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Practical considerations in medical cannabis administration and dosing

Article in European Journal of Internal Medicine · January 2018

DOI: 10.1016/j.ejim.2018.01.004

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 European Journal of Internal Medicine 49 (2018) 12–19

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review Article

Practical considerations in medical cannabis administration and dosing T

a,⁎ b
Caroline A. MacCallum , Ethan B. Russo
a
Faculty of Medicine, University of British Columbia, BC, Canada
b
International Cannabis and Cannabinoids Institute, Prague, Czech Republic

A R T I C L E I N F O A B S T R A C T

Keywords: Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical
Cannabis complexity and variability, quality control issues, previous dearth of appropriately powered randomised con-
Cannabinoids trolled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise
Marijuana patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/na-
Drug abuse
biximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology
Psychopharmacology
and therapeutics has become untenable. In this article, the authors endeavour to present concise data on can-
Adverse events
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 benefits on pain, inflammation, 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 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.

1. Introduction standards of safety, efficacy and consistency required of any pharma-

ceutical. The problem for physicians with respect to treatment with
Cannabis has a history of medical application likely exceeding that herbal cannabis remains acute, however: How does the responsible
of the written word, including mainstream usage in Europe and North healer and medical scientist approach the desperate patient for whom
America for a century between 1840 and 1940 [1,2]. It is only in the conventional medicine has failed and wishes to avail themselves of a
last century that quality control issues, the lack of a defined chemistry, purportedly healing herb that has been an international societal outlaw
and above all, politically and ideologically motivated prohibition re- for decades? The answer is simple: educational and scientific standards
legated it planta non grata. The discovery and elucidation of the en- apply to the cannabis controversy equally with that of any other pu-
docannabinoid system [3], coupled with a popular tidal wave of an- tative therapy.
ecdotal accounts and renaissance of therapeutic clinical trials renders Unfortunately, physicians of the world remain profoundly un-
that status quo ante untenable. educated with respect to cannabis and the endocannabinoid system
One preparation, Sativex® (USAN: nabiximols), an oromucosal (ECS) that underlies much of its activity. A recent USA study [4]
cannabis-based medicine with 2.7 mg of THC and 2.5 mg CBD plus documented that 89.5% of surveyed residents and fellows felt un-
terpenoids per spray has attained regulatory approval in 29 countries prepared to prescribe, while only 35.3% even felt ready to answer
for treatment of spasticity in multiple sclerosis, having met the cannabis questions. Additionally, only 9% of American medical schools

Abbreviations: 5-HT1A, serotonin 1A receptor; AE, adverse events; AIDS, acquired immunodeficiency syndrome; CB1, cannabinoid-one receptor; CB2, 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 immunodeficiency virus; MS, multiple sclerosis; PAH, polycyclic aromatic hydrocarbon; RCT, randomised controlled
trial; THC, Δ9-tetrahydrocannabinol; THCA, tetrahydrocannabinolic acid; TRPV1, transient receptor potential cation channel vanilloid subfamily receptor 1; USAN, United States Adopted
Name
⁎
Corresponding author.
E-mail addresses: [email protected] (C.A. MacCallum), [email protected] (E.B. Russo).

https://doi.org/10.1016/j.ejim.2018.01.004
Received 27 October 2017; Accepted 1 January 2018
Available online 04 January 2018
0953-6205/ © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19

documented pertinent clinical cannabis content in their curricula. selective full agonist at the CB2 receptor). The relative proportions of
While it remains a common complaint that cannabis therapeutics these and other components are the primary determinants of the
lacks adequate documentation, according to a recent publication [5], pharmacological effects and adverse events associated with a particular
scientist and clinicians are recognising the limitations of randomised cannabis chemovar, and is critical information that should be available
controlled studies in their generalisability to populations vs. customi- to patients and physicians recommending such treatment. Until recent
sation of best evidence based practices for individual patients. In- years, the vast majority of chemovars in Europe [13] and North
dividualized evidence based medicine may be delivered to a patient America [14] were THC-predominant (Type I cannabis). Con-
using an N-of-1, or single clinical trial, whereby the patient is the sole temporaneously, there has been greater interest in mixed THC:CBD
unit of observation for efficacy and side effects of various interventions. (Type II) and CBD-predominant (Type III cannabis) chemovars with
This method can be applied to a medical cannabis patient to find an broader mechanisms of action and improved therapeutic indexes [12].
optimal intervention or “sweet spot” combination of plant varieties and The acid cannabinoids have received much less research interest,
dosage forms that provide superior symptom control. but possess fascinating pharmacological properties. THCA has been
In this article, two experienced clinicians, internist and neurologist, noted to produce anti-inflammatory effects via antagonism of tumour
respectively, offer their review of the literature and personal observa- necrosis factor-alpha (TNF-α) [15], to be a strong anti-emetic [16] and
tions that might serve as an initial guide to suggested Good Clinical was recently demonstrated to be an agonist of the PPAR-γ nuclear re-
Practice (GCP) as applied to cannabis. These include our opinion that ceptor with neuroprotective effects [17], as well as anticonvulsant ef-
cannabis medicines, whether prescription or over-the-counter, should ficacy [18]. CBDA is also a powerful anti-emetic [19] and anti-anxiety
be ideally cultivated organically according to Mendelian selective agent [20] in rodents, and both acid cannabinoids have prominent
breeding techniques without the necessity of genetic modification or anecdotal reports of benefit on skin and other tumors.
CRISPR technology according to Good Agricultural Practice (GAP), be
extracted and processed under Good Manufacturing Practice (GMP) [6], 3. Pharmacokinetic considerations
and be made available to consumers with full information as to can-
nabinoid and terpenoid profiles, and certification that the material is Absorption, distribution, and metabolism determine the onset and
free of pesticide [7], microbial or heavy metal contamination. duration of action of each dosage form. Absorption has the most
variability, and is affected by product lipophilicity, bioavailability as
2. Cannabis pharmacology in brief well as the inherent organ tissue differences (i.e., alveolar, dermal vs.
gastric). Cannabinoids are lipophilic and have low water solubility.
Cannabis produces phytocannabinoids (plant cannabinoids) in Therefore, for topical or oral routes, they are best absorbed in the
greatest abundance in the unfertilised female flowers in acid form, most presence of fat, oils or polar solvents, such as ethanol. There is sug-
abundantly tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic gestion that newer technology such as using nano- or ionized particles
acid (CBDA), which are most frequently utilised after heating either by or the use omega fats in carrier oil can enhance absorption; or for to-
smoking, vaporisation, or baking in confections to produce decarbox- picals preparations, using ingredients to mildly disrupt the skin barrier
ylation of the more familiar neutral cannabinoids, tetra- may allow greater absorption of active ingredient. Factors such as re-
hydrocannabinol (THC) and cannabidiol (CBD) (see graphical abstract) cent meals, depth of inhalation, duration of breath holding, tempera-
[8]. ture of vaporizer all affect cannabis absorption, which can vary from
THC is the primary psychoactive component of cannabis, working 20%–30% orally, up to 10–60% for inhalation [21]. Clinicians will
primarily as a weak partial agonist on CB1 and CB2 receptors with well- benefit from an understanding of these factors to prescribe or re-
known effects on pain, appetite, digestion, emotions and thought pro- commend cannabis to enable estimation of a target quantity of dried
cesses mediated through the endocannabinoid system, a homeostatic product for their patients. See Dosing strategies and clinical pearls
regulator of myriad physiological functions [9], found in all chordates. section for more details.
THC can cause psychoactive adverse events depending on dose and
patient previous tolerance. Its use is applicable for many symptoms and 4. Modes of administration
conditions including; pain, nausea, spasticity/spasms, appetite stimu-
lation, anxiety, depression, post-traumatic stress disorder (PTSD), in- This information is summarised (Table 1, Table 2) [7,21–27].
somnia et al.
CBD, in contrast, has little affinity for these receptors directly, but 5. Therapeutic uses
rather is a negative allosteric modulator of CB1 [10], with protean
pharmacological effects on various other receptor systems including Cannabis can be a useful tool in the treatment of many complex
TRPV1, 5-HT1A, adenosine A2A and non-receptor mechanisms (re- diseases or rare conditions which lack effective conventional ther-
viewed [11]), productive of analgesic, anti-inflammatory, anti-anxiety, apeutic options, or where the side effects burden of such treatments
and anti-psychotic effects among many others. CBD is non-intoxicating, outweigh the benefits, for example, central sensitivity syndromes (fi-
and has been shown to help with similar symptoms, with added benefit bromyalgia, chronic fatigue syndrome, migraines, irritable bowel), or
as an anticonvulsant, anti-psychotic, neuroprotectant, and anti-in- multiple sclerosis, neuropathic pain, and refractory nausea. An assess-
flammatory (including autoimmune conditions). Cannabis is a multi- ment of current evidence in various indications is summarised (Table 3)
modal treatment. It can be used to treat multiple symptoms and con- [28–33].
ditions concurrently, which can therefore help to reduce polypharmacy
burden. 6. Dosing strategies and clinical pearls
There are thousands of individual cannabis types, which patients
and purveyors may erroneously refer to as ‘strains’, whereas the pre- • There is insufficient evidence to support the necessity of a trial of
ferred term is chemical variety or ‘chemovar’ [12]. Each chemovar synthetic cannabinoids prior to initiating cannabis-based medicine
contains varying concentrations of cannabinoids and other components treatment, unless legal availability is not an option.
with important pharmacological and modulatory effects include the • General approach to cannabis initiation is ‘start low, go slow, and
monoterpenoids [8,11] myrcene (analgesic, sedating), limonene (anti- stay low’.
depressant and immune-stimulating), pinene (acetylcholinesterase in- • For cannabis inhalation, patients should start with 1 inhalation and
hibitor alleviating short-term memory impairment from THC) and the wait 15 min. Then, they may increase by 1 inhalation every
sesquiterpenoid beta-caryophyllene (anti-inflammatory analgesic and 15–30 min until desired symptom control has been achieved.

13
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19

Table 1
Cannabis routes of administration.

Cannabis routes of administration

Smoking Vaporisation Oral Other routes

• Most common route of administration, but • Heats cannabis at 160–230 °C. • Oils, capsules and other po routes • Topicals ideal for localised symptoms
not recommended (joints, bongs, pipes, etc.) Reduced CO, but not complete increasingly popular due to convenience and (dermatological conditions, arthritis), with
• Combustion at 600–900 °C producing toxic elimination of PAH accuracy of dosing. limited research evidence
biproducts: tar, PAH (polycyclic aromatic demonstrated to date. • Edibles (brownies/cookies) may be more • Suppositories possibly indicated for specific
hydrocarbons), carbon monoxide (CO), • Vaporisation produces difficult to dose. populations (cancer, GI symptoms, young/
ammonia (NH3). significantly less harmful • Juicing and cannabis teas do not allow for elderly, etc.) with variable absorption. THC-
• Chronic use associated with respiratory biproducts vs. smoking. adequate decarboxylation of raw plant hemisuccinate may allow for best absorption
symptoms (bronchitis, cough, phlegm), but • Decreased pulmonary • Nabiximols oromucosal spray is currently with limited research.
not lung cancer nor COPD (if cannabis only). symptoms reported compared to the only cannabis-based prescription that • Recreational routes include ‘shatter’, ‘dabs’,
• Patients may mix with tobacco increasing smoking. delivers standardised dosage of CBD/THC in concentrates. Deliver very high doses of THC
respiratory/cancer risk a 1:1 ratio with extensive research with high risk of euphoria, impairment,
• 30–50% of cannabis is lost to ‘side-stream’ • Tinctures and lozenges intermediate onset reinforcement, toxic psychosis, orthostatic
smoke with limited research hypotension. Inappropriate for medical
application.

• Higher THC concentrations of herbal cannabis may allow utilization Table 3

of lower amounts. Patients should titrate accordingly to avoid ad- Levels of evidence for cannabis-based medicines in various conditions.
verse events.
•
Cannabis and nabiximols supporting evidence
THC-mediated side effects such as fatigue, tachycardia and dizziness
are avoidable when starting dose is low and titration is slow. Level of evidence Benefits
• Slow upward dose titration promotes tolerance to psychoactive se-
Conclusive or • Adult chronic pain treatment
quelae of THC, which is especially important for naïve users.
• Medical cannabis patients, in contrast to recreational users, fre-
substantial evidence
of efficacy
• Multiple sclerosis spasticity symptoms
• Chemotherapy-induced nausea and vomiting
quently use CBD-predominant chemovars with the smallest amount • Treatment of intractable seizures in Dravet and
of THC to get the greatest improvement in symptom control, func- Lennox-Gastaut syndromes (CBD)
tion, and quality of life, with fewest adverse events. Moderate evidence of • Improving outcomes in individuals with sleep

• Attainment of euphoric effects is not required to attain symptom efficacy disturbances associated with chronic pain, multiple
sclerosis, fibromyalgia, obstructive sleep apnea
control. syndrome
• For chronic conditions and symptoms, long acting oral preparations • Decreasing intraocular pressure in glaucoma
• Symptoms of dementia
are the mainstay of treatment. Limited evidence of

• Vaporisation can be utilised as an add-on prn technique for episodic efficacy • Symptoms of Parkinson disease
• Positive and negative symptoms of schizophrenia
exacerbations of symptoms. • Symptoms of posttraumatic stress disorder
• CBD can balance THC side effects, especially in daytime use, or • Appetite and decreasing weight loss associated with
when driving is required. HIV/AIDS

• Cannabis should be stored in a safe place, or lock box in the home. • Multiple sclerosis spasticity (clinician-measured)

• Physicians must clearly communicate the potential risks and safety • Traumatic brain injury/intracranial haemorrhage
associated disability, mortality, and other outcomes
of cannabis, no differently than with any psychoactive medication. • Symptoms of anxiety in social anxiety disorders
We suggest documentation in a standard ‘treatment agreement’ form (CBD)
for medical-legal purposes. (See https://www.drcarolinemaccallum. • Symptoms of Tourette syndrome
com/cannabis-resources/.) Limited evidence of • Depressive symptoms in chronic pain or multiple

• Patients should keep a ‘symptom inventory’ chart indicating re-

inefficacy
Insufficient evidence of
sclerosis patients
• Addiction abstinence
sponse or efficacy for each cannabis product for each symptom as efficacy or • Symptoms of irritable bowel syndrome
and aid for physicians in determining treatment response to can- inefficacy • Cancers, including glioma
nabis in follow up visits. (See https://www.drcarolinemaccallum. • Cancer-associated anorexia, cachexia syndrome and
anorexia nervosa
com/cannabis-resources/.)
•
• Symptoms of amyotrophic lateral sclerosis
Most patients use 1–3 g of herbal cannabis per day. < 5% of pa- • Chorea and some neuropsychiatric symptoms
tients use > 5 g per day [34]. Tolerance does not develop to the associated with Huntington disease
benefits. Over time dose escalation is not generally observed • Dystonia
[22,34,35]. Additional needs require reassessment.

Table 2
Administration factors in cannabis delivery methods.

Issue Smoking/vaporisation Oral Oromucosal Topical

Onset (min) 5–10 60–180 15–45 Variable

Duration (h) 2–4 6–8 6–8 Variable
Pro Rapid action, advantage for acute or Less odor, convenient and discrete, Pharmaceutical form (nabiximols) available, Less systemic effect, good for
episodic symptoms (nausea/pain) advantage for chronic disease/ with documented efficacy and safety. localised symptoms
symptoms
Con Dexterity required, vaporisers may be Titration challenges due to delayed Expensive, spotty availability Only local effects
expensive, and not all are portable onset

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C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19

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 figure legend, the
reader is referred to the web version of this article.)

• Most patients require 6–8 sprays of nabiximols per day for symp- preferably longer. Patients may then find that much lower doses pro-
tomatic relief with a limit of 12. Above this dose, adverse events are vide symptomatic benefit equal to or better than previously experi-
increased without improved efficacy. enced (see suggested regimen devised by Dustin Sulak, DO: www.
• Cannabis medicine doses must be individually determined, as this healer.com).
depends on underlying endocannabinoid tone. CBD-predominant chemovars produce fewer adverse events, but
• Use of homemade oral oils or topicals may require much higher there are no established dosing guidelines or maximum doses estab-
dried cannabis than utilised for inhalation. lished except in psychosis (800 mg) [30]and seizure disorders (2500 mg
• CBD-predominant preparations have fewer untoward psychotropic or 25–50 mg/kg) [29]. For other indications, many patients obtain
effects, and may require higher dosing. benefits with much lower doses, starting with 5–20 mg per day of oral
preparations divided BID-TID, which may reduce attendant expense.
7. Tactics in titration
8. Contraindications
Oral THC preparation effects are usually easier to judge vs inhala-
tion as the concentrations should be available from the producer. Cannabis is generally contraindicated in pregnancy and lactation,
Vaporisation is subject to more variables which can influence estimated despite a long history of usage [36], and foetal/neonatal sequelae re-
dose: size of chamber, depth of inhalation, breath holding, strength of main controversial [37,38]. It is also contraindicated in psychosis (ex-
THC in the chemovar, etc. Ideally, the patient would start using a THC- cept CBD-predominant preparations [30]). Cannabis should be utilised
predominant preparation at bedtime to limit adverse events and en- with caution in unstable cardiac conditions, such as angina, due to ta-
courage development of tolerance. However, this is not a must. chycardia and possible hypotension due to THC, but produces no QTc
issues [39]. Use in children and teens remains the subject of debate (see
• Days 1–2: 2.5 mg THC-equivalent at bedtime. (may start at 1.25 mg below), as does its use in addiction and dependency. Smoking should be
if young, elderly, or other concerns). avoided in COPD and asthma.
• Days 3–4: if previous dose tolerated, increase by 1.25–2.5 mg THC
at bedtime. 9. Adverse events
• Days 5–6: continue to increase by 1.25–2.5 mg THC at bedtime
every 2 days until desired effect is obtained. In event of side effects, Cannabis has a superior safety profile in comparison to many other
reduce to previous, best tolerated dose. medications, with no reported deaths due to overdose, due to a lack of
CB1 receptors in brainstem cardiorespiratory centres [40].
Some patients require THC for daytime use depending on their THC-mediated side effects are most pertinent and rate-limiting, and
symptoms. Consider use of a more stimulating chemovar unless seda- are dose-dependent. Using a ‘start low and go slow’ dosing strategy
tion is a desired result. Most patients dose orally two to three times per mitigates most adverse events of THC. Also, combining CBD with THC
day. can further reduce those effects (Fig. 1). Patients develop tolerance to
Consider the following regimen: psychoactive effects of cannabis quickly over period of days, without
concomitant tolerance to the benefits, and therefore maintain the same
• Days 1–2: 2.5 mg THC-equivalent once a day daily dose of many years [34,35], in stark contrast to opioids. A recent
• Days 3–4: 2.5 mg THC twice a day large review of herbal cannabis in Canada revealed no increase in
• Increase as needed and as tolerated to 15 mg THC-equivalent di- serious adverse events in chronic administration, no harm on cognitive
vided BID-TID function, pulmonary function tests, biochemistry (creatinine, liver
• Doses exceeding 20–30 mg/day may increase adverse events or in- function test, and CBC) [34], confirming patterns seen in decades-long
duce tolerance without improving efficacy. usage in the USA [35].
Common AEs are listed (Table 4) [34,41,42], and their reduction
Use of high doses of THC-predominant cannabis above 5 g per day with lower doses and slow titration with nabiximols [42,43] are
are probably unjustified, except in the case of primary cancer treatment documented (Fig. 1).
(vide infra), and suggest possible tolerance or misuse. THC tolerance The critical nature of dose and preparation are additionally ex-
may be readily abrogated via a drug vacation of at least 48 h, and emplified (Fig. 2), demonstrating that whereas even 10–15 mg of pure

15
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19

Table 4 monitoring for efficacy (consider changing dosage routes, dose, and/or
Adverse events associated with cannabis-based medicines. plant varieties if needed), side effects of THC, review of concomitant
medication changes, and when it is appropriate to initiate a gentle drug
Side effect Most common Common Rare
taper to minimise withdrawal symptoms, which are rarely problematic
Drowsiness/fatigue ✓ in medicinal cannabis patients [48–50]. Finally, consider implementing
Dizziness ✓ validated questionnaires and quality of life assessments to allow for
Dry mouth ✓
documentation of objective measures to capture improvement in
Cough, phlegm, bronchitis ✓
(Smoking only) symptoms and function.
Anxiety ✓
Nausea ✓ 12. Special cases
Cognitive effects ✓
Euphoria ✓
Blurred vision ✓ 12.1. Epilepsy
Headache ✓
Orthostatic hypotension ✓ Cannabis has a long traditional use in treatment of seizures [51], but
Toxic psychosis/paranoia ✓ has frequently been contraindicated in that context in RCTs due to the
Depression ✓
Ataxia/dyscoordination ✓
observed association of THC with proconvulsant effects in rodents at
Tachycardia (after titration) ✓ high doses. In contrast, CBD displays only anticonvulsant properties
Cannabis hyperemesis ✓ and as Epidiolex® cannabis extract, has been proven safe and effective
Diarrhea ✓ 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
oral THC may induce toxic psychosis in the naïve or susceptible in-
the latter settings has often required very high doses, as much as
dividual [44], such reactions were only identified in 4 of 260 exposures
2500 mg/d., whereas some clinicians have claimed similar efficacy at
to high dose nabiximols for a Phase I RCT containing 48.6 mg of THC by
much lower doses when CBD is utilised in preparations containing
virtue of its CBD and terpenoid profile [39]. Extrapolation of data in
concomitant low dose THC, THCA and even the anticonvulsant terpe-
Figs. 1 and 2 suggest that other Type II oral preparations may produce
noid, linalool [18].
similar results with slow titration.

12.2. Cancer
10. Drug interactions
The anti-emetic effects of THC in association with cancer che-
Most drug interactions are associated with concurrent use of other motherapy have long been known and a synthetic form was approved
CNS depressants with cannabis. Clinically, significant drug interactions for such use in the USA in 1985. Benefits as a palliative for sleep [53],
have proven rare [7], and there is no drug that cannot be used with and particularly for opioid-resistant cancer pain have also been de-
cannabis, if necessary. THC is oxidised by (CYP) 2C9, 2C19, and 3A4. monstrated in two Phase II clinical trials of nabiximols [54,55], but
Therefore, serum levels may increase with inhibitors, or decrease with unfortunately were not proven definitively in subsequent Phase III
enzyme inducers. Pertinent drug interaction studies are few [45,46]. studies. Cancer pain remains an indication in Canada under a Notice of
Existing studies have not demonstrated toxicity/ loss of effect of con- Compliance with conditions.
comitant medications, but still theoretically possible [47]. One excep- Cannabis has also been an historical primary treatment for cancer
tion is high dose CBD with clobazam, wherein high levels of a sedating [2], with extensive basic science documentation of its cytotoxic effects
metabolite, N-desmethyl clobazam will require a dose reduction for that with cytopreservative effects on normal cells. Initial trials and case
drug [29]. reports support the acute need for more formal investigation [56–59].
Thousands of patients worldwide are pursuing such treatment, most
11. Monitoring often without benefit of appropriate medical monitoring. Both basic
science [60,61] and anecdotal clinical reports suggest that cannabis-
Depending on the patient, they may need to be seen in follow up based treatment is most effective in conjunction with conventional
every 1–6 months depending on several factors such as; their familiarity approaches, whether chemotherapy or radiation. High doses (up to
with cannabis, comorbid medical conditions, ability to adhere to 1000 mg/d), preferably of mixed phytocannabinoids (as in cannabis
treatment plan instructions and keep an inventory of cannabis efficacy extracts), for up to 3 months may be required to eradicate some ma-
on individual symptoms/conditions. This should involve appropriate lignancies, but emphasis is required that this approach remains

Fig. 2. Graphical comparison of threshold dosing of THC vs. na-

biximols producing toxic psychosis.

16
C.A. MacCallum, E.B. Russo European Journal of Internal Medicine 49 (2018) 12–19

anecdotal without benefit of large published RCTs. High doses of THC- 12.7. Opioid and other addictions
containing preparations require slow titration over 2 weeks to induce
tolerance to psychoactive sequelae. There is some anecdotal evidence Nineteenth century observations of the use of cannabis with opioids
supporting use of acid cannabinoids in much lower doses, and CBDA [72,73] attested to its additive analgesic benefits, reduction of adverse
may improve the pharmacokinetics of CBD [47]. Prolonged main- events and even benefit to withdrawal symptoms. This has been sup-
tenance of cannabis therapy, at some lower dosage may be similarly ported by basic science investigation [74], and a variety of observa-
required to prevent recurrences. It should be borne in mind that ‘cure’ tional studies [75–77] and epidemiological evidence of decreased
of cancer can only be claimed after a 5-year interval without evidence opioid overdose mortality in US states with medical cannabis access
of tumour. Further objective evidence is needed to support adjunctive [78], as well as lowered costs for analgesics including opioids in such
cannabis-based medicine treatment of cancer. states in the Medicare (elderly) [79] and Medicaid (low-income) [80]
populations. An intriguing finding from a long-term safety study of
12.3. Pain nabiximols in survivors of a Phase IIA trial of cancer pain non-re-
sponsive to optimised opioids showed no increase in cannabis dosing
Cannabis treatment has not generally been useful in relation to requirements over ensuing months, without the expected escalation of
treatment of acute pain [62]. In contrast, both THC and CBD-pre- opioid requirements with continued disease progression and eventual
dominant cannabis preparations have proven safe and effective in nu- demise [81]. Studies do not report an increase in opioid serum levels
merous RCTs of chronic non-cancer pain, whether somatic or neuro- when used with cannabis [82].
pathic, peripheral or central (reviewed [22]) and examination in
national programs, as in Canada [34]. 12.8. Driving and safety sensitive occupations

12.4. The elderly It is important to include evaluation of social and occupational

history during a medical cannabis consultation. This may include de-
Whereas vigilance toward adverse events, particularly attributable termining if a patient works outside the home, has a safety sensitive
to polypharmacy are necessary in the elderly patient, monitoring of occupation, drives a motor vehicle, engages in childcare, etc. A rea-
adverse events with nabiximols reveal no specific increased suscept- sonable and conservative cannabis regimen for this patient population
ibility to problems in this age group [42]. THC has been used to ad- would be CBD-predominant preparations during working hours, and
vantage to treat agitation in dementia [32], and the neuroprotective THC-predominant ones after work or before sleeping.
effects of it and CBD portend to offer possible advantages in this, and Patients should not drive or utilise power tools or heavy equipment
related pathologies [63]. Slow titration is required to avoid AEs, in- until accustomed to the effects of the medicine [7]. It is recommended
cluding falls and orthostatic hypotension. 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
12.5. Parkinson disease patient feels impaired, regardless of cause, they should not be driving or
working safety sensitive jobs.
CB1 receptors are densely expressed in the basal ganglia, and can- In clinical practice we have observed that medical cannabis pa-
nabis has shown variable efficacy in various clinical studies [64]. Ad- tients, using daily, appropriate low doses of THC develop tolerance and
ditional investigation is required, however, to establish the optimal experience minimal if any impairment, as has been documented for
composition of components. Anecdotal surveys suggest that acid can- multiple sclerosis patients [83]. There are no serum assays that enable
nabinoids given orally over prolonged intervals (3 months) may be measurement of impairment due to THC accurately. Urine toxicology
necessary to achieve clinical improvement [65]. Slow titration is re- tests metabolites of THC which merely indicate THC ingestion some-
quired. time in the past two to three weeks. The authors believe a combination
of neurocognitive testing, along with physical examination or perfor-
12.6. Paediatrics mance specific activities to capture reaction time, coordination, bal-
ance, decision making et al. will prove more valuable in comparison to
Use of cannabis as medicine in children remains another forbidden bodily fluid THC levels.
territory [1], but as in any other context, the relative risks and benefits
must be weighed. Recent review has supported efficacy in nausea sec- 12.9. Standard of care
ondary to chemotherapy and in seizures [66]. It should be stated em-
phatically that there is a world of difference scientifically and ethically The authors believe that the standard of care for cannabis is no
between judicious administration of low doses of cannabinoids for different than that for any speciality in the practice of medicine. The
therapeutic purposes as compared to chronic use of high-dose THC for requirements are: examination of prior medical records whenever
recreational purposes by teenagers. Even synthetic THC has been used available, a comprehensive history and physical, a thorough discussion
to advantage in children with severe static encephalopathies with of the pros and cons of cannabis, plans for appropriate follow-up care,
spasticity and seizures in Germany where warranted [67,68]. Historical proper documentation of the consultation, and appropriate commu-
data [1] and modern experience in treatment of nausea secondary to nication with other care-givers.
chemotherapy [69] support the fact that children under the age of 10
are remarkably resistant to psychoactive sequelae of THC, and are able 13. Conclusions
to tolerate doses, when necessary, that might be more problematic in
the adult patient. As cannabis-based medicines return to mainstream usage, it is es-
In those at risk, younger age of first cannabis use is associated with sential that clinicians gain a greater understanding of their pharma-
earlier onset of schizophrenia and bipolar disorder and worse outcomes cology, dosing and administration to maximise therapeutic potential
[70,71]. CBD-predominant preparations, and even THCA, may be a and minimise associated problems. With standardised modern products,
useful therapy for children (or adults) with severe developmental/self- and educated caregivers, these are worthy and attainable goals.
harm, schizophrenia, seizures, brain tumors, refractory or rare diseases.
In these conditions, CBD (with low or no THC) may be more efficacious AcknowledgementsFunding
with fewer AEs than traditional therapies. (i.e., opioids, antiepileptic
etc). Risks and benefits need to be considered. This study did not receive any specific grant from funding agencies

17
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