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Official websites use. Share sensitive information only on official, secure websites. Isabel J. Skypala, Samira Jeimy and Hannelore Brucker should be considered joint first authors. Anne Kathleen Ellis, William S. Silvers and Didier G. Ebo should be considered joint senior authors. Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis-related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross-reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick-to-prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue. Keywords: allergy diagnosis, allergy treament, cannabis allergy, IgE, occupational allergies. Approximately million people, 3. Rising consumption underlines the need for greater awareness of the spectrum of cannabis allergy, its diagnosis and management. This group developed a plan of action, which includes a survey of the membership of the three societies, the development of an international registry and biobank, and the publication of this joint paper on cannabis allergy Figure 1. Cannabis has been used for five millennia for spiritual, medicinal, and recreational purposes, with recent archaeological evidence of ritualized consumption dating from BC. Although there is some variation between countries and continents, the highest use is in young adults, although the age range of cannabis users is increasing and is projected to continue to do so. Cannabis was prohibited in the United States by the Marijuana Tax Act, and further restricted in following its classification as a Schedule I substance. Currently, 36 states, and the District of Columbia DC , have moved to legalize medical cannabis, 15 states, and DC, legalizing recreational cannabis, and 16 states decriminalizing its use. Of the non-cannabis users, 2. In Canada, the Cannabis Act of legalized cannabis, giving it a similar status to that of alcohol. Cannabis is the most widely used illicit drug in Europe, with a higher prevalence in Mediterranean and Central-Western European countries. Medical cannabis generally refers to the use of cannabis to treat disease or alleviate symptoms. Cannabis belongs to the Cannabaceae family, can grow in diverse climates, and is found in most parts of the world. Cannabis is an annual herb, largely dioecious with separate male and female plants. It is easily recognized by the distinctive arrangement of leaves. The plant is marked by hair-like glandular projections called trichomes, which serve as a rich source of cannabinoids. Cannabis sativa and Cannabis indica and to a lesser extent Cannabis ruderalis are the most common botanical varieties, but there is significant diversity in the biological and vernacular use of terms to identify different strains. Consequently, a wide variety of cannabis strains are in circulation, selected for their unique biochemical and mood-altering profile. However, genetic studies have shown that there is a merging of Cannabis sativa and Cannabis indica and that the separation of the two is becoming less common. It is unrelated to water hemp Amaranthus tuberculatus which is a dioecious plant native to North America. Over phytocannabinoids have been identified in cannabis, although only those with a terpenyl residue including geranyl CBG-type , menthyl CBD-type and THC-type , or prenylchromanyl CBC-type are present in any significant amount. However, derivatives of cannabis containing less than 0. Cannabis proteins can act as high-molecular weight allergens and contribute to type I allergic reactions. Table 1. Molecular analysis has suggested the presence of other diverse allergenic proteins in cannabis including ribulose-1,5-bisphosphate carboxylase-oxygenase RuBisCo , adenosine triphosphate synthase, glyceraldehydephosphate dehydrogenase, phosphoglycerate kinase, heat shock protein 70, 63 thaumatin-like protein, 64 peptinesterases and polygalactouranases. Similarly, it is also unknown how prevalent sensitization is to other Cannabis sativa allergens such as the profilin Can s 2, the oxygen-evolving enhancer protein Can s 4, or the thaumatin-like protein, and whether they are relevant allergens in relation to food cross-reactions. Cannabis Allergens and homologous plant proteins. There is proven cross-reactivity between Can s 3 and other nsLTP, whereas for the other sequenced cannabis allergens, this has not been investigated. However, there are protein amino acid identity matches across species suggesting possible IgE cross-reactivity. Cannabis hypersensitivity spans the spectrum of allergic response and can provoke both type 1 and type 4 reactions. Early reports of allergic reactions were of contact dermatitis after touching cannabis leaves or flowers, and toxico-dermatitis after smoking hemp. If reported, such symptoms should not be ignored or misattributed if the index of suspicion for a serious reaction or anaphylaxis to cannabis is high. Cannabis varieties such as hemp contain very low or undetectable levels of THC and have been used for many years as an agricultural commodity and source of fiber, with the seeds used in food products. In recent years, occupational sensitization to cannabis has mostly centered on the cannabis exposures of law enforcement officers and forensic investigators. Most allergic symptoms observed from direct handling of cannabis are typically marked by respiratory symptoms, ranging from rhinoconjunctivitis to bronchial hyperresponsiveness and chest tightness. High levels of endotoxin in occupational hemp dust exposures have been consistently associated with adverse respiratory outcomes in exposed workers. For example, Can s 3, a mediator of cross-reactive allergies related to cannabis, has not been established as a relevant allergen in the context of occupational exposures. Cannabis consumption presents a risk to immunosuppressed patients via exposure to microbiological contaminants, particularly when inhaled. Aspergillus has been isolated from cannabis samples. The most important test for diagnosing IgE-dependent cannabis allergy is the clinical history, although patients may be reluctant to admit consumption where cannabis use is legally restricted. Determining whether symptoms are attributable to cannabis is challenging, especially in pollen allergic individuals. New-onset reactions to plant foods in teens and adults could also be linked to a cannabis allergy, but establishing whether a food allergy represents cross-reactivity with a pollen allergen e. Although younger patients may also be potentially exposed, cannabis allergy should be considered in those aged 16 years and over, presenting with symptoms of cough and wheeze indicating a new onset of asthma, or difficult to control existing asthma despite medication adherence. After establishing the clinical history, it may not always be possible to undertake standard allergy tests. There are no commercially available extracts, so unstandardized prick—prick tests PPT with the buds, leaves, or seeds of the cannabis plant is usually the only option, if available. An alternative option is to perform SPTs with pre-prepared cannabis extracts, which can be better standardized, and designed to concentrate known allergen components such as Can s 3. Note: A: Cannabis-anaphylaxis group vs. Although CCDs rarely trigger clinically irrelevant SPT results, they can decrease the specificity of sIgE tests due to their structural similarity to allergens originating from both taxonomically related and distant plants, e. Thus, a negative SPT or BAT with a crude extract, and negative sIgE to hemp, have a good negative predictive value, but a positive result for one of these tests warrants complementary diagnostics Figure 4. This is especially important when diagnosis is complicated by PR, profilin, nsLTP, or CCD sensitization, resulting in cross-reactivity between cannabis and other allergens. BAT and pMAT have also been used to study other cannabis allergens, but larger collaborative studies are needed to verify whether these tests could enter mainstream application. Cells are responsive to a raw extract, Can s 3, Can s 4, Can s 5, but not to Can s 2. Diagnostic algorithm for Cannabis Allergy. If the results are negative, cannabis allergy is highly unlikely. Given the lack of standardized extracts, and non-availability of commercial BAT and pMAT tests, it is currently not possible to optimize the process. A provocation challenge with inhaled cannabis is not recommended, as apart from the legal issues this may cause in many countries, inhalation of cannabis fumes can trigger nonspecific hyperresponsiveness without confirming allergy. As with any allergy diagnostic work-up, establishing sensitization to other relevant allergens including molds, pollens, and foods may be helpful, utilizing the most appropriate country-specific tests. Currently, the only available treatment for cannabis allergy is avoidance. When avoidance is difficult or impossible, such as occupational exposure, treatment of symptoms is identical to that of other allergens and based on the clinical phenotype upon exposure. For occupational exposure, while a combination of administrative, engineering, and protective controls may mitigate some of the exposures, most occupational settings have limited options to remedy the situation. Treatment with omalizumab has been tried successfully in one case of unavoidable occupational allergy with anaphylaxis. In established cannabis allergy it is important to understand the cross-reactivity profile to foods. Treatment for cannabis-related cross-reactivity to fruits, vegetables, and latex due either to pollens or nsLTP entails avoidance, not only of cannabis, but also of the reported food triggers. Besides avoidance and symptomatic treatments, there is limited evidence for other therapeutic approaches. The seminal paper on the potential of immunotherapy in cannabis allergy, published in a veterinary journal, described a dog successfully desensitized with cannabis pollen extract. For many allergy healthcare professionals, determining cannabis use is not part of routine history-taking. Initiating such a discussion is vital, and questions should address cannabis exposure in a non-judgmental manner. Patient-oriented information, both web-based, and written handouts can supplement the patient consultation. Healthcare professionals who see allergy patients would benefit from continuous professional development initiatives on cannabis allergy; for example, the development of competencies addressing practical approaches to its diagnosis and management. Continued education can increase the clinician's understanding and comfort level and improve the chances of them initiating an open discussion on cannabis use with each patient. Furthermore, it gives the clinician the opportunity to discuss the potential harm of recreational or non-evidence based medical use of cannabis. The diagnosis of any allergy can be problematic, and there are added difficulties with cannabis allergy, not least due to legal issues. There are currently no commercial allergy tests for the diagnosis of cannabis allergy in a clinical setting. Whole cannabis extracts could be purchased for SPT, depending on the legal status of cannabis in that area. Specific IgE to hemp is another option, but usually only available for use in research settings. Where possible, a connection should be made with laboratories that can perform IgE, molecular and cellular tests. A large survey demonstrated that people with asthma or allergies may not wish to discuss cannabis use with their physicians, but also physicians often did not inquire about cannabis use. The CAIG aims to emphasize the need for more data to establish the significance of cannabis allergies in context of increasing access. This collaboration also plans to identify challenges that currently limit studies on cannabis allergy for example, Schedule I drug limitations, access to patients, lack of guidance on management, poor validation of diagnostic assays. Another goal is to clarify the importance of the context of exposures and the need to collect details on strain diversity and complexity of use. Key aspects of cannabis allergy need to be addressed, including the relevant allergens, diagnostic work-up, surveillance programs for occupational and environmental exposures and the prevention of cannabis allergy. The intention is that these workstreams lead to the development of international guidelines on the diagnosis and management of cannabis allergy. Blaiss, Rohit Katial, David R. Naimi, Robert S. The authors would also like to express their very great appreciation to Miriam Standish from the ACAAI, who has supported the work of the group, arranged meetings and facilitated the progress of this document. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Published in final edited form as: Allergy. Find articles by Isabel J Skypala. Find articles by Samira Jeimy. Find articles by Hannelore Brucker. Find articles by Ajay P Nayak. Find articles by Ine I Decuyper. Find articles by Jonathan A Bernstein. Find articles by Lori Connors. Find articles by Amin Kanani. Find articles by Ludger Klimek. Find articles by Shun Chi Ryan Lo. Find articles by Kevin R Murphy. Find articles by Anil Nanda. Find articles by Jill A Poole. Find articles by Jolanta Walusiak-Skorupa. Find articles by Gordon Sussman. Find articles by Joanna S Zeiger. Find articles by Richard E Goodman. Find articles by Anne K Ellis. Find articles by William S Silvers. Find articles by Didier G Ebo. Issue date Jul. PMC Copyright notice. The publisher's version of this article is available at Allergy. Open in a new tab. Performance of different tests in Cannabis-sensitized and Cannabis allergic patients. Adapted from 75 :. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Profilin Nonspecific lipid transfer protein 75 , Oxygen-evolving enhancer protein 2 63 , Pathogenesis related protein 10 homologue

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