Cannabis
Summary
Considered one of the oldest domesticated multi-purpose crops, an important source of fiber, food and medicine, cannabis has been used for millennia in spiritual, religious and recreational activities due to its psychoactive properties. Cannabis is a generic term for different preparations derived from C. sativa that contain high levels of psychoactive substances like cannabinoids, particularly delta-9-tetrahydrocannabinol (THC). Despite the widespread use of cannabis, reports on cannabis allergy remain rare – possibly due to very low reporting (most likely due to varying legality) or difficulty distinguishing due to cross-reactivity caused by cannabis-fruit/vegetable syndrome. Inhalation of cannabis smoke is its most common use; however, cannabis-related allergic symptoms are not generally limited to the route of exposure. For example, cannabis smoking can trigger respiratory, cutaneous and gastrointestinal symptoms, potentially an artefact of recreational cannabis users preparing and handling their cigarettes. Most reports describe immediate-type hypersensitivity reactions, typically with a rapid onset of symptoms ranging from mild, isolated reactions to generalized, severe reactions.
Epidemiology
Worldwide distribution (of the disease)
Despite the widespread use of Cannabis, reports on cannabis allergy remain rare – possibly due to very low reporting (most likely due to varying legality) or difficulty distinguishing due to cross-reactivity caused by cannabis-fruit/vegetable syndrome – and generally deal with small numbers of cases. The quality and availability of evidence is limited by the extent of published literature, which is particularly relevant given that extent of cannabis legalization worldwide is fairly limited, which precludes extensive research. In addition, possible sensitization to drugs (including cannabis) has not been widely considered, as drug reactions are generally attributed to toxic causes and allergic hypersensitivity to immunological causes, with the two seen as mutually exclusive.
The first report of cannabis allergy dates to 1971 when a young housewife experienced an anaphylactic reaction after smoking a cannabis-containing cigarette. Only about 10% of cannabis users seek specific treatment, probably due to the illegality of its use and also to neurobehavioral alterations such as bias recall due to impaired memory. However, it is likely that increased cannabis availability and exposure (both as a drug and a food) will coincide with a rise in adverse events including cannabis-related allergies with detrimental effects on health and quality of life [.
Risk factors
An increasing number of reports describe mild to severe plant-derived food allergies associated with cannabis allergy, a phenomenon called the cannabis-fruit/vegetable syndrome, mainly attributed to sensitization to Can s 3, a nonspecific lipid transfer protein (nsLTP) from C. sativa. NsLTPs are heat stable allergens widely distributed through the plant kingdom which show extensive in vitro and in vivo cross-reactivity. Of note, sensitization with cannabis-fruit/vegetable syndrome is bidirectional, i.e. sensitization to nsLTP could cause subsequent sensitization to Cannabis.
Route Of Exposure
Main
Inhalation of cannabis smoke is its most common use, but it can also be inhaled as resin, vaporized, taken orally or applied to the skin or mucus membranes. A typical marijuana cigarette is produced from 1 g of C. sativa leaves, but can also include the whole plant including flowers, leaves, seeds, roots and stems. Marijuana is smoked without filters, and users inhale larger volumes, more deeply and at higher temperatures than tobacco.
More than 2,000 compounds are produced by pyrolysis during smoking of cannabis which altogether contribute to the unique pharmacological and toxicological profile of cannabis. Cannabis-related symptoms are not generally limited to the route of exposure, for example, cannabis smoking can trigger respiratory, cutaneous and gastrointestinal symptoms, potentially an artefact of recreational cannabis users preparing and handling their cigarettes.
Of note, the dose-response effect of cannabis exposure is difficult to evaluate due to a great variation in the amounts and strains of the plant used in a cigarette, as well as the wide variety of methods in which cannabis is smoked, all of which alters the characteristics of the inhaled smoke and health consequences. In addition, cannabis farms and plantations often use a large number of pesticides and other irritable substances, and can be located in poorly ventilated, hot and humid environments which are ideal for fungal proliferation. As such, respiratory and cutaneous irritability may not always be linked to an allergic cause and it can be highly challenging to differentiate symptoms mediated by allergy from nonspecific irritability.
Other
Estimates suggest that by 2021 over 300,000 workers will be employed in growing, harvesting, processing and distributing Cannabis. Occupational cannabis contact can elicit type 1 hypersensitivity reactions ranging from mild local reactions to life-threatening anaphylaxis, and many hemp workers have been demonstrated to exhibit high levels of serum IgE to hemp. Industrial hemp dust exposure has been implicated in byssinosis, an occupational obstructive (small airway) lung disease associated with organic textile dust exposure in work environments. Additional occupations at risk of cannabis exposure include law enforcement personnel, laboratory technicians and dispensary workers.
There have been only limited reports of hempseed allergy. In a small study among 15 patients presenting with allergic reaction to hempseed, cannabis, or both, which investigated the coexistence of cannabis and hempseed allergy, 10 were sensitized to cannabis. There was also evidence of further coexisting allergies. 12 patients were atopic (seasonal allergic rhinitis, asthma, eczema or food allergy) and five had food allergies tested by skin-prick test.
Hempseed, hemp oil and a hulled form of the seed that is free from THC have become popular as a food product with possible benefits to health. In one case study of a 44-year-old man with a history of seasonal allergic rhinitis, mild asthma, and occasional use of marijuana but no food allergies experienced an allergic response upon visiting a restaurant specializing in hempseed ingredients. Upon exposure to cooking fumes and ingestion of foods prepared with hempseed, he experienced anaphylaxis; comprising ocular pruritus, urticaria on the scalp, axillae, and groin, alongside facial angioedema, dyspnea and dysphonia, requiring emergency treatment with epinephrine and antihistamines. Immunoblotting of serum demonstrated IgE binding to a protein extract of raw hulled and roasted unhulled hempseed used in the meal.
Clinical Relevance
Allergic diseases associated with C. sativa include allergic rhinitis, asthma, allergic conjunctivitis, eczema, food allergy, drug eruption, contact urticaria and anaphylaxis. Cannabis allergy can significantly impact quality of life, manifesting severe and generalized symptoms with extensive cross-reactions.
Most reports describe immediate-type hypersensitivity reactions, typically with a rapid onset of symptoms starting within 20-30 minutes after cannabis exposure. Symptoms range from mild, isolated reactions which can involve the upper airway (nasal and pharyngeal pruritus, lacrimation, nasal congestion and rhinitis), lower airway (cough, mild to severe dyspnea, wheezing and chest tightness), cardiovascular (hypotension, palpitations, vertigo), cutaneous (localized/generalized pruritus and urticaria, eczema and periorbital angioedema) and gastrointestinal (nausea, vomiting and abdominal cramping) systems to generalized, severe reactions and life-threatening anaphylaxis.
Seasonal and occupational exposure to C. sativa can be considered as a precipitating factor for acute asthma and allergic attacks in clinical practice. Cannabis pollen contributes to the aerobiology wherever it grows wild, which can manifest a hay fever-like syndrome with symptoms of allergic rhinitis, conjunctivitis and asthma; this can be relevant in regions such as central India, urban Pakistan, southern Europe and parts of the United States.
Of note, contamination of marijuana samples with fungi such as Aspergillus and Penicillium species may put immunocompromised patients at risk for invasive disease. A case of allergic bronchopulmonary aspergillosis has been observed in a patient with a contaminated marijuana supply.
Diagnostics
The illicit nature of Cannabis use can create barriers to accurate and clear patient communications, however any physician suspecting a Cannabis allergy should attempt a detailed and thorough anamnesis focusing on the symptoms experienced during exposure, the type of exposure, the timeframe during which symptoms appear and subsequently disappear, and the presence of other environmental factors with the potential of eliciting allergic symptoms.
The “gold standard” in vivo diagnostic test for sensitization - a patient challenge with Cannabis - is hampered by legal restrictions in the majority of jurisdictions worldwide. To date, skin prick testing (SPT) for Cannabis allergy remains non-standardized, unvalidated and unreliable due to inherent differences in source material, extraction techniques, contaminants and additives.
Multiple authors have described using an in vitro specific IgE assay on patients’ sera using either crude cannabis/hemp extracts or purified/recombinant components [Reviewed in:], however the only sIgE (industrial) hemp assay test currently available on the market is limited to research purposes only. Cannabis allergy has been diagnosed successfully via an in vitro basophil activation test (BAT) [Reviewed in:]. While BAT is limited to research purposes, it may exhibit better specificity than sIgE assays as it is an ex vivo technique that needs cross-linking on the basophil membrane to produce a positive result, whereas sIgE assays only detect IgE without looking at its function. However, it is important to note that diagnostics – including BAT – which are based on crude extracts can produce clinically irrelevant results. Also, BAT has a further limitation as it requires whole blood or isolated peripheral blood mononuclear cells.
Prevention And Therapy
Avoidance
Most reports advise avoidance of cannabis and all foods implicated in clinical cross-reactivity. Complete avoidance can be challenging in an occupational setting but may be necessary in the case of anaphylaxis. Avoidance may also be challenging due to cross-reactivity caused by cannabis-fruit/vegetable syndrome. Careful consideration of crop locations may be indicated, for example Davidson et al. (2018) recommended avoiding growing hemp in regions known for thunderstorm asthma events because Cannabis pollen can be naturally dispersed over vast distances due to its small size.
Therapy
Symptomatic treatment for cannabis-induced allergic rhino-conjunctivitis and asthma can include antihistamines, intranasal steroids, nasal decongestants, β-agonists or corticosteroids as indicated, while epinephrine auto-injectors should be prescribed for patients with a history of anaphylaxis.
A single case report describes successful desensitization for cannabis with omalizumab: an asthmatic police detective aged 29 years, with regular occupational cannabis exposure resulting in anaphylaxis, received four months of omalizumab therapy after which no anaphylaxis episodes were seen and only some cutaneous tingle remained on contact with cannabis.
Cross-Reactivity
Apart from allergic symptoms reported from direct or indirect cannabis exposure, an increasing number of reports outline mild to severe plant-derived food allergies associated with Cannabis allergy [reviewed in]. Via the “cannabis-fruit/vegetable syndrome”, the nsLTP Can s 3 has been reported to cross-react with other nsLTPs including (ordered by sequence homology from highest to lowest): Mal d 3 (apple), 85%; Pru p 3 (peach), 85%; and Vit v 1 (grape), 85%; Sol l 3 (tomato), 84%; Nic t 1 (tobacco), 84%; Cor a 8 (hazelnut), 80%; Cit s 3 (citrus), 80%; Mus a 3 (banana), 80%; Hev b 12 (latex), 75%; Ara h9 (peanut), 70%; Tri a 14 (wheat), 68% [reviewed in:]. Of note, nsLTPs sensitization can occur as a result of in vitro cross-reactivity to Can s 3 from taxonomically related or more distant sources without any previous Cannabis contact.
NsLTPs are widely distributed throughout the plant kingdom and show extensive in vitro and in vivo cross-reactivity. Can s 3 sensitization presents a risk of systemic reactions to plant-derived foods and cofactor-mediated reactions (e.g. reported plant-derived food allergies with a history of overt or severe, generalized reactions in the presence of nonsteroidal anti-inflammatory drugs, alcohol, or physical exercise).
Can s 3 sensitization is not the only important allergen, so other cannabis allergens probably play a role in cross-reactivity.
Explained Results
Allergen Information
Cannabis is a generic term for different preparations (e.g., marijuana, weed, hashish) derived from Cannabis sativa that contain high levels of psychoactive substances like cannabinoids, particularly delta-9-tetrahydrocannabinol (THC). Hemp and hemp products are also derived from Cannabis sativa, but contain a THC level of 0.3% or less. Exposure to cannabis extends beyond personal recreational use and includes second-hand exposure, oral ingestion, aeroallergen/pollen contact, and cutaneous contact.
· Clinical information
Allergic diseases associated with C. sativa include allergic rhinitis, asthma, allergic conjunctivitis, eczema, food allergy, drug eruption, contact urticaria and anaphylaxis. Symptoms range from mild, isolated reactions to generalized, severe reactions and life-threatening anaphylaxis. Cannabis allergy can significantly impact quality of life, manifesting severe and generalized symptoms.
Cross-reactivity
An increasing number of reports describe mild to severe plant-derived food allergies associated with cannabis allergy, a phenomenon called the cannabis-fruit/vegetable syndrome, mainly attributed to sensitization to Can s 3, a nonspecific lipid transfer protein (nsLTP) from C. sativa. Of note, nsLTPs sensitization can occur as a result of in vitro cross-reactivity to Can s 3 from taxonomically related or more distant sources without any previous Cannabis contact.
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