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10 Things I Wish My Endocrinologist Would Have Told Me

When I first started experiencing symptoms (before my Hashimoto’s diagnosis), and before I had started thinking that they could be related to my thyroid, I faced a lot of challenges in getting the adequate diagnosis and treatment for my condition.

I spent almost a decade undiagnosed because I only had my TSH levels tested. I had been told that my thyroid was normal, even though my TSH was 4.5 μIU/mL.

I continued experiencing a worsening of my symptoms (along with some new ones!). However, it wasn’t until my TSH levels had skyrocketed to 8 μIU/mL (back then, 0.4-4.0 μIU/mL was considered the “normal” TSH reference range), that my doctor referred me to an endocrine specialist.

I was eventually diagnosed with Hashimoto’s, but didn’t feel like I had a good understanding of what was really going on with my thyroid. I was trained as a pharmacist, and conventional medicine’s go-to for addressing thyroid conditions is primarily focused on prescribing thyroid medications. Endocrinologists are the designated medical experts for thyroid issues. However, most endocrinologists are not taught about the root causes behind the development of Hashimoto’s, or the lifestyle interventions that can help a person feel significantly better.

If you feel like you’re still trying to understand what is going on with your thyroid, or if you’re trying to get a deeper understanding of Hashimoto’s, I’d like to share with you a few things that would have been helpful to know at the beginning of my journey.

In this article, I’ll discuss:

  • The different thyroid medication options available today
  • How gluten and diet choices impact the thyroid
  • Why iodine can exacerbate thyroid disease
  • The connection between the thyroid and mental health
  • Markers of thyroid dysfunction

1. Thyroid Medication Can Help with Symptoms — Even In Early Stages

If you are having symptoms of subclinical hypothyroidism — like fatigue, weight gain, sadness/apathy, hair loss, fertility challenges, cold intolerance, brain fog, and joint pain — it may be helpful to start thyroid hormones, if you haven’t yet been prescribed any.

Hashimoto’s has five progressive stages — subclinical hypothyroidism is the third stage. This is the stage when thyroid labs come back “normal” but the individual is experiencing symptoms such as weight gain, rheumatoid arthritis, chronic fatigue, and gastrointestinal disturbances, among others.

In a lot of cases, the “normal” lab results do not reflect what is actually happening within the body. For example, in the case of subclinical hypothyroidism, while T4 and T3 thyroid hormone levels may be within normal ranges, thyroid antibody levels may be elevated. Antibodies can be elevated for years prior to a proper diagnosis, and can contribute to the symptoms mentioned above.

However, studies have found that starting thyroid hormones can make us feel better and even slow down the progression of the condition. By helping the body produce optimal amounts of thyroid hormones, appropriate medication management can allow us to recover from the effects of hypothyroidism and will give us energy, vitality, and support to continue working on optimizing our health.

T4 (thyroxine) and T3 (triiodothyronine) are the two main thyroid hormones. T4-only medications, such as Synthroid or generic levothyroxine, are the most commonly prescribed thyroid medications. That said, there are different thyroid hormone medications out there, including T3-only and T4/T3 combination options — the type and dosages should be individualized for each person.

For more information, you can download my free eBook, Optimizing Thyroid Medications, to help you get started on finding the right thyroid medication plan for you.

2. You May Need to Try a T3-Containing Medication

As mentioned above, T4 and T3 are the two main thyroid hormones, and T4-only medications are the most commonly prescribed thyroid medications.

While they are generally well tolerated, not every individual with Hashimoto’s is able to convert the T4 from their medication into T3 (the more biologically active thyroid hormone) due to factors such as aging, nutritional deficiencies, liver backlog, and more. As such, taking a T4-only-containing medication may not relieve all of one’s symptoms.

There may be an advantage to taking a T3-containing medication in such cases, and many individuals report feeling better on T4/T3 combination medications.

T3-only medications (such liothyronine, Cytomel, and compounded T3 medications) are typically used as an add-on to T4-only medications.

T4/T3 combination medications (like WP Thyroid, Nature-Throid, Armour Thyroid and compounded combo medications) are another option to consider. These types of medications mimic the ratio of thyroid hormones, T4 and T3, within our body.

You can check out my article reviewing thyroid medications to learn more about the pros and cons of each type of thyroid medication available on the market.

Remember, thyroid medications should be individualized, as different individuals will feel best on different types of medications, so be sure to consult a practitioner to find what may work best for you. (It’s important to note, however, that conventional doctors are not always comfortable with prescribing combination medications due to issues of poor quality control and medication recalls, so you may wish to work with a functional medicine practitioner.)

3. Try Going Gluten Free

Gluten (a hard-to-digest protein found in foods made of wheat, barley or rye) can be a trigger for many individuals, and is the most common food sensitivity found in those with Hashimoto’s.

Gluten can create intestinal permeability, or leaky gut (one of the three factors required for autoimmunity to occur). Intestinal permeability occurs when there are “gaps” within the tight junctions of the intestinal barrier, allowing for digested food molecules, such as gluten, to leak out.

Once gluten “leaks out” and enters the bloodstream, it can lead the body to attack its own thyroid (as the body can confuse the structure of gluten with cellular components found in the thyroid gland), leading to gluten sensitivity.

For some individuals, gluten may be the sole trigger of their autoimmune thyroid disease. Thus, in some cases, we see a complete remission of the condition when an individual goes on a gluten-free diet. In other cases (88 percent of the time), the person feels significantly better and experiences a reduction in symptoms such as bloating, diarrhea, low energy, excess weight, constipation, stomach pain, acid reflux, hair loss, and anxiety.

4. Diet Can Have a Big Impact on Thyroid Health

As mentioned above, a gluten-free diet can be immensely helpful for those with Hashimoto’s whether gluten is the sole trigger of an individual’s Hashimoto’s, or there are other root causes involved. Making further dietary interventions can also be helpful in eliminating one’s thyroid symptoms and reducing thyroid antibodies. Some people have even been able to eliminate their thyroid antibodies through dietary changes alone!

It’s been my experience, and the experience of many of my clients, that along with gluten, eliminating dairy and soy can reduce inflammation and improve Hashimoto’s. In my survey of over 2000 individuals with Hashimoto’s, 57 percent said that they react to dairy, and around 80 percent said they felt better on a dairy-free diet. Similarly, 63 percent of individuals felt better on a soy-free diet.

As such, along with a gluten, dairy, and soy-free diet, other healing diets such as the Paleo or Autoimmune Paleo (AIP) diets, can be immensely beneficial as well, as they eliminate these common foods, help to reduce inflammation, and focus on nutrient-dense foods (helping to prevent nutrient deficiencies). Of the 2000+ individuals in my survey, 75 percent said that they felt better on an AIP diet.

That said, diets are not one-size-fits-all. While there isn’t one diet that works for everyone, I do recommend incorporating foods such as beets and cruciferous vegetables (some do better with cooked vegetables), pasture-raised meats, and probiotic-rich foods (such as kefir). And, as always, be sure to tailor any healing diet to your own needs!

To learn what a thyroid-healing diet entails, I recommend checking out my article on the best diet for Hashimoto’s.

5. You May Have a Selenium Deficiency

A selenium deficiency has been recognized as a nutrition-related trigger of Hashimoto’s.

Selenium is a nutrient that is needed for thyroid function. It’s crucial in our body’s conversion of the inactive thyroid hormone, T4, to the more biologically active thyroid hormone, T3. It also helps balance iodine levels (too much iodine can be harmful to the thyroid — more on that in a minute).

Selenium deficiency is associated with symptoms such as anxiety, low mood, depression, and fatigue, to name a few.

This deficiency is one of the most common nutrient deficiencies that I’ve seen in Hashimoto’s. One of the most common reasons why I see individuals become deficient in this nutrient is because they are on a gluten-free diet. While a gluten-free diet can be incredibly beneficial for the thyroid, it can be lacking in selenium, making an individual on this diet more susceptible to selenium deficiency.

A daily dose of 200 mcg of the selenomethionine form of selenium, has been shown to reduce thyroid antibodies by about 50 percent over the course of three months, in people with Hashimoto’s. Additionally, research has found that selenium supplementation, alongside myo-inositol supplementation, can help the thyroid revert to normal functioning (referred to as an euthyroid state).

In my experience, selenium can help people feel calmer, as well as improve energy levels and promote hair regrowth.

In my survey of over 2000 individuals with Hashimoto’s, 62 percent shared that selenium supplementation (at a dose of 200 mcg/day) helped them feel better. As this dose may be difficult to achieve through diet alone (one would have to consume large amounts of selenium-rich foods to obtain the recommended amount), I recommend a high quality selenium supplement such as Selenium (Selenomethionine) by Pure Encapsulations.

6. Hashimoto’s and Iodine Deficiency-Induced Hypothyroidism Should Be Treated Differently

There is a lot of controversy surrounding iodine in the thyroid world. This nutrient, which is combined with the amino acid tyrosine to make thyroid hormones T3 and T4, is sometimes recommended as the one nutrient that all people with thyroid issues need more of. This is because iodine deficiency can lead to hypothyroidism.

However, medical professionals refer to iodine as a “Goldilocks” nutrient, as the levels have to be just right — low levels of this nutrient are needed for thyroid function, but high levels can be detrimental to thyroid health. In the case of Hashimoto’s, hypothyroidism induced by an iodine deficiency, is rare.

I have found that most people with thyroid disease have excess levels of iodine. Iodine excess may aggravate Hashimoto’s in some cases, leading to anxiety, irritability, brain fog, palpitations, and fatigue, as well as accelerated damage to the thyroid gland.

Iodine needs to be processed by the thyroid gland, and when the thyroid is inflamed, the processing of iodine will likely produce more inflammation. If you give an angry and overwhelmed organ more work to do, you’ll likely see it become even angrier!

A person may feel more energetic when first starting an iodine supplement, but lab tests will reveal that their “new energy” is coming from the destruction of thyroid tissue, which dumps thyroid hormone into the circulation. Reports will show an elevated TSH, elevated thyroid antibodies, and in some cases, low levels of active thyroid hormones.

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This is why I don’t generally recommend iodine supplements to people with Hashimoto’s. I don’t believe that the short-term artificial boost in energy is worth destroying your thyroid gland!

In one study, researchers from the Mayo Clinic in Minnesota tracked the rate of Hashimoto’s thyroiditis in patients from 1935 to 1967. Within two years, the doctors saw an increase in autoimmune thyroid disease caused by iodine fortification in table salt and processed food.

That said, the low doses of iodine (150 mcg–220 mcg) that are found in multivitamins and prenatal vitamins, are generally safe for people with Hashimoto’s. To learn more about dosing iodine for those with Hashimoto’s, check out my article on iodine here.

7. Your Hair Loss Could Be Caused by Low Ferritin

Hair loss is a common symptom in those with Hashimoto’s. Along with selenium, ferritin — a stored form of iron (and an accurate predictor of iron stores) — is a nutrient that is often depleted in Hashimoto’s.

This nutrient is required for the utilization of the thyroid hormone T3 by cells. Thus, if low ferritin leads to an individual not being able to utilize T3 well, the thyroid may slow down its metabolism and conserve resources for more important physiological processes. As hair isn’t high on this priority list, ferritin depletion will then lead to hair loss.

I highly recommend checking ferritin levels for any woman who is experiencing hair loss and/or has Hashimoto’s. Normal ferritin levels for women are between 20 and 200 ng/mL. However, the optimal ferritin level for thyroid function is between 90-110 ng/mL — this is the range that is most conducive to healthy, lustrous hair (and overall well-being).

Most men are not lacking in ferritin (compared to women who are at higher risk of low ferritin due to menstruation).

Regardless of gender, you can check your ferritin levels easily with Ulta Lab Tests.

If you are found to be low in ferritin, I recommend supplementing with OptiFerin-C by Pure Encapsulations at a dose of 1-3 capsules per day, in divided doses, taken with meals.

8. You Are Not Going Crazy!

When patients come in describing mood imbalances or reporting that they feel “crazy,” doctors are often quick to suggest a mood disorder (and often, antidepressants) without investigating thyroid health. If this sounds like something you’ve experienced, please know that the anxiety, depression, irritability, mood swings, and emotional numbness you are feeling, could be related to your thyroid.

Specifically, an increase in thyroid antibodies can contribute to these mood imbalances.

Thyroid antibodies are a marker of autoimmune thyroid disease. They let us know that the immune system is destroying thyroid tissue, which can cause a release of hormones into the bloodstream. This can lead to transient (or temporary) hyperthyroidism, as well as mood-related symptoms such as anxiety and irritability. The transient hyperthyroidism is soon followed by an onset of hypothyroidism, resulting in apathy and depression.

Another reason for low mood and/or anxiety may be due to blood sugar imbalances.

Taking the right thyroid medication for you, considering selenium supplementation if needed (as mentioned earlier in this article), and balancing blood sugar (dips in blood sugar can lead to low mood), can all help with mood regulation. In fact, I recommend focusing on these strategies before considering antidepressants.

For an in-depth explanation of the root cause approach to improving low mood, I recommend reading my articles on anxiety and depression.

9. It’s Important to Monitor Your TPO and TG Antibody Levels

There are two types of thyroid antibodies associated with Hashimoto’s: thyroid peroxidase antibodies (TPO antibodies) and thyroglobulin antibodies (TG antibodies). These are markers of how aggressive the attack is on your thyroid gland, and can be used as a marker to track the progress of your condition (and healing!).

These antibodies can show up as elevated long before other, more commonly tested markers of thyroid health — TSH (optimal range is between 0.5-2 μIU/mL), free T3 (optimal range is 5-7 pmol/L), and free T4 (optimal range is 15-23 pmol/L) — appear as out of range (sometimes as early as 5 to 15 years before a diagnosis is made).

They are often elevated in subclinical hypothyroidism, which is an earlier stage of Hashimoto’s, and are warning signs of thyroid disease (even if TSH comes back “normal” on a lab test). About 80 to 90 percent of people with Hashimoto’s will have either elevated TPO or TG antibodies, or both.

When I underwent a physical exam in 2009, my lab results showed my thyroid antibodies to be at over 2000 IU/mL. After hours of researching and much trial and error, I found some research suggesting methods such as following a gluten-free diet and supplementing with selenium, could reduce antibodies by 20 to 50 percent (I personally found these two methods to help decrease my antibodies).

Antibodies fluctuate in response to triggers and lifestyle habits. As you make changes to your lifestyle and diet (and medications as discussed with your doctor), you should retest your antibodies every three months to see if your lifestyle and/or diet interventions are working.

10. Your Thyroid May Function and Work On Its Own Again in the Future

Most conventional doctors will say that Hashimoto’s, and other thyroid diseases, are irreversible and require one to stay on thyroid medication for the rest of their life.

It is true that some individuals may find that along with addressing their root causes, they function best with thyroid medications, and may opt to use medications long-term to live their best life. However, it is also possible to recover thyroid function.

Research shows that once the autoimmune attack on the thyroid stops, the thyroid gland has the ability to recover function. It has also been shown that thyroid function spontaneously recovers in 20 percent of Hashimoto’s patients (referred to as a euthyroid state).

One case study examined the occurrence of three girls who spontaneously recovered (either partially or fully) from autoimmune hypothyroidism (before starting medications). None of them had excessive levels of iodine or goitrogens during the study investigation. The authors suggested that their recovery may have been due to their elimination of iodine (which can aggravate hypothyroidism and Hashimoto’s), and/or not taking suboptimal medication(s) that may have made them feel worse.

So what does this mean? Addressing the root causes behind the autoimmune attack on the thyroid, can reverse the autoimmunity!

Going gluten free, incorporating selenium, and targeting the root cause(s) behind the development of Hashimoto’s, are some ways to reduce or stop the autoimmune attack on the thyroid. Innovative new therapies like low level laser therapy may also help people improve the function of their thyroid and wean off meds. You can read more about addressing the most common root causes of Hashimoto’s here.

If, at some point in your journey, you are interested in seeing whether you may be able to wean off thyroid medications, there is a test that you can do — the test involves thyrotropin-releasing hormone (or TRH) to be administered by a doctor (this article goes into detail on the full procedure).

The Takeaway

Hashimoto’s is a complex and challenging condition to navigate. Sometimes, despite their best intentions, not every endocrinologist will have a grasp on the set of unique characteristics and root cause factors associated with Hashimoto’s. I wasn’t told many of these things, and had to learn through trial and error.

Sometimes, we need to be Root Cause Rebels and advocate for our own health. That could mean learning the effects of gluten on the thyroid, identifying nutrient deficiencies commonly observed in Hashimoto’s, or looking into the variety of options available for thyroid medications — all of these are immensely helpful in digging deeper into our root cause(s) and addressing them.

There are so many other things that can be helpful as well! The mission behind my first book, Hashimoto’s: The Root Cause, was to spread awareness about lifestyle interventions for Hashimoto’s thyroiditis. Personally, they have made a huge difference in my life, and after addressing all of my root causes, I was able to put my thyroid condition into remission! (Read about my success story here.)

My book Hashimoto’s Protocol builds on this information to deliver guided protocols for finding and addressing your own root causes.

I want to empower patients with knowledge — and also hope — that every person who is diagnosed with Hashimoto’s, will be able to walk into his/her physician’s office to learn about lifestyle interventions that will help them feel like themselves again. We may even get to the point of being able to reverse autoimmunity.

I wish you all the best in your healing journey!

P.S. You can also download a free Thyroid Diet Guide, 10 thyroid-friendly recipes, and the Nutrient Depletions and Digestion chapter. You will also receive occasional updates about new research, resources, giveaways and helpful information.

References

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  21. Carta M, Loviselli A, Hardoy M et al. The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future. BMC Psychiatry. 2004;4(1). doi:10.1186/1471-244x-4-25.
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  25. Wentz I. Top 9 takeaways from 2232 people with Hashimoto’s. Thyroid Pharmacist. https://thyroidpharmacist.com/articles/top-9-takeaways-from-2232-people-with-hashimotos/. Published June 22, 2015. Accessed June 26, 2015.
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  27. Höfling DB Low-level laser in the treatment of patients with hypothyroidism induced by chronic autoimmune thyroiditis: a randomized, placebo-controlled clinical trial. Lasers Med Sci. 2013;28(3):743-53.doi: 10.1007/s10103-012-1129-9.
  28. Carta M, Loviselli A, Hardoy M et al. The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future. BMC Psychiatry. 2004;4(1). doi:10.1186/1471-244x-4-25.
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Note: Originally published in February 2015, this article has been revised and updated for accuracy and thoroughness.

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

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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 )