
and aid for physicians in determining treatment response to can-
nabis in follow up visits. (See https://www.drcarolinemaccallum.
com/cannabis-resources/.)
Most patients use 13 g of herbal cannabis per day. < 5% of pa-
tients use > 5 g per day [34]. Tolerance does not develop to the
benets. Over time dose escalation is not generally observed
[22,34,35]. Additional needs require reassessment.
Table 1
Cannabis routes of administration.
Cannabis routes of administration
Smoking Vaporisation Oral Other routes
Most common route of administration, but
not recommended (joints, bongs, pipes, etc.)
Combustion at 600900 °C producing toxic
biproducts: tar, PAH (polycyclic aromatic
hydrocarbons), carbon monoxide (CO),
ammonia (NH
3
).
Chronic use associated with respiratory
symptoms (bronchitis, cough, phlegm), but
not lung cancer nor COPD (if cannabis only).
Patients may mix with tobacco increasing
respiratory/cancer risk
3050% of cannabis is lost to side-stream
smoke
Heats cannabis at 160230 °C.
Reduced CO, but not complete
elimination of PAH
demonstrated to date.
Vaporisation produces
signicantly less harmful
biproducts vs. smoking.
Decreased pulmonary
symptoms reported compared to
smoking.
Oils, capsules and other po routes
increasingly popular due to convenience and
accuracy of dosing.
Edibles (brownies/cookies) may be more
dicult to dose.
Juicing and cannabis teas do not allow for
adequate decarboxylation of raw plant
Nabiximols oromucosal spray is currently
the only cannabis-based prescription that
delivers standardised dosage of CBD/THC in
a 1:1 ratio with extensive research
Tinctures and lozenges intermediate onset
with limited research
Topicals ideal for localised symptoms
(dermatological conditions, arthritis), with
limited research evidence
Suppositories possibly indicated for specic
populations (cancer, GI symptoms, young/
elderly, etc.) with variable absorption. THC-
hemisuccinate may allow for best absorption
with limited research.
Recreational routes include shatter,dabs,
concentrates. Deliver very high doses of THC
with high risk of euphoria, impairment,
reinforcement, toxic psychosis, orthostatic
hypotension. Inappropriate for medical
application.
Table 2
Administration factors in cannabis delivery methods.
Issue Smoking/vaporisation Oral Oromucosal Topical
Onset (min) 510 60180 1545 Variable
Duration (h) 246868 Variable
Pro Rapid action, advantage for acute or
episodic symptoms (nausea/pain)
Less odor, convenient and discrete,
advantage for chronic disease/
symptoms
Pharmaceutical form (nabiximols) available,
with documented ecacy and safety.
Less systemic eect, good for
localised symptoms
Con Dexterity required, vaporisers may be
expensive, and not all are portable
Titration challenges due to delayed
onset
Expensive, spotty availability Only local eects
Table 3
Levels of evidence for cannabis-based medicines in various conditions.
Cannabis and nabiximols supporting evidence
Level of evidence Benets
Conclusive or
substantial evidence
of ecacy
Adult chronic pain treatment
Multiple sclerosis spasticity symptoms
Chemotherapy-induced nausea and vomiting
Treatment of intractable seizures in Dravet and
Lennox-Gastaut syndromes (CBD)
Moderate evidence of
ecacy
Improving outcomes in individuals with sleep
disturbances associated with chronic pain, multiple
sclerosis, bromyalgia, obstructive sleep apnea
syndrome
Decreasing intraocular pressure in glaucoma
Limited evidence of
ecacy
Symptoms of dementia
Symptoms of Parkinson disease
Positive and negative symptoms of schizophrenia
Symptoms of posttraumatic stress disorder
Appetite and decreasing weight loss associated with
HIV/AIDS
Multiple sclerosis spasticity (clinician-measured)
Traumatic brain injury/intracranial haemorrhage
associated disability, mortality, and other outcomes
Symptoms of anxiety in social anxiety disorders
(CBD)
Symptoms of Tourette syndrome
Limited evidence of
inecacy
Depressive symptoms in chronic pain or multiple
sclerosis patients
Insucient evidence of
ecacy or
inecacy
Addiction abstinence
Symptoms of irritable bowel syndrome
Cancers, including glioma
Cancer-associated anorexia, cachexia syndrome and
anorexia nervosa
Symptoms of amyotrophic lateral sclerosis
Chorea and some neuropsychiatric symptoms
associated with Huntington disease
Dystonia
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19
14
Most patients require 68 sprays of nabiximols per day for symp-
tomatic relief with a limit of 12. Above this dose, adverse events are
increased without improved ecacy.
Cannabis medicine doses must be individually determined, as this
depends on underlying endocannabinoid tone.
Use of homemade oral oils or topicals may require much higher
dried cannabis than utilised for inhalation.
CBD-predominant preparations have fewer untoward psychotropic
eects, and may require higher dosing.
7. Tactics in titration
Oral THC preparation eects are usually easier to judge vs inhala-
tion as the concentrations should be available from the producer.
Vaporisation is subject to more variables which can inuence estimated
dose: size of chamber, depth of inhalation, breath holding, strength of
THC in the chemovar, etc. Ideally, the patient would start using a THC-
predominant preparation at bedtime to limit adverse events and en-
courage development of tolerance. However, this is not a must.
Days 12: 2.5 mg THC-equivalent at bedtime. (may start at 1.25 mg
if young, elderly, or other concerns).
Days 34: if previous dose tolerated, increase by 1.252.5 mg THC
at bedtime.
Days 56: continue to increase by 1.252.5 mg THC at bedtime
every 2 days until desired eect is obtained. In event of side eects,
reduce to previous, best tolerated dose.
Some patients require THC for daytime use depending on their
symptoms. Consider use of a more stimulating chemovar unless seda-
tion is a desired result. Most patients dose orally two to three times per
day.
Consider the following regimen:
Days 12: 2.5 mg THC-equivalent once a day
Days 34: 2.5 mg THC twice a day
Increase as needed and as tolerated to 15 mg THC-equivalent di-
vided BID-TID
Doses exceeding 2030 mg/day may increase adverse events or in-
duce tolerance without improving ecacy.
Use of high doses of THC-predominant cannabis above 5 g per day
are probably unjustied, except in the case of primary cancer treatment
(vide infra), and suggest possible tolerance or misuse. THC tolerance
may be readily abrogated via a drug vacation of at least 48 h, and
preferably longer. Patients may then nd that much lower doses pro-
vide symptomatic benet equal to or better than previously experi-
enced (see suggested regimen devised by Dustin Sulak, DO: www.
healer.com).
CBD-predominant chemovars produce fewer adverse events, but
there are no established dosing guidelines or maximum doses estab-
lished except in psychosis (800 mg) [30]and seizure disorders (2500 mg
or 2550 mg/kg) [29]. For other indications, many patients obtain
benets with much lower doses, starting with 520 mg per day of oral
preparations divided BID-TID, which may reduce attendant expense.
8. Contraindications
Cannabis is generally contraindicated in pregnancy and lactation,
despite a long history of usage [36], and foetal/neonatal sequelae re-
main controversial [37,38]. It is also contraindicated in psychosis (ex-
cept CBD-predominant preparations [30]). Cannabis should be utilised
with caution in unstable cardiac conditions, such as angina, due to ta-
chycardia and possible hypotension due to THC, but produces no QTc
issues [39]. Use in children and teens remains the subject of debate (see
below), as does its use in addiction and dependency. Smoking should be
avoided in COPD and asthma.
9. Adverse events
Cannabis has a superior safety prole in comparison to many other
medications, with no reported deaths due to overdose, due to a lack of
CB
1
receptors in brainstem cardiorespiratory centres [40].
THC-mediated side eects are most pertinent and rate-limiting, and
are dose-dependent. Using a start low and go slowdosing strategy
mitigates most adverse events of THC. Also, combining CBD with THC
can further reduce those eects (Fig. 1). Patients develop tolerance to
psychoactive eects of cannabis quickly over period of days, without
concomitant tolerance to the benets, and therefore maintain the same
daily dose of many years [34,35], in stark contrast to opioids. A recent
large review of herbal cannabis in Canada revealed no increase in
serious adverse events in chronic administration, no harm on cognitive
function, pulmonary function tests, biochemistry (creatinine, liver
function test, and CBC) [34], conrming patterns seen in decades-long
usage in the USA [35].
Common AEs are listed (Table 4)[34,41,42], and their reduction
with lower doses and slow titration with nabiximols [42,43] are
documented (Fig. 1).
The critical nature of dose and preparation are additionally ex-
emplied (Fig. 2), demonstrating that whereas even 1015 mg of pure
Fig. 1. Graphic comparison of nabiximols adverse events en-
countered in > 3% of multiple sclerosis RCT patients with rapid ti-
tration and higher dosing (blue) vs. slower titration and capping
dosing at 12 sprays per day (red) (32.4 mg THC, 30 mg CBD). (For
interpretation of the references to colour in this gure legend, the
reader is referred to the web version of this article.)
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19
15
oral THC may induce toxic psychosis in the naïve or susceptible in-
dividual [44], such reactions were only identied in 4 of 260 exposures
to high dose nabiximols for a Phase I RCT containing 48.6 mg of THC by
virtue of its CBD and terpenoid prole [39]. Extrapolation of data in
Figs. 1 and 2 suggest that other Type II oral preparations may produce
similar results with slow titration.
10. Drug interactions
Most drug interactions are associated with concurrent use of other
CNS depressants with cannabis. Clinically, signicant drug interactions
have proven rare [7], and there is no drug that cannot be used with
cannabis, if necessary. THC is oxidised by (CYP) 2C9, 2C19, and 3A4.
Therefore, serum levels may increase with inhibitors, or decrease with
enzyme inducers. Pertinent drug interaction studies are few [45,46].
Existing studies have not demonstrated toxicity/ loss of eect of con-
comitant medications, but still theoretically possible [47]. One excep-
tion is high dose CBD with clobazam, wherein high levels of a sedating
metabolite, N-desmethyl clobazam will require a dose reduction for that
drug [29].
11. Monitoring
Depending on the patient, they may need to be seen in follow up
every 16 months depending on several factors such as; their familiarity
with cannabis, comorbid medical conditions, ability to adhere to
treatment plan instructions and keep an inventory of cannabis ecacy
on individual symptoms/conditions. This should involve appropriate
monitoring for ecacy (consider changing dosage routes, dose, and/or
plant varieties if needed), side eects of THC, review of concomitant
medication changes, and when it is appropriate to initiate a gentle drug
taper to minimise withdrawal symptoms, which are rarely problematic
in medicinal cannabis patients [4850]. Finally, consider implementing
validated questionnaires and quality of life assessments to allow for
documentation of objective measures to capture improvement in
symptoms and function.
12. Special cases
12.1. Epilepsy
Cannabis has a long traditional use in treatment of seizures [51], but
has frequently been contraindicated in that context in RCTs due to the
observed association of THC with proconvulsant eects in rodents at
high doses. In contrast, CBD displays only anticonvulsant properties
and as Epidiolex®cannabis extract, has been proven safe and eective
in a variety of intractable epilepsies, such as Dravet and Lennox-Gastaut
syndromes in both observational settings [52] and Phase III clinical
trials [29]. Regulatory approval in the USA is expected in 2018. CBD in
the latter settings has often required very high doses, as much as
2500 mg/d., whereas some clinicians have claimed similar ecacy at
much lower doses when CBD is utilised in preparations containing
concomitant low dose THC, THCA and even the anticonvulsant terpe-
noid, linalool [18].
12.2. Cancer
The anti-emetic eects of THC in association with cancer che-
motherapy have long been known and a synthetic form was approved
for such use in the USA in 1985. Benets as a palliative for sleep [53],
and particularly for opioid-resistant cancer pain have also been de-
monstrated in two Phase II clinical trials of nabiximols [54,55], but
unfortunately were not proven denitively in subsequent Phase III
studies. Cancer pain remains an indication in Canada under a Notice of
Compliance with conditions.
Cannabis has also been an historical primary treatment for cancer
[2], with extensive basic science documentation of its cytotoxic eects
with cytopreservative eects on normal cells. Initial trials and case
reports support the acute need for more formal investigation [5659].
Thousands of patients worldwide are pursuing such treatment, most
often without benet of appropriate medical monitoring. Both basic
science [60,61] and anecdotal clinical reports suggest that cannabis-
based treatment is most eective in conjunction with conventional
approaches, whether chemotherapy or radiation. High doses (up to
1000 mg/d), preferably of mixed phytocannabinoids (as in cannabis
extracts), for up to 3 months may be required to eradicate some ma-
lignancies, but emphasis is required that this approach remains
Table 4
Adverse events associated with cannabis-based medicines.
Side eect Most common Common Rare
Drowsiness/fatigue
Dizziness
Dry mouth
Cough, phlegm, bronchitis
(Smoking only)
Anxiety
Nausea
Cognitive eects
Euphoria
Blurred vision
Headache
Orthostatic hypotension
Toxic psychosis/paranoia
Depression
Ataxia/dyscoordination
Tachycardia (after titration)
Cannabis hyperemesis
Diarrhea
Fig. 2. Graphical comparison of threshold dosing of THC vs. na-
biximols producing toxic psychosis.
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19
16
anecdotal without benet of large published RCTs. High doses of THC-
containing preparations require slow titration over 2 weeks to induce
tolerance to psychoactive sequelae. There is some anecdotal evidence
supporting use of acid cannabinoids in much lower doses, and CBDA
may improve the pharmacokinetics of CBD [47]. Prolonged main-
tenance of cannabis therapy, at some lower dosage may be similarly
required to prevent recurrences. It should be borne in mind that cure
of cancer can only be claimed after a 5-year interval without evidence
of tumour. Further objective evidence is needed to support adjunctive
cannabis-based medicine treatment of cancer.
12.3. Pain
Cannabis treatment has not generally been useful in relation to
treatment of acute pain [62]. In contrast, both THC and CBD-pre-
dominant cannabis preparations have proven safe and eective in nu-
merous RCTs of chronic non-cancer pain, whether somatic or neuro-
pathic, peripheral or central (reviewed [22]) and examination in
national programs, as in Canada [34].
12.4. The elderly
Whereas vigilance toward adverse events, particularly attributable
to polypharmacy are necessary in the elderly patient, monitoring of
adverse events with nabiximols reveal no specic increased suscept-
ibility to problems in this age group [42]. THC has been used to ad-
vantage to treat agitation in dementia [32], and the neuroprotective
eects of it and CBD portend to oer possible advantages in this, and
related pathologies [63]. Slow titration is required to avoid AEs, in-
cluding falls and orthostatic hypotension.
12.5. Parkinson disease
CB
1
receptors are densely expressed in the basal ganglia, and can-
nabis has shown variable ecacy in various clinical studies [64]. Ad-
ditional investigation is required, however, to establish the optimal
composition of components. Anecdotal surveys suggest that acid can-
nabinoids given orally over prolonged intervals (3 months) may be
necessary to achieve clinical improvement [65]. Slow titration is re-
quired.
12.6. Paediatrics
Use of cannabis as medicine in children remains another forbidden
territory [1], but as in any other context, the relative risks and benets
must be weighed. Recent review has supported ecacy in nausea sec-
ondary to chemotherapy and in seizures [66]. It should be stated em-
phatically that there is a world of dierence scientically and ethically
between judicious administration of low doses of cannabinoids for
therapeutic purposes as compared to chronic use of high-dose THC for
recreational purposes by teenagers. Even synthetic THC has been used
to advantage in children with severe static encephalopathies with
spasticity and seizures in Germany where warranted [67,68]. Historical
data [1] and modern experience in treatment of nausea secondary to
chemotherapy [69] support the fact that children under the age of 10
are remarkably resistant to psychoactive sequelae of THC, and are able
to tolerate doses, when necessary, that might be more problematic in
the adult patient.
In those at risk, younger age of rst cannabis use is associated with
earlier onset of schizophrenia and bipolar disorder and worse outcomes
[70,71]. CBD-predominant preparations, and even THCA, may be a
useful therapy for children (or adults) with severe developmental/self-
harm, schizophrenia, seizures, brain tumors, refractory or rare diseases.
In these conditions, CBD (with low or no THC) may be more ecacious
with fewer AEs than traditional therapies. (i.e., opioids, antiepileptic
etc). Risks and benets need to be considered.
12.7. Opioid and other addictions
Nineteenth century observations of the use of cannabis with opioids
[72,73] attested to its additive analgesic benets, reduction of adverse
events and even benet to withdrawal symptoms. This has been sup-
ported by basic science investigation [74], and a variety of observa-
tional studies [7577] and epidemiological evidence of decreased
opioid overdose mortality in US states with medical cannabis access
[78], as well as lowered costs for analgesics including opioids in such
states in the Medicare (elderly) [79] and Medicaid (low-income) [80]
populations. An intriguing nding from a long-term safety study of
nabiximols in survivors of a Phase IIA trial of cancer pain non-re-
sponsive to optimised opioids showed no increase in cannabis dosing
requirements over ensuing months, without the expected escalation of
opioid requirements with continued disease progression and eventual
demise [81]. Studies do not report an increase in opioid serum levels
when used with cannabis [82].
12.8. Driving and safety sensitive occupations
It is important to include evaluation of social and occupational
history during a medical cannabis consultation. This may include de-
termining if a patient works outside the home, has a safety sensitive
occupation, drives a motor vehicle, engages in childcare, etc. A rea-
sonable and conservative cannabis regimen for this patient population
would be CBD-predominant preparations during working hours, and
THC-predominant ones after work or before sleeping.
Patients should not drive or utilise power tools or heavy equipment
until accustomed to the eects of the medicine [7]. It is recommended
that driving should be avoided for 4 h after inhaled cannabis use, 6 h
after ingested cannabis use, or 8 h if euphoria was experienced. If a
patient feels impaired, regardless of cause, they should not be driving or
working safety sensitive jobs.
In clinical practice we have observed that medical cannabis pa-
tients, using daily, appropriate low doses of THC develop tolerance and
experience minimal if any impairment, as has been documented for
multiple sclerosis patients [83]. There are no serum assays that enable
measurement of impairment due to THC accurately. Urine toxicology
tests metabolites of THC which merely indicate THC ingestion some-
time in the past two to three weeks. The authors believe a combination
of neurocognitive testing, along with physical examination or perfor-
mance specic activities to capture reaction time, coordination, bal-
ance, decision making et al. will prove more valuable in comparison to
bodily uid THC levels.
12.9. Standard of care
The authors believe that the standard of care for cannabis is no
dierent than that for any speciality in the practice of medicine. The
requirements are: examination of prior medical records whenever
available, a comprehensive history and physical, a thorough discussion
of the pros and cons of cannabis, plans for appropriate follow-up care,
proper documentation of the consultation, and appropriate commu-
nication with other care-givers.
13. Conclusions
As cannabis-based medicines return to mainstream usage, it is es-
sential that clinicians gain a greater understanding of their pharma-
cology, dosing and administration to maximise therapeutic potential
and minimise associated problems. With standardised modern products,
and educated caregivers, these are worthy and attainable goals.
AcknowledgementsFunding
This study did not receive any specic grant from funding agencies
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19
17
in the public, commercial, or not-for-prot sectors.
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... In addition, the use of combined therapy of THC and CBD was reported in studies on other indications [e.g., chronic pain (Überall, 2020)], and the use of CBD alone is noted for the treatment of psychosis in Parkinson's disease (Zuardi et al., 2009). The patients of this study received a natural plant formulation standardized in THC and CBD (1:2) contents according to the hypothesis that the natural extract might have better tolerability and efficacy, the presence of CBD counterbalancing the psychoactive effects of THC (Niesink and van Laar, 2013;MacCallum and Russo, 2018). ...
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Context The management of behavioral symptoms and rigidity in patients with dementia constitutes a significant challenge. Short-term studies suggest an interest in the use of medical cannabis, but long-term data are lacking. Objectives The objective of this study was to investigate the feasibility and long-term safety of administering tetrahydrocannabinol/cannabidiol (THC/CBD) treatment as an additional drug to a poly medicated population with severe dementia, evaluate clinical improvements, and collect information on the pharmacokinetics of cannabinoids and possible drug–drug interactions. Methods A prospective observational study of patients with severe dementia living in a long-term care home to whom the physicians had prescribed a medical cannabis treatment. Data were collected over 2 years. We assessed the changes in medical cannabis dosages, safety parameters, variations in neuropsychiatric problems, agitation, rigidity, the most invalidating daily activity, and disabling behavior trouble scores. We evaluated the pharmacokinetics of cannabinoids by measuring plasma levels and analyzing the enzymatic activity. Results We assessed 19 patients (81.4 years—17 women and two men) receiving an average of 12.4 mg THC/24.8 mg CBD per day for up to 13 months, with no reported problems related to the treatment and limited adverse drug reactions. Clinical scores showed a marked improvement that was stable over time, deprescription of other medications, and care facilitated. The pharmacokinetic evaluation showed an expected slight reduction in the enzymatic activity of CYP1A2 and CYP2C19. Conclusion A long-term THC/CBD (1:2) medication can be administered safely and with overall positive clinical improvement to poly medicated older adults with severe dementia and associated problems. The results must be confirmed in a randomized trial.
... For example, THC, CBD, and cannabinol inhibit carboxylesterases, which have key roles in the bioactivation and bioinactivation of several medications, including multiple cardiovascular medica-tions such as clopidogrel, warfarin, dabigatran, and angiotensin-converting enzyme inhibitors [60]. While the focus has been directed toward pharmacokinetic interactions, additive pharmacodynamics interactions between cannabis and other coadministered drugs with akin physiological effects are more clinically relevant, especially if they can induce the same undesirable side effects, such as increased tachycardia with the coadministration of cannabis and sympathomimetics or tricyclic antidepressants [61]. ...
... En el campo del dolor, no está claro si el CBD es mejor o peor analgésico que el THC. En ausencia de evidencia o de guías clínicas basadas en estudios rigurosos, se aconseja ejercer de forma precavida si se usan productos con dosis elevadas de THC (16). ...
... The latter has anti-inflammatory and analgesic traits. The THC:CBD therefore determines the product's overall effect [220]. CB1 cannabinoid receptors are found predominantly in the CNS and peripheral nervous system. ...
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