About the Authors
Dennis Wong, MD, PhD
Dr. Wong is a resident in Clinical Immunology and Allergy at University of Toronto. He completed his PhD in Microbiology and Immunology at University of British Columbia under the supervision of Dr. Yossef Av-Gay. He subsequently received his MD and completed Internal Medicine residency at University of Toronto.
Gordon Sussman, MD, FRCPC, FAAAAI
Dr. Sussman is a Professor of Medicine in the Division of Clinical Immunology and Allergy at University of Toronto. His research includes the characterization of marijuana allergy and allergens, which has become more relevant in recent years with its legalization and increased medicinal use. His previous research focused on natural rubber latex allergy. Dr. Sussman recognized and reported some of the first cases of latex allergy, which eventually lead to widespread declines in latex allergy
An overview of Cannabis allergy
Cannabis refers to a genus of annual, herbaceous, dioecious flowering plants that are members of the family Cannabaceae, which include about 102 plant species.1 Although there is much debate, the most common taxonomy is that the genus Cannabis comprises one species, Cannabis sativa L (C. sativa)., which includes the highly polymorphic subspecies sativa, and indica.22
Hemp and cannabis both refer to the same species C. sativa; however, there is important distinction between the two. Whereas hemp (fiber-type) is grown for its cellulose-rich fiber in the stem, cannabis (drug-type) is cultivated for its flowers where the glandular trichomes produce the psychoactive delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC provides the analgesic and relaxing effects of cannabis, whereas CBD produces other effects such as antiemetic and soporific properties. Researchers have used the THC content to define C. sativa subspecies sativa as containing less than 0.3% THC in dried flowering tops of female plants and C. sativa subspecies indica as containing ≥0.3% THC.3 This threshold has been used by regulatory bodies to legally differentiate hemp plants (<0.3% THC) and cannabis plants (≥0.3% THC).
Canada legalized the production, distribution, sale and non-medical use of cannabis for adults in October 2018. Recent data from nation-wide surveys show that approximately 6.2 million people aged 15 or older, or 20% in this age group, reported using cannabis in the past 3 months.4 which represents an increase from 14% before legalization. Cannabis can be used and/or ingested in a variety of forms including capsules, oils, dried flower, vaporization and through the consumption of edibles. With the increased use of recreational cannabis in Canada, it is expected that there will be a concomitant increase in cases of cannabis hypersensitivity.
CLINICAL MANIFESTATIONS OF CANNABIS ALLERGY
Since the first description of reactions to cannabis-containing cigarettes in 1971, there have been numerous reports of cannabis hypersensitivity associated with different routes of exposure and a wide-range of symptoms.5-11 Most case reports described an immediate onset of upper airway symptoms such as rhinitis and conjunctivitis after smoking cannabis in recreational users.6-10 There has also been evidence suggesting that long-term use of cannabis can result in chronic airway inflammation and exacerbate existing asthma, despite its mild and short bronchodilator effect.12 Indeed, there are several reports of patients experiencing the immediate onset of lower respiratory symptoms such as dyspnea, coughing, wheezing and chest tightness with recreational cannabis use. Gastrointestinal symptoms such as vomiting and abdominal cramps can also occur especially after ingestion of marijuana edibles.7 In regions where C. sativa is cultivated or wild cannabis plants exist, environmental exposure to C. sativa pollen, which typically peak in summer months, has also been implicated in seasonal allergic rhinoconjunctivitis.11 Contact urticaria has also been described in patients who have repeated direct contact with the plant.6,13,14 In general, the symptoms of cannabis allergy can be variable and are not limited by the route of exposure. Not surprisingly, anaphylactic reactions from recreational cannabis use have been reported.7,15 There is also one report of cannabis-dependent exercise-induced anaphylaxis where the patient reported allergic reaction only when he engaged in rigorous activity after smoking cannabis.9 Hemp seed ingestion can result in anaphylaxis in patients sensitized to cannabis from recreational cannabis use.16 It is important for patients who have a history of cannabis allergy to be educated on the risk of hemp seed as a potential food allergy.
Occupational exposure has also been recognized as a risk of sensitization to cannabis.17,18 There also have been several reports of workers in cannabis facilities and forensic laboratory personnel developing allergic symptoms including rhinitis, urticaria and angioedema from cannabis exposure in the work environment despite having no history of recreational cannabis use.13,14,19 A recent study involving law enforcement officers with a reported history of cutaneous or respiratory symptoms from work-related cannabis exposure was unable to establish a causal relationship between cannabis allergy and symptomology.20 This potentially suggests that a non-immune mechanism exists for some of the symptoms experienced with cannabis exposure or that the relevant cannabis allergens implicated in occupational exposure remain yet to be identified.
CANNABIS ALLERGENS AND CROSS-REACTIVITY
Although cannabis allergy has long been recognized, it is only recently that investigations into the allergenic component have been reported. Can s 3, a non-specific lipid transfer protein (ns-LTP) that belongs to the pathogenesis-related (PR)-14 group, is the first IgE-binding allergenic protein identified (Table 1).6,8,21
This protein is believed to be the major allergen in the European population. In a Spanish study, sensitization to Can s 3 was observed in 124 of 130 patients with primary cannabis allergy and a similar trend was also observed in another European study.22,23 Since ns-LTP is ubiquitous throughout the plant kingdom, sensitization to Can s 3 could lead to secondary plant-derived food allergies as reported in the literature. This pattern of cross-reactivity has been termed “cannabis-fruit/vegetable syndrome”.23,24 The foods most commonly implicated are allergies to peach, banana, apple, nuts, grapes, cherry, and tomato (Figure 1).
The symptoms due to cannabis-fruit/vegetable syndrome are typically more severe as compared to those observed in Bet v 1-related pollen food syndrome. This is likely because ns-LTPs are resistant to gastroduodenal proteolysis and thermal processing. Cross-reactivity with Can s 3 has also been shown to extend to latex and tobacco (Figure 1).25 The cannabis homologue of Bet v 1 and C. sativa profilin, now termed Can s 5 and Can s 2 respectively, have also been demonstrated to play a role in cannabis allergy.26
Unlike the European investigations, the first study on C. sativa allergen in the North American population did not show the same pattern of sensitization.27 Rather than Can s 3, the predominant IgE-binding allergens were found to be ribulose-1,5-bisphosphate carboxylase oxygenase (RuBisCO) and oxygen evolving enhancer protein 2 (Can s 4), both of which are involved in photosynthesis.27 Interestingly, in line with the different pattern of sensitization, there is also a lack of association between cannabis allergy and plant-food allergies in the North American population.7,27,28 Whether this is related to geographical differences in C. sativa resulting in different clinical phenotypes is unknown. A more recent study did detect Can s 3 sensitization in a small number of Canadian patients with cannabis allergy although the exact prevalence remains to be eludicated.29
DIAGNOSTICS AND MANAGEMENT
As with other allergies, the diagnosis of cannabis allergy relies mainly on an accurate history of the allergic reaction. However, several important factors can make this challenging. Although cannabis is now legalized in Canada, patients may not be forthcoming about their cannabis use due to social stigma and taboos. Another challenge is that cannabis smoking or ingestion can result in side effects such as conjunctival injection and panic attacks that can be misattributed as allergic reaction. For workers in cannabis facilities or law enforcement officers, occupational exposure to pesticide, organic dusts or fungi from handling or processing cannabis can also elicit or mimic allergic symptoms.
Currently, there is no standardized or commercially available diagnostic test for cannabis allergy. Even direct provocation testing, which is the gold standard in allergy diagnosis, has unclear reliability given the paradoxical short-term bronchodilator effect of cannabis. For skin prick testing, most case reports in the literature use prick-prick tests with crude cannabis or non-standardized cannabis extracts for diagnosis.30 This approach could potentially be confounded by variable results depending on the composition of the source material or varieties of C. sativa used. A recent European study showed that Can s 3-based testing is the most effective and reliable.30 Although not commercially available, skin prick testing with a Can s 3 enriched extract and specific IgE testing to recombinant Can s 3 were both demonstrated to have positive and negative predictive value of around 80% and 60%, respectively.30 However, whether these results apply to the North American population, which seems to have different pattern of sensitization, remains unknown. Specific IgE testing to hemp, which is commercially available, can be considered a proxy although it lacks specificity (32%).30 Certainly, more research in the development of diagnostic testing, targeted towards the North American population is needed.
With regards to management of cannabis allergy, strict avoidance when feasible is the only available treatment. There is one case report in the literature describing the use of omalizumab for the treatment of cannabis allergy in a patient who had regular occupational exposure to cannabis resulting in anaphylactic reactions.31 After 4 months of therapy, the patient was able to tolerate exposure to large amounts of cannabis with only mild cutaneous symptoms. Successful immunotherapy treatment for cannabis allergy has also been previously reported.32 However, the lack of a standardized extract along with uncertain efficacy and safety data make it challenging to foresee broad application particularly for recreational cannabis users.
With the legalization of cannabis, there is likely to be a continuing trend of increased numbers of recreational users and an increased prevalence of cannabis allergy. Occupational exposure is also recognized as a risk for cannabis sensitization. Diagnosing cannabis allergy remains challenging due to a lack of standardized testing, however, there is hope that commercially available testing will be available in the near future with a better understanding of the allergenic components. An important question to answer concerns the role that geographical differences may play in cannabis allergy as shown by the distinct sensitization and clinical phenotypes between North American and European populations, which will most certainly impact the diagnosis and management of cannabis allergy. As there are numerous strains and varieties of C. sativa., it is unclear whether the various strains have different allergenicity and more research is needed in this regard. Component-specific cannabis extracts including Can s 3 are not yet available as allergen extracts. Research is ongoing using component-specific diagnostics.
- Ren G, Zhang X, Li Y, et al. Large-scale whole-genome resequencing unravels the domestication history of Cannabis sativa. Sci Adv. 2021;7(29).
- McPartland JM. Cannabis Systematics at the Levels of Family, Genus, and Species. Cannabis Cannabinoid Res. 2018;3(1):203-212.
- Small E, Cronquist A. A practical and natural taxonomy for Cannabis. Taxon. 1976:405-435.
- Rotermann M. Looking back from 2020, how cannabis use and related behaviours changed in Canada. Health reports. 2021;32 4:3-14.
- Liskow B, Liss JL, Parker CW. Allergy to marihuana. Ann Intern Med. 1971;75(4):571-573.
- Gamboa P, Sanchez-Monge R, Sanz ML, Palacin A, Salcedo G, Diaz-Perales A. Sensitization to Cannabis sativa caused by a novel allergenic lipid transfer protein, Can s 3. J Allergy Clin Immunol. 2007;120(6):1459-1460.
- Tessmer A, Berlin N, Sussman G, Leader N, Chung EC, Beezhold D. Hypersensitivity reactions to marijuana. Ann Allergy Asthma Immunol. 2012;108(4):282-284.
- Larramendi CH, Lopez-Matas MA, Ferrer A, et al. Prevalence of sensitization to Cannabis sativa. Lipid-transfer and thaumatin-like proteins are relevant allergens. Int Arch Allergy Immunol. 2013;162(2):115-122.
- Wong DD, Abbas KF, Grunberg RW, Sussman G. Cannabis Allergy: A Melting Pot of Clinical Manifestations. The Journal of Allergy and Clinical Immunology. 2018;141.
- Decuyper, II, Faber MA, Lapeere H, et al. Cannabis allergy: A diagnostic challenge. Allergy. 2018;73(9):1911-1914.
- Stokes JR, Hartel R, Ford LB, Casale TB. Cannabis (hemp) positive skin tests and respiratory symptoms. Ann Allergy Asthma Immunol. 2000;85(3):238-240.
- Tashkin DP. Airway effects of marijuana, cocaine, and other inhaled illicit agents. Curr Opin Pulm Med. 2001;7(2):43-61.
- Williams C, Thompstone J, Wilkinson M. Work-related contact urticaria to Cannabis sativa. Contact Dermatitis. 2008;58(1):62-63.
- Rojas Perez-Ezquerra P, Sanchez-Morillas L, Davila-Ferandez G, et al. Contact urticaria to Cannabis sativa due to a lipid transfer protein (LTP). Allergol Immunopathol (Madr). 2015;43(2):231-233.
- Perez JA, Jr. Allergic reaction associated with intravenous marijuana use. J Emerg Med. 2000;18(2):260-261.
- Stadtmauer G, Beyer K, Bardina L, Sicherer SH. Anaphylaxis to ingestion of hempseed (Cannabis sativa). J Allergy Clin Immunol. 2003;112(1):216-217.
- Decuyper, II, Green BJ, Sussman GL, et al. Occupational Allergies to Cannabis. J Allergy Clin Immunol Pract. 2020;8(10):3331-3338.
- Sussman GL, Beezhold DH, Cohn JR, Silvers WS, Zeiger JS, Nayak AP. Cannabis: An Emerging Occupational Allergen? Ann Work Expo Health. 2020;64(7):679-682.
- Herzinger T, Schopf P, Przybilla B, Rueff F. IgE-mediated hypersensitivity reactions to cannabis in laboratory personnel. Int Arch Allergy Immunol. 2011;156(4):423-426.
- Decuyper, II, Van Gasse A, Faber MA, et al. Occupational cannabis exposure and allergy risks. Occup Environ Med. 2019;76(2):78-82.
- de Larramendi CH, Carnes J, Garcia-Abujeta JL, et al. Sensitization and allergy to Cannabis sativa leaves in a population of tomato (Lycopersicon esculentum)-sensitized patients. Int Arch Allergy Immunol. 2008;146(3):195-202.
- Armentia A, Herrero M, Martin-Armentia B, Rihs HP, Postigo I, Martinez-Quesada J. Molecular diagnosis in cannabis allergy. J Allergy Clin Immunol Pract. 2014;2(3):351-352.
- Ebo DG, Swerts S, Sabato V, et al. New food allergies in a European non-Mediterranean region: is Cannabis sativa to blame? Int Arch Allergy Immunol. 2013;161(3):220-228.
- Decuyper, II, Van Gasse AL, Cop N, et al. Cannabis sativa allergy: looking through the fog. Allergy. 2017;72(2):201-206.
- Faber M, Van Gasse A, Sabato V, et al. Marihuana allergy: beyond the joint. J Investig Allergol Clin Immunol. 2015;25(1):70-72.
- Ebo DG, Decuyper, II, Rihs HP, et al. IgE-binding and mast cell-activating capacity of the homologue of the major birch pollen allergen and profilin from Cannabis sativa. J Allergy Clin Immunol Pract. 2021;9(6):2509-2512 e2503.
- Nayak AP, Green BJ, Sussman G, et al. Characterization of Cannabis sativa allergens. Ann Allergy Asthma Immunol. 2013;111(1):32-37.
- Lo SCR, Abbaslou M, Abbas KF, Kobric D, Silvers WS, Sussman G. Cannabis Hypersensitivity Prevalence and Presentation: A Survey-based Study of an Allergic Adult Population in a Toronto Clinic at Onset of Canadian Legalization of Recreational Marijuana. The Journal of Allergy and Clinical Immunology. 2020;145.
- Morelli HP, Thorpe C, Decuyper II, et al. Non-specific Lipid Transfer Protein (Can s 3) Is a Relevant Cannabis Allergen in North America. The Journal of Allergy and Clinical Immunology. 2021;147.
- Decuyper, II, Van Gasse AL, Faber MA, et al. Exploring the Diagnosis and Profile of Cannabis Allergy. J Allergy Clin Immunol Pract. 2019;7(3):983-989 e985.
- Engler DB, Malick AA, Saraf S, Dargel LA. Severe Marijuana Allergy Controlled with Omalizumab. The Journal of Allergy and Clinical Immunology. 2013;131.
- Kumar R, Gupta N. A case of bronchial asthma and allergic rhinitis exacerbated during Cannabis pollination and subsequently controlled by subcutaneous immunotherapy. Indian Journal of Allergy, Asthma and Immunology. 2013;27:143.