Cbd oil benefits for hashimoto& 39

CBD for Thyroid Health – June 2022

Why Some People Are Using CBD for Thyroid Disorders

Although the studies on cannabinoids and thyroid are limited, so far, findings suggest that CBD (cannabidiol) may be be neficial for promoting healthy thyroid conditions (5 )

In a 2015 study published in BioMed Research , researchers examined the role of th e endocannabinoid system and the significance of cannabinoid receptors (CB1 receptor and CB2 receptor) in human malignant and benign thyroid lesions (6 ) .

The results supported evidence that both receptors interfere with molecular pathways and influence the formation of thyroid tumors. Thus, these receptors could be considered as potential therapeutic targets to inhibit tumor progression.

While it is not clear how CBD’s influence on cannabinoid receptors may affect conditions like hypothyroidism or hyperthyroidism, the presence of these receptors and their impact on thyroid health and function suggest CBD may possibly have therapeutic applications (7 ) .

Evidence from other research also suggests that CBD and other cannabinoids can be useful in managing symptoms commonly linked to thyroid disorders, such as pain, depression, dry skin, inflammation, and anxiety.

Researchers of a study published in the Journal of Experimental Medicine indicated that the administration of CBD and its modified derivatives significantly suppressed chronic inflammatory and neuropathic pain in rodents (8 ) .

A study published in Neurotherapeutics in 2015 examined CBD as a potential treatment for anxiety disorders (9 ) .

In a 2018 review of existing studies published in Frontiers in Immunology, the authors concluded that CBD has anti-stress effects, which may reduce depression related to stress (10 ) .

The authors of a 2019 study published in Clinical Therapeutics found that the topical administration of CBD ointment improved the quality of life in individuals with skin disorders, especially those that are linked to inflammation (11 ) .

How CBD Oil Works to Help Support Thyroid Health

The endocrine system is a series of glands in the body that produce and secrete hormones for a wide range of functions .

These hormones control many different body processes, including respiration, metabolism, reproduction, sensory perception, growth, and movement (12 ) .

Research published by the Polish Society of Endocrinology in 2018 suggests interrelations between the endocannabinoid system (ECS) and the activity of the endocrine system (13 ) .

The ECS, a communication network vital to overall well-being and health, is responsible for regulating balance in many bodily functions, including thyroid function.

To understand how CBD works to help with thyroid health, it is essential that one understands how the ECS works.

The therapeutic effects of cannabinoids, such as CBD, are realized by their interaction with the body’s ECS and its specialized cannabinoid receptors.

Scientists in a study published in the European Journal of Endocrinology found that there are functional CB1 receptors on the thyroid of animal models. These CB1 receptors modulate the release of thyroid hormones triiodothyronine (T3) and thyroxine (T4) (14 ) .

Each type of thyroid hormone plays an important role in the regulation of body weight, energy levels, internal temperature, skin, hair, and nail growth (15 ) .

Cannabinoid receptors have also been found within the hypothalamic paraventricular nucleus (PVN). The PVN is an area of the brain that sends signals to the pituitary gland nearby that then releases different types of stimulating hormones that travel in the bloodstream to organs such as the thyroid, gonads, and adrenal glands regulating these organs’ activities (16 ) .

Meanwhile, CBD acts indirectly against cannabinoid agonists, which are substances that bind to a receptor and cause the same action as the substances that typically attach to the receptor.

CBD also interacts with several other receptors in the body, such as the 5-HT1A receptor, which is linked to serotonin, a neurotransmitter found to be a contributor to feelings of well-being. It is through this interaction that these cannabinoids promote healing and balance (17 ) .

The Pros and Cons of CBD Oil for Thyroid Health

  • Studies mentioned previously demonstrate CBD’s therapeutic benefits in helping alleviate symptoms of thyroid disorders, such as pain, depression, dry skin, inflammation, and anxiety.
  • CBD is non-addictive, says Nora Volkow, director of the National Institute on Drug Abuse (NIDA) in a 2015 article (26). This characteristic makes CBD safe for daily intake (18 ) .
  • CBD “is generally well tolerated with a good safety profile,” as the World Health Organization (WHO) stated in a critical review (19 ) . may be purchased without a prescription in locations where they are legally available.
The Cons
  • Studies are too limited to determine whether or not CBD is an effective treatment for conditions other than the ones approved by the U.S. Food and Drug Administration (FDA).
  • As with the use of any natural chemical compound, there are risks involved in using CBD. According to the Mayo Clinic, poss ible side effects i nclude drowsiness, dry mouth, diarrhea, fatigue, and reduced appetite (20 ) .
  • CBD has been shown to interact with other drugs and alter how the body metabolizes certain medications, as a 2017 research revealed (21 ) . Consult with a doctor experienced in cannabis use before starting a CBD regimen or combining it with current prescription thyroid medications.
  • Dr. Doris Trauner, professor of neurosciences and pediatrics at the University of California San Diego School of M edicine and a physician at San Diego’s Rady Children’s Hospital, cautions that CBD products marketed online and in dispensaries are mostly unregulated (22 ) .

The lack of regulation makes it difficult to determine whether the CBD gummies , tinctures, patches, balms, and gelcaps contain what the product label claims.

A 2107 review published in the Journal of the American Medical Association revealed labeling inaccuracies among CBD products. S ome products had less CBD than stated, while others had more (23 ) .

How CBD Oil Compares to Alternative Treatments for Thyroid Disorders

According to the American Thyroid Association (ATA), people with thyroid disease choose complementary and alternative medicine (CAM) to help them cope with the side effects of medication and treatments, including dry mouth, fatigue, weight gain, and mental fogginess.

People with thyroid disorders also use CAM to ease the stress and anxiety of medication and treatments or worries about having a lifelong diagnosis (24 ) .

  • Physical activities like exercise improve the ability to sleep , which in turn reduces stress, says the Anxiety and Depression Association of America (ADAA) (25 ) . The ATA, meanwhile, suggests Pilates, yoga, and massage reduce stress (26 ) .
  • Improve overall immunity to fight environmental toxins. Maintaining a diet that includes plenty of vegetables and fruits, as well as taking steps to avoid infection, such as frequent washing of hands and cooking meats thoroughly, also helps strengthen immunity.
  • Consume more anti-inflammatory foods like berries, fatty fish, broccoli, avocados, turmeric, and olive oil. Many of the causes of thyroid conditions are associated with autoimmunity and inflammation.
    • A 2019 research in The Permanente Journal suggests that CBD helps with anxiety and sleep problems (27 ) .
    • Published in Frontiers in Immunology, a 2017 study showed that phytocannabinoids deeply influence the immune functions of the body (28 ) .
    • Data from a 2018 study demonstrated CBD’s anti-inflammatory property (29 ) . The results of the said review, which focused on pain and inflammation treatment, were published in Molecules .

    How to Choose the Right CBD for Thyroid Health

    Studies cited previously show that CBD is not the only cannabinoid found in cannabis that can help promote thyroid health. Hence, when choosing a CBD product, opt for one that contains full-spectrum CBD oil.

    Full-spectrum CBD oil contains all phytonutrients from hemp, including trace amounts of THC, terpenes, flavonoids, amino acids, and essential oils. These compounds work together to intensify the therapeutic benefits of each cannabinoid, resulting in the “entourage effect”.

    Those with allergies to THC may opt to use broad-spectrum CBD oil, which is like full-spectrum CBD but without the THC that makes the user high.

    However, regardless of the form of CBD product of choice, careful consideration must still be employed in selecting the best CBD oil to help with the immune system , inflammation, pain, and anxiety.

        1. Research on the exact legal stipulations applicable to CBD in the area where it would be bought and used.
        2. Purchase only high-quality CBD products from legitimate and reliable brands. The majority of companies that manufacture the best CBD oil products grow their hemp from their own farm, or they purchase from licensed hemp producers.
        3. Research product reviews before buying from an online store. When purchasing from a physical store or dispensary, check whether the store is authorized by the government to sell CBD.
        4. One important thing to look for in CBD products is certification codes. Several certification authorities approve certain products only after some thorough screening tests.
        5. Compare company claims about their products’ potency with that of the third-party lab reports. Look for a certificate of analysis for every product purchased.
        6. Consulting with a trusted medical professional experienced in CBD use is ideal before one purchases his or her first bottle of CBD.

      CBD Dosage for Thyroid Health

      There is no recommended CBD dosage specific for thyroid disorders or any other diseases.

      According to an article written by Peter Grinspoon, MD, on Harvard Health in August 2019, experts do not know the most effective therapeutic dose of CBD for any particular medical condition (30 ) .

      Without sufficient high-quality evidence in human studies, effective doses cannot be determined. Also, Grinspoon says given that CBD is currently mostly available as an unregulated supplement, it is difficult to know what the consumers are getting.

      Grinspoon’s advice to those looking to try and purchase CBD products is to talk with their doctor to make sure that taking CBD would not cause adverse interactions with other medications that are currently taken.

      In a 2017 study , researchers said that chronic CBD use and large doses of up to 1500 mg a day had been repeatedly shown to be well tolerated by humans (31 ) .

      While CBD is considered generally safe, as the 2011 review in the Current Drug Safety Journal suggests, the long-term effects are yet to be examined further (32 ) .

      How to Take CBD Oil for Thyroid Health

      There are different ways to take CBD oil to manage symptoms commonly associated with thyroid disorders, such as pain, depression, anxiety, dry skin, and inflammation.

      The delivery method an individual chooses for taking CBD depends on one’s preference and lifestyle.

      CBD oil capsules and edibles, such as brownies, gummies, and lozenges, are a convenient and straightforward way to take CBD oil, especially for beginners.

      This format is easy to work into a routine, and the dose is consistent. Depending on the metabolism of an individual, the effects can last between 6 and 12 hours. Thus, one dose is probably all that is needed during the day.

      CBD oil tinctures or drops are a practical option for those who seek fast results and maximum dosage control.

      Tinctures and drops may be administered sublingually (under the tongue), through which the CBD oil is absorbed directly into the bloodstream.

      Place the desired quantity of drops under the tongue using a dropper, and then let the CBD oil stay in place for at least 60 seconds. Once 60 seconds have passed, swallow the CBD oil.

      Sublingual application allows for results to be experienced within 30 to 60 minutes after its use, and the effects can be felt for 4 to 6 hours.

      In a 2010 review, published in the International Journal of Pharmacy and Pharmaceutical Sciences , researchers found that peak blood levels of most substances given sublingually are achieved in 10 to 15 minutes, which is faster than when those same drugs are ingested orally (33 ) .

      Topicals, like CBD creams, lotions, and patches may be applied to a target area on the skin to address dryness and other skin problems.

      Look for keywords on the product labels that indicate that the product uses nano technology , encapsulation, or micellization of CBD. These words indicate that their solution can carry CBD through the dermal layers, rather than just staying on the surface of the skin.

      Vaping CBD is also a preferred method for some people. However, vaping may cause lung problems (34 ) . Thus, smoking medical cannabis or medical marijuana may not be an option for others.

      The Thyroid and Its Functions

      The thyroid is the small butterfly-shaped gland found near the throat. The thyroid gland releases thyroid hormones, like thyroxine (T4) and , triiodothyronine (T3) that regulate the way the body uses energy.

      The thyroid plays an essential role in regulating body weight, body temperature, muscle strength, and even mood (35 ) .

      The thyroid also controls metabolism and impacts the nervous system, digestive tract, cardiovascular system, appetite, hair, skin, and nail growth.

      In addition, thyroid activity influences heart rate, muscle functions, and brain development, particularly during infancy.

      Thyroid Disorders

      The thyroid is sensitive to deficiencies in nutrients like iodine, zinc, and selenium, as well as specific environmental contaminants, which can cause it to over function or under function (36 ) .

      Also, the immune system can start attacking the thyroid gland, resulting in autoimmune thyroid conditions, such as Hashimoto’s thyroiditis and Graves’ disease.

          • Thyroid nodules, which are small lumps that may cause excessive hormone production
          • Hyperthyroidism-excess thyroid hormone production
          • Hypothyroidism-low levels of thyroid hormone production
          • Goiter, which is a swelling of the thyroid
          • Thyroid storm, which is a rare type of hyperthyroidism
          • Thyroid cancer

          When thyroid hormone release is too much or too little, the results can be damaging to organ functions and can impact one’s health and well-being.

          It can be challenging to detect and identify a specific disorder as thyroid conditions can cause several problems related to bodily functions.

          However, specific tests are available to check for thyroid imbalances. These procedures include biopsies and imaging scans, such as ultrasound and iodine scans. Blood tests that check for healthy levels of T3, T4, and thyroid-stimulating hormone (TSH) can also assess thyroid imbalances.

          A TSH is a blood test that measures the amount of thyroxine (T4) that the thyroid is being signaled to make.

          Graves’ Disease (Hyperthyroidism)

          Graves’ disease is named after Dr. Robert J. Graves, who first described it in a patient in 1835.

          Graves’ disease is a form of autoimmune thyroid disease that causes hyperthyroidism, which is a condition when the thyroid gland generates too much thyroid hormones. Graves’ disease is usually the underlying cause of hyperthyroidism.

          Typical symptoms of this thyroid disorder include goiter, fast and irregular heartbeat, diarrhea, irritability or nervousness, muscle weakness or tiredness, trembling hands, trouble sleeping, and weight loss (38 ) .

          Hashimoto’s Thyroiditis (Hypothyroidism)

          Also known as chronic lymphocytic thyroiditis or Hashimoto thyroiditis, Hashimoto’s disease is a common cause of hypothyroid symptoms. Most patients are middle-aged women, although the disease can affect anyone at any age (39 ) .

          This autoimmune thyroid disorder, which was first described by the Japanese physician Hakaru Hashimoto in 1912 , triggers the immune system to attack and reduce thyroid function, impeding its hormone production.

          As symptoms are mild, one may not be able to recognize that he or she has this disease. These symptoms include constipation, dry skin, fatigue, intolerance to cold temperatures, irregular menstrual cycles, weight gain, hair loss, changes in body temperature, and muscle aches, tenderness, and stiffness (40 ) .

          Levothyroxine is a thyroid hormone used to treat hypothyroidism. It is also used with radioactive iodine therapy and surgery to treat thyroid cancer (41 ) .

          Levothyroxine works by replacing thyroid hormones usually produced by the body.

          Without thyroid hormones, the body cannot function properly, which may result in slow growth, slow speech, lack of energy, thick skin, increased sensitivity to cold, muscle and joint pain, eye problems, and depression, among other problems.

          When taken correctly, levothyroxine reverses these symptoms and eventually treats underactive thyroid issues (42 ) .

          The Thyroid Antibodies Test

          A thyroid antibody test is used to diagnose autoimmune disorders of the thyroid. This test measures the level of thyroid antibodies in the blood (43 ) .

          A doctor who suspects that an individual has symptoms of a thyroid problem, which may be caused by Hashimoto disease or Grave’s disease, may recommend this test.

          Conclusion

          Due to its properties, C BD (cannabidiol) allows individuals an alternative option for treating symptoms of various conditions, including thyroid disorders.

          A properly adjusted dose of thyroid hormone is essential in dealing with hypothyroidism (underactive thyroid) or hyperthyroidism (overactive thyroid). Adequate nutrition and a healthy lifestyle can lead to a reduction in symptoms.

          CBD oil may also help treat these symptoms and assist the body in regulating its functions. However, CBD for thyroid conditions is an area that still necessitates more research.

          A consultation with a doctor is excellent advice to those interested in trying CBD. Making changes to one’s health care regimen without the supervision of a trusted medical professional is not recommended. Doctors also have to be informed if one is already tak ing thyroid medication or a ny other prescription medications.

          Therapeutic Cannabis and Endocannabinoid Signaling System Modulator Use in Otolaryngology Patients

          1 Thomas Jefferson Hospital–Otolaryngology Head & Neck Surgery, Philadelphia, Pennsylvania, U.S.A.

          Kelly E. Daniels

          1 Thomas Jefferson Hospital–Otolaryngology Head & Neck Surgery, Philadelphia, Pennsylvania, U.S.A.

          David M. Cognetti

          1 Thomas Jefferson Hospital–Otolaryngology Head & Neck Surgery, Philadelphia, Pennsylvania, U.S.A.

          Patrick Tassone

          1 Thomas Jefferson Hospital–Otolaryngology Head & Neck Surgery, Philadelphia, Pennsylvania, U.S.A.

          Adam J. Luginbuhl

          1 Thomas Jefferson Hospital–Otolaryngology Head & Neck Surgery, Philadelphia, Pennsylvania, U.S.A.

          Joseph M. Curry

          1 Thomas Jefferson Hospital–Otolaryngology Head & Neck Surgery, Philadelphia, Pennsylvania, U.S.A.

          * Send correspondence to Lucas M Bryant, MD, Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson Hospital, 925 Chestnut St, Fl6, Philadelphia, PA 19107. Email: [email protected]

          Copyright © 2018 The Authors Laryngoscope Investigative Otolaryngology published by Wiley Periodicals, Inc. on behalf of The Triological Society

          This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

          Abstract

          Objectives

          1) review benefits and risks of cannabis use, with emphasis on otolaryngic disease processes; 2) define and review the endocannabinoid signaling system (ESS); and 3) review state and federal regulations for the use and research of cannabis and ESS modulators.

          Methods

          This manuscript is a review of the current literature relevant to the stated objectives.

          Results

          Cannabis (marijuana) use is increasing. It is the most widely used illicit substance in the world. There is increasing interest in its therapeutic potential due to changing perceptions, new research, and legislation changes controlling its use. The legal classification of cannabis is complicated due to varied and conflicting state and federal laws. There are currently two synthetic cannabinoid drugs that are FDA approved. Current indications for use include chemotherapy‐related nausea and vomiting, cachexia, and appetite loss. Research has demonstrated potential benefit for use in many other pathologies including pain, inflammatory states, and malignancy. Data exists demonstrating potential antineoplastic benefit in oral, thyroid, and skin cancers.

          Conclusions

          ESS modulators may play both a causal and therapeutic role in several disorders seen in otolaryngology patients. The use of cannabis and cannabinoids is not without risk. There is a need for further research to better understand both the adverse and therapeutic effects of cannabis use. With increasing rates of consumption, elevated public awareness, and rapidly changing legislation, it is helpful for the otolaryngologist to be aware of both the adverse manifestations of use and the potential therapeutic benefits when talking with patients.

          INTRODUCTION

          The purpose of this review is to provide the practicing otolaryngologist with a foundational knowledge of current therapeutic uses of cannabinoids and effectors of the endocannabinoid signaling system (ECS). It includes a brief overview of the biochemical principles guiding the physiologic effects of the ECS, addresses the risks and adverse effects of cannabis use, and finally reviews current state and federal legislation.

          Cannabis (marijuana) use is increasing and is currently the most widely used illicit substance both worldwide and within the United States. 1 Cannabis has been used for centuries as a treatment for myriad medical ailments. It has shown potential to be of therapeutic use in several pathologies including nausea, pain, weight/appetite loss, inflammation, anxiety, multiple sclerosis‐related muscle spasticity, neuropathy, seizure, and even cancer. 2 , 3 , 4 , 5 , 6 , 7 , 8 There has been a recent resurgence of interest in its therapeutic potential, which is likely due to a combination of changing societal perceptions, new scientific discoveries, and recent legislation measures relating to its regulation. The legal classification of cannabis is complicated due to conflicting legislation of the state and federal governments. At present, the federal government still classifies marijuana as a schedule I controlled substance and does not approve it for any medical uses. At the state level, 29 states and the District of Columbia have legalized comprehensive medical marijuana and cannabis programs, while an additional 17 states have highly regulated medical marijuana programs legalizing its use in more limited medical situations. This means that for patients in a majority of states, medical marijuana is increasingly becoming an accessible and entirely novel option for management of their ailments. The current increase in use for medical purposes appears to be commensurate with recent changes in state and federal legislative policies as well as international studies demonstrating a biochemical basis for the therapeutic effects seen with cannabis use. As the use of marijuana and other complementary medicine therapies continues to rise, patients may expect their physicians to explain both the potential merits and harms they may experience with its use.

          Unlike many other bioceutical therapies which may be used by the otolaryngology patient, marijuana poses additional challenges due it its current federal classification as a schedule I substance. As scientific evidence of its therapeutic benefit advances, it is vital that physicians are well informed in order to confidently provide sound guidance when questioned by patients. Additionally, the physician must be kept abreast of the current regulatory status in order to ensure they keep their practice within the rapidly changing legal boundaries of both state and federal legislation.

          CANNABIS CLASSIFICATION AND BIOLOGY

          Marijuana is derived from plants in the Cannabis family. There are two main species: Cannabis sativa and Cannabis indica. Hemp is a nonpsychoactive cannabis plant product that is used in beauty creams, rope, clothing and other domestic goods. There are hundreds of marijuana “chemotypes” derived from the foundational sativa and indica strains. Each strain is designed with a goal of modulating the relative concentrations of certain biologically active molecules, called phytocannabinoids. Customized variations in phytocannabinoid levels subsequently provide the user with a customized sensory experience (in the case of recreational use) or therapeutic effect (medicinal use).

          Although there are many biologically active phytocannabinoids in cannabis, two predominate in the current literature. In 1964, Gaoni and Mechoulam described the psychoactive cannabinoids found in Cannabis sativa: Δ8‐tetrahydrocannabinol (Δ8‐THC) and Δ9‐tetrahydrocannabinol (Δ9‐THC). 9 Δ9‐THC is more potent and found in higher concentrations within the plant. It is the primary cannabinoid referred to when “THC” is referenced in this paper. THC is metabolized within the lungs and liver into 11‐hydroxy‐Δ9‐THC which is active within the CNS and elsewhere. 10 Jean‐Baptiste Lamarck described Cannabis indica as a second strain of cannabis in 1785. Cannabis indica is clinically distinct from Cannabis sativa due to the higher relative concentration of cannabidiol (CBD), another phytocannabinoid.

          THC is most commonly associated with the euphoric feelings users experience due to its psychoactive effects. In addition to a sense of euphoria, it also appears to possess anti‐emetic, anti‐inflammatory, analgesic, and antioxidant properties. 11 In contrast to THC, CBD has traditionally been viewed as a nonpsychoactive cannabinoid. CBD is credited for offering users analgesic, anticonvulsant, anxiolytic, antipsychotic, and sedative effects. 11 , 12 , 13 , 14 The anxiolytic and antipsychotic effects have been purported to participate in decreasing these adverse effects seen with THC use. This observation is one reason some proponents argue for extracts instead of synthetic cannabinoids which could ultimately cause more adverse effects through loss of this natural synergistic relationship between phytocannabinoids. When derived from hemp, and absent of THC, CBD containing products are not under federal regulation.

          METHODS OF CONSUMPTION

          There are several methods commonly used in cannabis consumption. The most traditional method of cannabis consumption is unfiltered smoking. This results in the user inhaling the combustion products in cannabis smoke. Smoking cannabis allows for rapid onset of effects (2–10 minutes), short duration of action, and ease of titratability. 8 , 15 It is important to note that smoking is the primary delivery method used in nearly all studies assessing the risks of cannabis use. Cannabis is typically smoked in an unfiltered manner and the smoke itself may reach temperatures as high as 700°C. The combustion process results in partial breakdown of cannabinoids with simultaneous production of undesirable carcinogens. 16 , 17 Marijuana smoke has a similar carcinogen profile as tobacco smoke, but may have higher relative concentrations of certain carcinogens. 18 , 19

          Another method of cannabis use is enteral consumption. Although this method avoids the carcinogen exposure of smoked cannabis, it has several downfalls. The onset of action and maximum effect is significantly more delayed (1–6 hrs) than smoking, therapeutic effects are less easily titratable secondary to inconsistent bioavailability (6–20%), and the duration of action is prolonged (20–30 hours). 8

          Recently, vaporization has gained popularity as a method of cannabis consumption. Vaporization is a process by which a material is heated to temperatures that allow for vaporization of phytocannabinoids (170–300°C). Vaporization retains the desirable pharmacokinetic profile of smoked marijuana while preventing the creation of harmful carcinogens by avoiding combustion. 15 , 20 , 21 , 22 Although vaporization appears to be a promising delivery method, it is not well studied and vaporization units are not FDA regulated, subjecting users to potential untoward exposure to heat mediated degradation products of plastics or heavy metals within the vaporizer unit. 23 , 24

          ENCANNABINOID SIGNALING SYSTEM

          The endocannabinoid signaling system (ESS) is complex and promiscuous. In vivo, it acts as a short‐range, short‐term response system to acute physiologic events. 25 The ESS can be thought of as an “on demand” system, where endocannabinoids are synthesized locally in response to acute local stimuli. It is composed of ligands (cannabinoids), cell surface receptors, and several intracellular signaling pathways that induce enzymatic reactions. These enzymatic reactions may either agonize or attenuate cellular function. 25 Stimulation of the ESS can induce myriad effects, which are discussed elsewhere in this paper. Ligands of the ESS can be autogenous molecules (endocannabinoids), plant derivatives (phytocannabinoids), or synthetic cannabinoids. Phytocannabinoids, synthetic cannabinoids, and ESS modulating drugs exert their effects within the body through manipulation of normal ESS physiology. 10

          Endocannabinoids are biologic molecules made within the body that act on known cannabinoid receptors. In 1992, the first endocannabinoid, anandamide (AEA), was described. 25 , 26 Since then, several other arachidonic acid‐derived endocannabinoids have been described, including 2‐arachidonylglycerylether (2‐AG), O‐arachidonoyl‐ethanolamine (virohdamine), and N‐arachydonoyl dopamine (NADA). In general, endocannabinoids act in a paracrine fashion by binding to appropriate cell surface receptors that express appropriate cannabinoid‐sensitive receptors. 27 , 28 , 29 After internalization, endocannabinoids are metabolized by various degradatory enzymes including FAAH, DAGL, and MAGL (fatty acid amine hydrolase, diacyl glycerol lipase, monoacyl glycerol lipase) (Table ​ (Table1 1 ). 30 , 31

          Table 1

          Select Endocannabinoids by Common and Chemical Name.

          Anandamide/AEA N‐arachidonoyl‐ethanolamine
          NADA N‐arachidonoyl‐dopamine
          2‐AG 2‐arachidonoyl glycerol
          Noladin ether 2‐arachidonyl glyceryl ether
          Virodhamine O‐arachidonoyl‐ethanolamine

          There are two primary cannabinoid receptors that have been well described. They were sequentially named cannabinoid receptor 1 and 2 (CB1, CB2) based on timing of discovery. CB1 was discovered and described in the late 1980s and early 1990s using a rat model. CB2 was subsequently described in 1993 in a study using human cell cultures. 26 , 32 , 33 Both CB1 and CB2 are G‐protein coupled receptors (GPCRs), and each of them has been shown to function in unique physiologic pathways, in part due to their distinct sites of expression. 34 , 35 , 36 , 37 , 38 Apart from CB1 and CB2, transient receptor potential vanilloid type 1 (TRPV1), a lipid responsive ion channel, has also demonstrated some cannabinoid binding affinity. 39 Of note, CBD has a relatively weak affinity for both CB1 and CB2, which may explain the apparent antagonistic effect it has been reported to have when used with other CB receptor agonists. 25 , 40

          CB1 is predominantly found within the brain and other central nervous system structures but is also expressed in other locations including the spleen, eye, and reproductive organs (Fig. ​ (Fig.1). 1 ). Upon receptor activation, CB1 acts through a variety of intracellular mechanisms. It inhibits adenylate cyclase, resulting in decreased levels of cyclic adenosine monophosphate (cAMP). CB1 also activates mitogen‐activated protein kinase (MAPK), extracellular signal‐related kinase (ERK), and phosphatidylinositol‐3 kinase (PI3K) signaling pathways, among others. 6 , 19 , 34 , 41 , 42 CB1 is able to couple with any class of receptor‐activated G‐proteins, including Gs,Gi, and Gq, each of which initiates its own set of unique signaling mechanisms. CB1‘s diversity in effector mechanisms is further broadened by the receptor’s ability to form heterodimers with other receptors. The distinct combination of g‐protein pairing and heterodimerization of any one CB1 receptor creates a nuanced structural conformation, which influences its affinity for specific ligands. Through structural modulation and diverse binding interactions, CB1 exerts broad and complex downstream effects. 43

          CB1 and CB2 are membrane bound GPCRs. CB1 receptors (left) are found predominantly in the brain and in tissues of the central nervous system. It is expressed to a lesser degree in the spleen, eye, and reproductive organs. Upon activation, CB1 activates MAPK, ERK, and PI3K pathways, while inhibiting AC and decreasing cellular cAMP. CB2 receptors (right) are found in immune tissues, predominantly B cells and natural killer cells, with additional expression in T cells and neutrophils. Upon activation, CB2 activates MAPK and PI3K pathways while decreasing the generation of ROS.

          Unlike CB1, CB2 appears to predominate peripherally within immune regulatory tissues. CB2 expression appears to be highest in B cells and natural killer (NK) cells but is also found in T cells and polymorphonuclear (PMN, neutrophils). 44 CB2 acts to help regulate inflammatory responses. Similar to CB1, CB2 induces many of its physiologic effects through MAPK and PI‐3K signaling pathways. 45 , 46 Unlike CB1, which may promote a proinflammatory response, CB2 signaling appears to decrease reactive oxygen species (ROS). 47

          OTOLARYNGIC AND GENERAL MANIFESTATIONS OF CANNABIS USE

          As with other aspects of marijuana, there is conflicting data regarding the risks associated with cannabis and cannabinoid use. In general, adverse effects can be separated into those seen with acute or chronic use, and those seen with extremely high (intoxication) doses. These effects are summarized in Tables ​ Tables2 2 and ​ and3. 3 . Most purported adverse effects of marijuana use appear to present in a dose‐dependent manner, regardless of age. 48

          Table 2

          Overview of Adverse Effects of Cannabis Use.

          Acute 48 Chronic Intoxication
          Tachycardia, bronchodilation, conjunctival irritation, decreased intraocular pressure 48 Dependence Anxiety
          Impaired judgment Respiratory tract inflammation (smoked) Psychosis, paranoia, mania
          Impaired short‐term memory Correlation with mental illness incl. depression & schizophrenia a Hallucinations
          Increased appetite Cognitive impairment
          Driving impairment Depression
          Paranoia

          Table 3

          ENT‐Specific Adverse and Therapeutic Effects Associated With Cannabinoid Use. a

          Associated Increased Risk Associated Decreased Risk
          Allergic reaction (type I hypersensitivity) Tongue cancer
          HPV‐related oropharyngeal cancer Other oropharyngeal cancers
          Cough, increased sputum production Decreased intraocular pressure
          Fungal sinusitis (Aspergillus) Potential antineoplastic effects in skin cancer (melanoma, basal cell, squamous cell)
          Inflammation of respiratory mucosa (rhinitis, stomatitis, uvulitis, pharyngitis, bronchitis) Potential antineoplastic effects in thyroid cancer (anaplastic)
          Peridontal disease, dental caries
          Stomatitis, xerostomia

          a Most data of adverse effects relates to smoked marijuana use and may not apply for other delivery methods.

          Acute physiologic effects of cannabis use include tachycardia, bronchodilation, conjunctival irritation, and decreased intraocular pressure. 49 Although previous data appears to support marijuana use having a negative effect on neural development when used in young people, a recent prospective study conducted in the UK demonstrated this tendency might be negated in moderate users when other factors such as tobacco and alcohol use are accounted for. 48 , 50 , 51 , 52 There is data supporting a correlation with mental illness, including schizophrenia, and heavy use. 50 The association between marijuana use and mental illness has not been shown to be causative. Marijuana may induce earlier or stronger psychotic events in individuals with a preexisting disposition toward mental illness. 3

          Driving impairment remains a concern in patients under the influence of marijuana. In contrast to alcohol intoxication, cannabis intoxication levels and risk of driving impairment are not as predictable due to wider levels of tolerance between users. 53 Cannabis intoxication does not appear to impair drivers to the same extent as alcohol, but has been shown to function synergistically when individuals are intoxicated by both. 53 , 54 This association with increased motor vehicle accidents extends to other sources of trauma as well. Gerberich et al. found that cannabis use to increase hospital admission rates for all causes of injury. 55

          Chronic effects of marijuana use include respiratory tract inflammation (primarily if smoked), dependence, depressive symptoms, and failure to achieve academically and professionally. Although less addictive than many other illicit substances, marijuana does carry a risk of dependence, with approximately 1 in 10 users demonstrating some level of dependence. 3 , 48 , 56 Marijuana does not appear to increase the rate of birth defects when used during pregnancy, but may be associated with decreased birth weight, preterm labor, and increased rate of admission to a neonatal intensive care unit after birth. 57 Finally, although the mortality risk of marijuana use remains unclear, it has also been associated with an increased risk of cardiac events and stroke. 48 , 58 , 59

          Despite the apparently similar carcinogenic profile between marijuana and tobacco smoke, current data does not clearly support marijuana smoking as a clear risk factor for lung cancer. 60 , 61 , 62 , 63 , 64 Studies assessing marijuana use and risk of head and neck cancers are also mixed and data is weakened by confounding factors (namely tobacco), low power, and exposure to recall bias due to their retrospective nature. 61 , 62 , 64 , 65 , 66 , 67 Some data shows marijuana use to be potentially protective against tongue cancers (OR 0.47, 95% CI 0.29–0.75) and other oropharyngeal cancers, while concomitantly serving as an independent risk factor for human papilloma virus (HPV)–positive oral tumors. 68 , 69 Gillison et al reported the possibility that the increased risk of HPV positive cancers seen in marijuana smokers may be due to certain immunomodulatory effects of cannabis. By inducing a shift from Th1 to TH2 immune responses, cannabinoids may decrease resistance to intracellular bacterial and viral infection. Once infected, the host would also suffer from attenuation of normal physiologic clearing of viral infection. This would ultimately result in more virulent HPV infections and increased rates of HPV‐positive cancer. 68 There are no clinical studies assessing cancer risk in users via oral ingestion or vaporization.

          Although a correlation between cannabis smoking and lung cancer is non‐definitive, there is data that demonstrates cannabis smoke as a mucosal irritant and source of oxidative stress to respiratory epithelium. 70 There are also reports of increased incidence of fungal sinusitis; possibly due to Aspergillus contaminant of the smoked plant. 71 , 72 Although rare, allergic reactions to marijuana have also been reported. These reactions range from type I hypersensitivity (rhinoconjunctivitis) to anaphylaxis. 73 There is also evidence that marijuana users experience increased rates of periodontal disease and dental carries. 74 Data also correlates marijuana smoking with respiratory mucosa inflammation, stomatitis, uvulitis, cough, and increased sputum production. 19 , 75 Fortunately, these acute respiratory inflammatory responses to smoked marijuana tend to subside soon after cessation of smoking. 76

          CURRENT CANNABINOID‐BASED THERAPIES

          At the time of this writing, there are no FDA approved uses for cannabis. There are currently two synthetic THC formulations available within the United States, dronabinol (Marinol) and nabilone (Cesamet). Dronabinol is a schedule III cannabinoid and nabilone is a schedule II cannabinoid. Nabiximols (Sativex) is a liquid cannabis extract composed of THC and CBD. It is used as an oral spray and is approved for use in several European countries, but not currently within the United States. Indications for both dronabinol and nabilone include the treatment of recalcitrant nausea and vomiting following chemotherapy in cancer patients. Dronabinol is also approved as an appetite stimulant in diseases such as AIDS which result in severe weight loss. 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 (Table ​ (Table4 4 )

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