Medical cannabis general use guidelines

Evidence-based guidelines

Definitions
General instructions
Dose guidance
Dosage forms
Treatment suggestions
Contraindications
Warnings and precautions
Drug interactions

About the general use guidelines

This evidence-based guidance was reviewed and approved on 10/11/2022.
The suggested adult medical cannabis starting doses outlined in this document are not backed up by clinical trials and may not be appropriate recommendations for all patients or for all conditions being treated, but are included in this document to provide recommending medical providers with some basic considerations when initiating treatment with medical cannabis, especially in cannabis-naïve patients.  

Definitions

Cannabidiol (CBD): a plant-derived cannabinoid that lacks intoxicating or psychoactive properties. 

Cannabinoids: biologically active constituents of cannabis, or synthetic compounds that have affinity for, and activity at cannabinoid receptors (e.g.  THC, CBD, Dronabinol, Nabilone). 

Cannabis-based medicines or cannabis-derived medicines: medicinal cannabis extracts with defined or standardized cannabinoid content (e.g.  nabiximols/Sativex (CBD+THC), cannabidiol/Epidiolex).  

Chemotype: chemically distinct plant phenotypes defined by content ratios of THC:CBD. Medical cannabis and cannabis-based medicines can be divided into  3 broad chemotype categories based on relative content ratios of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) (Hillig & Mahlberg, 2004): 

  • Chemotype I - delta-9-tetrahydrocannabinol (THC)-predominant with  THC:CBD ratio >10:1
  • Chemotype II - significant quantities of both THC and CBD with THC:CBD  ratio <10:1 and >2:10  
  • Chemotype III - cannabidiol (CBD)-predominant with THC:CBD ratio <2:10 

Endocannabinoids: endogenous ligands found in the body (e.g. anandamide and 2AG) that have affinity for and activity at cannabinoid receptors (CB1, CB2) that also interact at other peripheral and central nervous system receptors (e.g., TRPV1, PPAR alpha and gamma, orphan GPCR receptors). 

Entourage effects: the presence of multiple cannabis compounds being present to create a unique benefit in the body.

Delta-9-tetrahydrocannbinol: the primary active component of cannabis that acts at the cannabinoid CB1 receptor to produce a wide range of biological and behavioral responses (Cooper & Haney 2009).  

Epidiolex®: a U.S. Food and Drug Administration (FDA)-approved medication consisting of plant-derived, highly purified CBD, indicated for the treatment of certain types of seizures.  

Full spectrum: a cannabis product that contains a complete spectrum of the plant’s compounds, preserving the total range of cannabinoids and terpenes of the cannabis plant. Not all cannabis extracts are considered full spectrum;  those that are commonly known as full spectrum include live resin or high terpene full-spectrum extract (HT-F SE). 

Herbal cannabis: the whole plant or parts, or material from the whole plant (e.g. buds/flowers, resin, leaves).  

Medical cannabis, or medical marijuana: cannabis plants and plant material such as flowers, buds, hashish, leaves, or full-plant extracts intended for treatment of a defined medical condition. 

  1. Does NOT include any drug approved by the FDA
  2. Does NOT include CBD-only products

Phytocannabinoid: cannabinoids derived from the plant (e.g., cannabinol (CBN), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabigerol (CBG), and over 100 other known components).  

Synthetic cannabinoid: cannabinoids made in laboratories. 

Tetrahydrocannabinol (THC): a plant-derived cannabinoid that has psychoactive properties. 

General instructions for the use of medical cannabis

  1. Cannabis should be stored in a safe place, such as a lock box in the home, out of reach of children.  
  2. Recommending medical providers must clearly communicate the potential risks of cannabis, no different than with any other psychoactive medication.
  3. Differences in Chemotypes. One chemotype may be preferable over another depending on the disease process being treated, desired effects, desired avoidance of side effects, and prior clinical experience or preference of individual patients. There is a general lack of robust controlled clinical trials addressing therapeutic synergy (the “entourage effect”) of various cultivars and chemotypes, and current scientific information regarding therapeutic synergy is often observational in nature with conflicting results.  Case-by-case individualization of treatment dosage and chemotype will remain a significant reality until more robust clinical data are available to help better guide clinical decision-making.  

Note: Current Utah law requires batch testing and labeling of THC and CBD content on the package of all medical cannabis products dispensed in Utah.

  1. Starting dose guidance for oral or sublingual (e.g., ingested) medical cannabis products – chemotypes I and II (significant amounts of THC)  
    • Bioavailability of orally administered THC and CBD may be increased when administered in conjunction with a fatty meal (Zgair et al., 2016). 
    • To avoid unwanted psychoactive side effects, “start low and go slow”, especially when using chemotype I products.  
    • Consider starting oral dosing at bedtime to limit adverse events and encourage the development of tolerance as follows:  
      • Days 1–2: 1 mg to 2.5 mg THC-equivalent at bedtime (start at 1 mg if young, elderly, or other concerns)
      • Days 3–4: if previous dose tolerated, increase by 1 mg to 2.5 mg of THC at bedtime
      • Days 5–6: continue to increase by 1 mg to 2.5 mg THC at bedtime every 2 days until the desired effect is obtained, or side effects limit additional dose increases 
    • Most patients dose orally 2 to 3 times per day. Consider the following regimen for daytime dosing: 
      • Days 1–2: 1 mg to 2.5 mg THC-equivalent once a day at bedtime to establish individual tolerance 
      • Days 3–4: 1 mg to 2.5 mg THC-equivalent twice a day 
      • Days 5–6+: increase if needed and as tolerated by 1 mg to 2.5 mg increments administered 2-3 times per day up to 15 mg THC-equivalent/24 hours 

Note: All patients using cannabis and providers recommending cannabis to patients should consider the warnings, precautions, and adverse side effects listed in this document before beginning the use of cannabis or increasing dosages of current cannabis use. 

  1. Starting dose guidance for oral or sublingual administration of medical  cannabis products – chemotype III – CBD predominant  
    • Bioavailability of orally administered THC and CBD may be increased if administered in conjunction with a fatty meal. 
    • Chemotype III medical cannabis oral extracts with a THC:CBD ratio of 1:20 have been used in several clinical trials in Israel for the treatment of autism spectrum disorder and seizures. These trials used an extract from a high  CBD strain dissolved in olive oil with a THC:CBD ratio of 1:20, (1.5% THC and  30% CBD) administered sublingually. Extrapolating from these studies and general “start low and go slow” dose titration recommendations, consider  the following for oral or sublingual dosing of Chemotype III – CBD  predominant medical cannabis products:
      • Days 1-2: 1mg THC and 20mg CBD once at bedtime
      • Days 3-4: 1mg THC and 20mg CBD twice per day
      • Days 5-6+: Increase dose if needed and if tolerated every 2-3 days to 15 mg THC/300mg CBD/24 hours divided BID-TID  
  2. In the event of side effects, reduce to the previous, best-tolerated dose.  
  3. Doses exceeding 20-30 mg THC/day may increase adverse events or induce tolerance without improving efficacy.  

Medical cannabis dosage forms – advantages and disadvantages (MacCallum & Russo, 2018):

Table 1. Comparison of medical cannabis administration methods
Method Vaporization (flower/bud or cartridges) Oral (pill, capsule, tincture, or gel cube) Oral-mucosal (sublingual tincture) Topical (oil, cream, or ointment)
Onset (min) 5-10 minutes 60-180 minutes 15-45 minutes Variable
Duration (hr) 2-4 hours 6-8 hours 6-8 hours Variable
Pros
  • Rapid onset of action
  • Advantage for acute or episodic symptoms
  • Rapid titration is easier to do
  • Convenient and discrete
  • Possible higher potency and protracted duration
  • Useful for continuous symptoms
  • Longer duration than vaporization
  • More rapid onset than swallowed oral doses
  • Localized benefit for specific symptoms
  • Less systemic (whole-body) effect
Cons
  • Dexterity required to load vaporizer
  • Vaporizer costs and portability
  • More frequent dosing required
  • Variable blood levels based on inhalation depth
  • Delayed onset of action
  • Difficult to titrate for acute symptoms
  • Higher potential for excessive initial dosing
  • Variable bioavailability of CBD
  • May irritate the mucosa of the mouth/throat
  • Limited to local area of application
  • Systemic absorption may be variable
  • Topical dosing of medical cannabis: No clinical studies have been published regarding the percutaneous absorption of cannabis containing ointments, creams, or lotions (Health Canada, 2013).  Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion process, but absorption of cannabinoids does occur transdermal in preclinical animal studies (Paudel et al., 2010). 
    • There is not enough published clinical data to make any recommendations regarding dosing of transdermal delivery of medical cannabis. 
  • Vaporization of herbal cannabis for first-time use or when using a new cultivar or chemotype: Bioavailability of cannabinoids and terpenes from a specific cultivar of  herbal cannabis when inhaled via a heated-air vaporization device may vary significantly depending on inhalation technique, the physical  characteristics of the vaporizing device, and the temperature of the heated air used to heat the herbal preparation (Swortwood et al.,  2016). The air temperature in the chamber where the plant material is  present is particularly important due to at least two separate mechanisms: 
    • Higher set point temperatures in the herbal vaporizer chamber result in progressively complete decarboxylation of cannabinoid acids (THCA and CBDA) contained in the flower into their more pharmacodynamically active states (THC and CBD) (Wang et al., 2016 & Lanz et al., 2016). Vaporizer temperature setpoints of 210-230°C result in rapid and near complete decarboxylation of THCA and CBDA. Lower vaporizer temperature set points result in slower decarboxylation rates (Wang et al., 2016) and complete decarboxylation of all THCA and CBDA may be less likely to occur which may result in a clinical response that is significantly different (and in some situations preferable) when compared to what happens with a higher temperature set point.  
    • The vaporizer temperature set point also influences what portion of individual cannabinoids and terpenoids get vaporized and inhaled due to the wide range of individual cannabinoid boiling point temperatures and terpenoid vapor pressures at any given temperature (Lovestead & Bruno, 2017; Haynes, 2016). At lower vaporizer chamber temperature setpoints, cannabinoids and terpenoids with higher vapor pressures and lower boiling points will generally be more completely vaporized and inhaled than the cannabinoids and terpenoids that have higher boiling points and lower vapor pressures.  

Understanding these 2 effects of temperature setpoints and adjusting the setpoint upwards or downwards can be used as a tool to improve desired clinical outcomes and/or minimize unwanted side effects of inhaled herbal cannabis.  

Current commercially available vaporizer devices are not third-party calibrated, standardized, or regulated, and therefore, labeled or electronic temperature setpoints, if they exist, may not accurately represent what is happening inside the vaporizing machine at the level of the trichromes in the herb. An in-vitro study comparing 5 different commercially available herbal cannabis vaporizing devices set at 210°C  showed significant differences in delivery efficiency of THC and CBD  from inhaled herbal cannabis (Lanz et al., 2016).  

The amount of herbal cannabis administered by a heated vaporizer device required to achieve an inhaled dose of THC that would be comparable to an oral dose of synthetic THC (dronabinol), can be estimated from the table below that was extracted from an inhaled/smoked cannabis dosing article (Carter et al., 2004). 

Table 2. Amount of cannabis calculated to contain equivalent amounts of THC to dronabinol (2.5 to 60 mg).
% of THC in cannabis Amount of cannabis (g) required to obtain:
2.5 mg of THC 10 mg of THC 30 mg of THC 60 mg of THC
5% 0.60 1.24 3.70 7.40
10% 0.30 0.62 1.85 3.70
15% 0.16 0.41 1.23 2.46
20% 0.10 0.31 0.93 1.86
25% 0.08 0.25 0.75 1.50
30% 0.05 0.20 0.62 1.24

Table 2. Table adapted from Medical Cannabis Dosing: Rational Guidelines for Dosing (Carter et al., 2004)

The data in this table applies to inhaled cannabis administered by combustion (smoking) which is not allowed under Utah law. However, a separate clinical trial looking at THC bioavailability comparing smoked cannabis with vaporized whole flower cannabis showed similar results of about 50% bioavailability when using a Volcano® heated air vaporizer device with a temperature set point of 190°C (Abrams et al., 2007). Hence, it is reasonable to assume that the dosing comparisons in this table can be appropriately applied to the quantity of cannabis placed in a heated air vaporizer device, assuming a set point temperature of 190°C and a heater air vaporizer device with a function comparable to that of a Volcano® vaporizer device. 

Note: Due to a lack of vaporizer device regulation and calibration, and a lack of any dose-finding clinical trial data, it is currently impossible to give precise vaporizing and titration recommendations that will be appropriate for all patients in all treatment circumstances. 

Medical cannabis dosing guidance

The starting and titrating dose suggestions outlined above are adapted from several sources, including:

  1. Caroline A. MacCallum, and Ethan B. Russo. Practical Considerations in Medical Cannabis Administration and Dosing. European Journal of Internal Medicine 40 (2018) 12-19. 
  2. Dosing recommendations from the United Kingdom package insert for nabiximols/Sativex (cannabis whole-plant extract oral mucosal spray with 2.5mg of CBD and 2.7mg THC per spray). 
  3. Several observational reports from Israel using chemotype III medical cannabis in the treatment of autism spectrum disorder and epilepsy (Schleider et al., 2019 & Tzadok et al., 2016).

Treatment suggestions for medical providers and cannabis-naïve adult patients on starting and titrating the dosing of vaporized herbal cannabis

The following treatment suggestions may or may not be appropriate for a specific patient with a specific disease process using a specific cultivar/chemotype in a specific vaporizer device, but are provided to give recommending medical providers and cannabis-naïve adult patients a general idea of how to start and titrate the dosing of vaporized herbal cannabis.

  • Load the herbal cannabis vaporizer device with an appropriate quantity of prepared herbal cannabis. Turn on the vaporizer device with the temperature set to 180-195°C (356 - 383°F).  
  • Wait an appropriate amount of time for the temperature in the heating chamber to reach the set point temperature. This process and quantity of herbal cannabis used may vary depending on the vaporizer device being used and the desired approximate dose needed based on experience with prior dosing.  
  • Start with 1 full inhalation drawn in over 5 seconds, hold for 10 seconds, then exhale. Wait 15 minutes and, if needed, add 1 additional inhalation every 15–30 minutes until desired symptom control has been achieved or side effects limit use. 
  • Dosing intervals using a vaporizer device are usually determined by the need for symptom control and may be as frequent as every 2-4 hours. 
  • Slow upward dose titration and use of chemotypes II or III (containing significant quantities of CBD) has been observed anecdotally to promote some tolerance to the psychoactive sequelae and other side-effects of THC, which may be especially important for naïve users and those who may be more sensitive to the psychogenic effects of THC.  
  • Unwanted side effects such as fatigue, anxiety, euphoria, impairment of mental status, tachycardia, drop in blood pressure, and dizziness may be less likely to be severe or clinically significant when the vaporizer set point temperature is between 180 - 195°C (or lower), and the starting dose is low and titration is slow. 
  • Higher vaporizer setpoint temperatures (e.g. 210 - 230°C) will likely result in rapid and more complete decarboxylation of THCA and CBDA, and are more likely to promote decarboxylation and release of other less-studied cannabinoids, terpenes, and other plant constituents into the vapor phase, especially cannabinoids and terpenes with higher boiling points and lower vapor pressures which may result in increased sedation and intoxication. Set point temperatures approaching the temperature of combustion (230℃) may also increase the amounts of pre-combustion products of pyrolysis, and promote degradation of THC into CBN. Due to these effects, higher temperature set points are more likely to result in possibly unwanted side effects, including mental impairment, excessive intoxication, sedation, and euphoria, but may be considered when lower temperature set points do not result in adequate management of symptoms. 
  • Most patients using a vaporizer device for medicinal purposes will use 1–3 grams of herbal cannabis per day.  Dose escalation over time is not generally observed. Additional needs over time require reassessment. Less than 5% of patients require > 5 g of herbal cannabis per day.  
  • Use of THC-predominant herbal cannabis via a vaporizing device in high doses above 5 grams per day is probably not justified and may suggest possible tolerance, misuse, or need for additional evaluation or a different treatment approach.

In the event of side effects, reduce to previous, best-tolerated dose and consider adjusting the temperature set point to a lower temperature.

Treatment suggestions for medical providers and cannabis-naïve adult patients on starting and titrating the dosing of medical cannabis concentrates administered via vape pen. 

Inhalation of medical cannabis concentrates administered via vape pens: Medical cannabis vape pens can be used for acute relief of symptoms and can be used on an as-needed basis, or as add-on therapy to oral treatments for breakthrough symptoms when managing chronic problems. Unlike herbal cannabis vaporization devices, there is no adjustable temperature set point for vape pens.

The approximate dose of THC and CBD per inhalation from a vape pen can be estimated based on batch lab-test results for CBD and THC content of the vape cartridge, divided by the estimated number of inhalations per cartridge for a specific vape pen. These sorts of calculations may be helpful when comparing inhaled doses to oral and sublingual doses, and may help avoid excessive dosing and side effects. However, due to individual variability of inhalation technique and lack of precise dosing due to uncalibrated and non-standardized vape pen devices, it may be more prudent to follow the general symptom-based titration suggestions above. There are no device-specific dose-finding studies for use of vape pens for the delivery of medical cannabis for the treatment of any specific disease.

The following treatment suggestions may or may not be appropriate for a specific patient with a specific disease process using a specific cultivar/chemotype in a specific vape pen device, but are provided to give recommending medical providers and cannabis-naïve adult patients a general idea of how to start and titrate the dosing of medical cannabis concentrates administered via a vape pen device. 

Start low and go slow. 

  • In cannabis naive individuals, start with chemotype II or chemotype III medical cannabis extracts with moderate or low THC content. Chemotype I medical cannabis may be considered, but should start with low THC content cartridges to avoid intoxication and other significant reactions.
  • Take 1 full inhalation drawn in over 5 seconds, hold for 10 seconds, then exhale. Wait 15 minutes and, if needed,  add 1 additional inhalation every 15–30 minutes until desired symptom control has been achieved or side effects limit use.
  • Consider use of vape pen cartridges with lower THC content coupled with less-aggressive dosing frequency if using vape pens to treat children, the elderly, and in otherwise compromised adults.
  • Vape pens and cartridges used in vape pens should be purchased at state-inspected and regulated medical cannabis pharmacies with labeled THC and CBD content, and then only after review of batch testing results performed by independent laboratories.

Warning: The Centers for Disease Control and Prevention (CDC) has reported a nationwide large number of cases of severe pulmonary injury with respiratory failure and deaths associated with the antecedent use of unregulated, black-market cannabis vape pens and cartridges.  Analysis of these adverse events has revealed that most affected individuals were using unregulated cannabis extracts in their vape pens and that these extracts had been cut/adulterated/diluted using vitamin E acetate. Based on current data as of January 2020, the CDC believes that the majority of the cases of severe pulmonary injury and death are due to the presence of vitamin E acetate in THC-containing e-cigarettes/vape pens. 

There may be some medical cannabis products that are produced and intended for oral ingestion or topical administration that contain vitamin E acetate as a carrier. Use of a vape pen to administer medical cannabis concentrates that were intended for topical administration, or oral/sublingual ingestion, may result in acute lung injury and possibly death. 

Contraindications

Pregnancy

There are potential adverse effects of maternal cannabis use on fetal development and child/adolescent development (Health Canada, 2018).

The endocannabinoid system, first detected around day 16 of human gestation, is thought to play an important role in neural circuitry and brain development by regulating neurogenesis and migration and outgrowth of axons and dendrites, and axonal pathfinding. Because THC crosses the placenta and interacts with the endocannabinoid system of the developing embryo and fetus, use of cannabis during pregnancy may have significant adverse effects on fetal somatic and neural development and may have long-term neuropsychiatric effects (Alpar et al., 2016).  

Preclinical studies in rodents have shown that in-utero exposure to THC or cannabinoids is associated with axonal bundle malformation prenatally;  decreased birth weight neonatally; hyperactivity, learning impairment, vocalization, and impaired synapse formation postnatally; impaired consolidation of long-term memory and inhibited social interaction and play behavior during adolescence; and memory impairment, reduced synaptic plasticity, cognitive impairment, altered social behavior, and an anxiogenic-like profile in adulthood (Calvigioni et al., 2014). The endocannabinoid system also regulates skeletal development, and these effects may account for the observation that small-for-gestational-age babies are associated with maternal use of cannabis during pregnancy.  

A recent systematic review of human studies concluded that cannabis use during pregnancy is associated with reduced birth weight, increased likelihood of requiring neonatal intensive care unit treatment, and maternal anemia (Gunn et al., 2016), but there also appears to be some possible long-term effects on the development of children born to mothers who used cannabis heavily during pregnancy. Prenatal cannabis use has been associated with lower scores on language, memory and abstract/visual reasoning domains in children of preschool age (Day et al., 1994; Fried &  Watkinson, 1990; Fried et al., 1992a). In school-aged children, prenatal cannabis exposure was also associated with deficits in attention and presence of impulsivity and hyperactivity (Fried & Watkinson, 1992b). Later, in children between 9 and 12 years of age, prenatal cannabis exposure was associated with decreased performance in executive functions (e.g., impaired working memory, inattention, impulsivity and inability to plan) (Fried &  Watkinson, 1998; Richardson et al., 2002), with these deficits also appearing in 13- to 16-year olds (Fried & Watkinson, 2003) and 18- to 22-year olds  (Smith et al., 2006). The exact mechanisms behind these effects are not yet completely understood, but are theorized to result from cannabis’ interference with the endocannabinoid system and resulting nervous system development (Volkow et al., 2017). 

Based on current available data, the risk of adverse pregnancy and postpartum outcomes in women using cannabis during pregnancy appears to be substantial. Women who are pregnant and women who are sexually active and not on a reliable form of contraception should not use cannabis or cannabis-based medical treatments.  

Lactation

Clinical evidence shows that cannabinoids and their metabolites accumulate in the breast milk of mothers who smoke cannabis and are transferred to newborns through breastfeeding (Jaques et al., 2014; Baker et al., 2018). THC concentrations in breast milk in humans may be up to eight-fold higher than that found in maternal blood (Perez-Weyes & Wall, 1982). In a case-control study, exposure to cannabis/cannabinoids from breast milk during the first month postpartum appeared to be associated with a decrease in infant motor development at 1 year of age, but separating out the effects of breastfeeding from prenatal exposure was problematic (Astely & Little, 1990). Although robust clinical data are lacking, it is clear that cannabinoids and their metabolites are present in breast milk in concentrations that could result in a significant exposure for a nursing infant. Weighing the uncertain, but potential risks of this exposure against the risks of alternatives to breastfeeding is problematic, but the available data regarding exposure to cannabis through breast milk, and the evidence suggesting potential for harm to infants and children due to cannabis are concerning. Women who are breastfeeding their infants should not use cannabis or cannabis-based medicines. 

Unstable cardiovascular conditions, including ischemic heart disease, arrhythmia, congestive heart failure, poorly controlled hypertension   

Cannabis is known to cause peripheral vasodilatation, postural hypotension,  and characteristic conjunctival reddening after smoking, but the most consistent acute physiological effect of cannabis is dose-related tachycardia  (Health Canada, 2013). While cannabis-induced tachycardia is not usually considered dangerous for healthy young users, it may be dangerous to those already suffering from cardiac disorders or angina (Mittleman & Mostofsky,  2011). Inhalation of cannabis smoke reduces the amount of exercise required to cause an angina attack by 50% (Aronow & Cassidy, 1974) and has been associated with a five-fold increased risk of myocardial infarction in the first hour following smoking (Mittleman et al., 2001). This increased risk may be caused by a delta-9-THC-related increase in cardiac output, myocardial oxygen demand, catecholamine levels, and, in the case of combustion of cannabis, which typically happens at temperatures > 230℃, the formation of carbon monoxide.  

Schizophrenia spectrum and other psychotic disorders 

Clinical studies suggest that acute exposure to THC or THC-predominant cannabis is associated with dose-dependent, acute, and usually transient behavioral and cognitive effects mimicking acute psychosis (D’Souza et al.,  2004). While this does not happen in the majority of individuals using cannabis, if it does happen, it warrants stopping the use of cannabis-based medicines, lowering the dose of cannabis-based medications, or switching to a chemotype that has a lower quantity of THC (chemotypes II or III).  

Epidemiological studies suggest a significant association between THC-predominant (chemotype I) cannabis use and subsequent development of psychosis and schizophrenia, especially in individuals who begin use at an early age and use larger quantities on a daily basis (heavy use) (Marconi et al., 2016a; Di Forti et al., 2009). The risk of schizophrenia associated with cannabis use is especially high in individuals who have a personal or family history of schizophrenia (Radhakrishnan et al., 2014). A number of studies also show certain gene polymorphisms that, when combined with early cannabis use, are associated with a much higher incidence of the development of psychosis and schizophrenia than individuals with the same gene polymorphisms who do not use cannabis (Wilkinson et al., 2014).  

Cannabis use is associated with earlier onset of schizophrenia in vulnerable individuals and exacerbation of existing schizophrenic symptoms (Marconi et al., 2016b). Continued cannabis use after the onset of psychosis predicts adverse outcomes, including higher relapse rates, longer hospital admissions, and more severe symptoms when compared with individuals who discontinue cannabis use or are non-users (Schoeler et al., 2016). The overall weight of evidence suggests that the association between cannabis exposure and schizophrenia is modest, but consistent. 

Individuals with current psychosis or history of schizophrenia and other psychotic disorders should not use cannabis or cannabis-based medicines with significant THC content (chemotypes I and II).  

Individuals with a family history of schizophrenia or history of significant adverse childhood experiences may be at increased risk for psychotic outcomes related to cannabis use (Wilkinson et al., 2014) and, if contemplating treatment with cannabis or cannabis-based medicines, they should start treatment with lower doses of chemotypes III, and only if necessary, chemotype II cannabis-based medicines. They should avoid treatment using chemotype I cannabis or cannabis-based medicines that contain high amounts of THC or are THC-predominant. 

Warnings, precautions, and adverse reactions

Patients using cannabis and providers recommending cannabis to patients should consider the possible effects of cannabis use listed below. A few of the acute effects of cannabis include euphoria, relaxation, dream-like states including vivid dreams, paradoxical insomnia, altered sensory perception and increased appetite  (Candrey & Haney, 2009).  

Use in children, adolescents, and adults under the age of 26 

Use in this age category may result in altered brain development and function with possible long-term negative consequences, including negative mental health outcomes and long-term cognitive impairments (Meier et al.,  2012; Brumback et al., 2016; Morin et al., 2019). Use of cannabis or cannabinoids for treatment of various conditions in this population should be considered only after failure of robust treatment attempts using conventional interventions and then only after a careful risk/benefit assessment and discussion with the patient or patient’s guardian(s). A recent systematic review of the use of medical cannabis in children may be helpful when considering the use of medical cannabis in the pediatric population  (Wong & Wilens, 2017). 

Note: Under the current Utah code, all individuals using cannabis under age 21 will need approval from the Compassionate Use Board.

Impaired cognition (Karlson; 2019)

  • Acute effects of cannabis use are established with strong evidence and include impairment of short-term memory, attention, concentration, executive functioning, and visual perception (Health Canada, 2018).
  • Cognitive effects persist after last use to a degree and duration dependent on multiple factors, including length and frequency of exposure, age of onset of use, duration of abstinence, and residual confounding factors (Lenné et al., 2010).
  • Some brain imaging studies associate regular (weekly or more frequent) cannabis use with structural changes in gray and white matter in different brain regions (Hartman et al., 2013).
  • Early-onset use and use of high-potency, THC-predominant cannabis is associated with a higher degree of impairment (Hartman et al., 2015).
  • Methodological limitations and differences in duration of abstinence and measures of cognition contribute to discrepancies in available study results. Drawing definitive conclusions on the long-term brain effects of cannabis use is further confounded by factors such as polysubstance use and mental health functioning of study participants (Volkow et al., 2016).

Altered mental status

  • Use of cannabis, especially in cannabis-naive patients or in patients who use higher doses of THC, may cause acute problems with altered mental status, confusion, disorientation, and sometimes more serious reactions, such as psychotic reactions and suicidal ideation. Patients should be warned not to engage in safety-sensitive activities such as driving, machine or equipment operation, or other potentially dangerous activities that require unimpaired judgement or coordination while using medical cannabis.

Psychomotor performance and driving 

  • Cannabis significantly impairs judgment, motor coordination, and reaction time, and studies have found a direct relationship between blood THC concentration and impaired driving ability. Higher blood levels are associated with more significant impairment.
  • Substantial measurable impairment of psychomotor function, reaction time, and simulated driving skills occurs during the first 2-3 hours after inhaled doses of cannabis, but significant impairment has been detected up to 6-8 hours after inhaled doses of cannabis. Based on available data and making conservative recommendations, patients should abstain from driving for a minimum of 8 hours after an inhaled dose of cannabis (Neavyn et al., 2014). 
  • Effects of oral ingestion on psychomotor function and driving skills are usually delayed in onset compared with inhaled doses of cannabis but may be more intense and typically persist longer than inhaled doses of cannabis. Patients may need to abstain from driving substantially longer than 8 hours after an orally ingested dose of cannabis-based medicine. Additional caution may be needed during initiation of treatment in treatment-naive individuals or when making a change in medical cannabis product or dosage.
  • Period of driving impairment may persist for several days after the last use in some individuals who use cannabis regularly (weekly or more frequently). This effect may be due to the gradual release back into the bloodstream of fat-soluble cannabinoids that were deposited and built up in fatty tissues during regular or heavy use of cannabis.
  • Regular (weekly or more frequent) cannabis users develop only partial tolerance to impairing effects. 

Alcohol use

  • Use of cannabis in combination with alcohol has been observed to result in substantial additive intoxication and impairment of cognition and motor skills, including driving ability. Concurrent use of alcohol and cannabis should be strongly discouraged. 

Central nervous system sedating medications

  • Cannabis should be avoided or used with significant caution in patients using sedative-hypnotics or other medications that may cause mental sedation.

Use in the elderly

  • Elderly patients may experience lightheadedness, mental confusion, balance problems, unstable gait, and may increase risk of falls, injuries, and other adverse outcomes.

Cannabis use disorder (CUD)

  • CUD may develop in up to 10% of adults using cannabis and up to 16% of children and adolescents using cannabis (World Health Organization, 2020).  The age of onset of cannabis use is inversely proportional to the incidence of cannabis use disorder (e.g., the younger a person is when they start to use cannabis, the more likely they are to have a problem with cannabis dependence and abuse).

Cannabis hyperemesis syndrome

  • Use of cannabis regularly or at high doses may result in cannabis hyperemesis syndrome. The symptoms include episodic severe intractable vomiting, abdominal pain, and compulsive use of hot showers to temporarily relieve symptoms. Treatment with antiemetics is usually not effective. The most successful treatment consists of stopping cannabis use completely  (Sorensen et al., 2017).

Cardiovascular risk and cerebrovascular risk

  • There is evidence of a statistical association between cannabis use and ischemic stroke, subarachnoid hemorrhage, and the triggering of acute myocardial infarction (National Academies of Sciences, Engineering, and  Medicine, 2017a). Use of cannabinoids may cause tachycardia, substantial changes in blood pressure, and episodes of postural hypotension. Cannabis and cannabinoids should not be used in patients with unstable vital signs,  congestive heart failure, angina, myocardial infarction, known/suspected structural or vascular heart disease, or known cerebrovascular disease.  

Cardiovascular and cerebrovascular risk among otherwise healthy young adults

  • Cannabis use may be a risk factor for acute myocardial infarction and stroke even among otherwise healthy young adults. In a systematic review of case series, 62 cases of MI occurred among adults with a mean age of 27.7 years who reported either regular marijuana use (n = 36), synthetic marijuana use (e.g., spice) (n = 21), or a combination of both (n = 5). From the cases reporting the onset of AMI symptoms, the average time was within 5 hours after last marijuana use (Patel et al., 2019). A cross-sectional observational study reported on the risk of stroke among young adults ages 18-44. They found 1.82 times higher odds of stroke (adjusted OR 1.82 (95%CI 1.08 - 3.10)) compared to nonusers of marijuana. The odds of stroke were higher among frequent users of marijuana (>10 days/month) compared to nonusers (adjusted OR 2.45 (95%CI 1.31-4.60)) (Tarang et al., 2020). 

Seizures and people with epilepsy 

  • Seizure and seizure-like activity have been reported in patients receiving MARINOL® capsules during marketed use of the drug and in clinical trials, but a causal relationship has not been established (FDA, 2006). Preclinical data in some animal studies and case reports suggest possible proconvulsant effects of THC, but other case reports suggest possible anti-convulsant effects of THC (Rosenberg et al., 2017). Until better clinical data are available, high doses of THC should probably be avoided in individuals with seizure disorder, and THC-predominant cannabis (chemotype I) should be used with significant caution.

Schizophrenia and other psychotic disorders

  • THC-predominant cannabis (chemotype I) and high doses of THC should be avoided in individuals with a history of schizophrenia and other psychotic disorders. As noted in the “contraindications” section above, the use of cannabis is associated with earlier onset of schizophrenia in vulnerable individuals and exacerbation of existing schizophrenic symptoms (Marconi et al., 2016b). Continued cannabis use after the onset of psychosis predicts adverse outcomes, including higher relapse rates, longer hospital admissions, and more severe symptoms when compared with individuals who discontinue cannabis use or are non-users (Schoeler et al., 2016).  

Bipolar and other mood disorders

  • A 2015 systematic review and meta-analysis of 6 studies of bipolar disorder and cannabis use sampled a total of 2,391 individuals who had experienced mania symptoms. The studies reviewed support a significant association between cannabis use and the exacerbation of manic symptoms in those with previously diagnosed bipolar disorder (Gibbs et al., 2015). The available evidence suggests that cannabis may worsen the course of bipolar disorder by increasing the likelihood, severity, or duration of manic phases. Furthermore, a meta-analysis of 2 studies suggests that cannabis use is associated with an approximately threefold (odds ratio: 2.97; 95% CI: 1.80– 4.90) increased risk for new onset of manic symptoms (Gibbs et al., 2015). 

Depression and suicidality

  • Epidemiologic evidence suggests a link between regular (weekly or more frequent) or high dose cannabis use and suicidality. A 2019 systematic review and meta-analysis of 11 studies comprising 23,317 adolescents showed an odds ratio (OR) of developing depression for cannabis users in young adulthood compared with nonusers was 1.37 (95% CI, 1.16-1.62)  (Gobbi et al., 2019). The pooled OR for suicidal ideation in cannabis using adolescents was 1.50 (95% CI, 1.11-2.03), and the OR for suicidal attempt was 3.46 (95% CI, 1.53-7.84) in cannabis users vs non-users. 

Anxiety

  • Clinical studies indicate that while occasional (less than weekly) cannabis use can reduce anxiety symptoms, regular (weekly or more frequent) cannabis use, or use of high-dose THC can produce anxiety symptoms (Childs et al.,  2017).

Pre-existing substance use disorders

  • Medical cannabis should generally be avoided in persons with a history of substance use disorders, including alcohol use disorder, due to increased risk of developing cannabis use disorder (CUD). However, there may be circumstances where a recommending medical provider may determine that this risk may be outweighed by the potential benefits of medical cannabis in an individual with complex problems that are not adequately managed with usual interventions.

Pre-existing pulmonary diseases

  • Chronic inhalation of smoked cannabis has been associated with symptoms of morning cough, sputum production, and wheezing that improved with cessation of use of cannabis (Hancox et al., 2015). There is substantial evidence of a statistical association between cannabis smoking and worse respiratory symptoms and more frequent episodes of chronic bronchitis (National Academies of Sciences, Engineering, and Medicine, 2017b).  Although some data suggest improved airway dynamics with acute use of smoked cannabis, chronic use is not associated with improvements in pulmonary function (National Academies of Sciences,  Engineering, and Medicine, 2017b). Smoked cannabis should be avoided in persons with respiratory diseases such as chronic obstructive pulmonary disease. Data regarding the pulmonary effects of inhalation of herbal cannabis using a vaporizer device or cannabis extracts using a vape pen are lacking. Inhalation of vaporized herbal cannabis, or cannabis extract administered via a vape pen device, should be done with caution in individuals with pre-existing pulmonary diseases.  

Vitamin E acetate

  • Any hemp extract, cannabidiol, or oral medical cannabis preparation that contains vitamin E acetate has the potential to cause severe pulmonary injury and death if administered via the inhalation route (Taylor et al.,  2019). Vape pens should never be used to administer medical cannabis preparations that were not specifically intended to be used in vape pens. 

Possible pregnancy

  • Cannabis should be avoided in women of childbearing age who are not on a reliable contraceptive and should be stopped immediately if pregnancy occurs.

Diabetic ketoacidosis risk in patients with insulin-dependent diabetes mellitus

  • A retrospective study from Colorado showed that self-reported cannabis users had a twofold increase in the incidence of diabetic ketoacidosis compared to self-reported non-users (Akturk et al., 2019). Patients with diabetes should be monitored to ensure adequate glucose control while using medical cannabis.

Osteoporosis and metabolic bone disease 

  • Animal and in vitro human studies implicate cannabinoids in age-related bone remodeling, and possible osteopenia and osteoporosis (Ehrenkranz &  Levine, 2019). Patients with metabolic bone disease or risk for osteoporosis who are using cannabis on a regular or frequent basis should consider bone densitometry monitoring to assess possible adverse effects of cannabinoids on bone metabolism.

Transaminase elevation

  • Based on the Epidiolex package insert, chronic daily use of higher doses of  CBD should probably include monitoring serum hepatic transaminase levels, especially in patients with active hepatic inflammation, history of hepatic insufficiency, or concurrent use of valproate, clobazam, or other medications that have been associated with transaminase elevations.

Potential risk of cancer associated with use of cannabis

  • A systematic review and meta-analysis of 25 studies assessing marijuana use and the risk for developing lung, head and neck, urogenital, and other cancers showed that regular marijuana use was associated with the development of testicular germ cell tumors, although the strength of evidence was low. Evidence regarding other cancers was insufficient (Ghasemiesfe et al., 2019).  

Hypersensitivity

  • Cannabis should be avoided in persons with hypersensitivity to cannabinoids, including plant, extract, oil, pharmaceutical, and other forms of cannabinoids.

Note: Other adverse reactions from the use of cannabis may include, but are not limited to, fatigue, insomnia, diarrhea, nausea, potential for “hangover,” and a decrease in appetite. For medical providers, determining a patient’s use of cannabis before procedural sedation can be important for planning patient care and assessing both medication needs and possible risks related to increased dosage requirements during endoscopic procedures (Twardowski et al., 2019). 

Cannabis drug interactions

The clinical relevance of possible drug interactions with cannabis and cannabinoids is expected to vary considerably depending on the specific product used, route of administration, individual characteristics, ratio of THC (delta-9-tetrahydrocannbinol) and CBD (cannabidiol), and dose of the product (Ghasemiesfe et al., 2019). Significant pharmacokinetic drug interactions are possible, either through the effects on drug metabolizing enzymes (e.g.,  cytochrome [CYP] P450 enzymes) or drug transporters. Pharmacodynamic effects leading to additive toxicity are also possible. It has been suggested that clinically significant drug interactions are unlikely to occur; however, few well designed clinical studies of drug interaction studies have been conducted  (MacCullum & Russo, 2018). Predictions from in vitro and animal studies suggest a high potential for significant first pass drug interactions after oral administration due to THC and/or CBD inhibition of CYP isoenzymes in the intestine and liver (Cox et al., 2018). The lack of documented interaction should not be interpreted as the absence of an interaction, but rather a lack of published evidence. Given the possibility of drug-drug interactions and limited understanding of these effects, cannabis should be used cautiously with other medications. Monitor clinical and adverse effects closely; consider dose adjustments as clinically indicated.  

Clinicians may refer to available resources on cannabis drug interactions.

Note: Patients taking blood thinners or medications with sedative effects should talk to their doctor before using cannabis products.

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