In a study that was published in June 2020 it was shown that 41% of patients with test-confirmed COVID-19 had dysfunctions of their sense of smell and 38.2% had dysfunctions of their taste. These results were based on self-reports. When objective measurements of dysfunction were used these rates were even higher. Given the prevalence of this long-term side effect, many who have recovered from COVID-19 are looking for a treatment that will help improve their sense of smell and taste. Several therapies have been considered for treating these conditions. One medication that has been studied for many years is theophylline – which is currently being tested in clinical trials for managing loss of smell and taste from COVID-19.

How Loss of Smell and Taste Occurs

In most cases the loss of smell after onset of COVID-19 is temporary and subsides within a few weeks after recovery. For some patients however the loss of smell continues long after other symptoms have subsided. Olfactory impairment is common after upper respiratory tract infections. For COVID-19, it is thought that this is due to either involvement of the olfactory bulb or damage to the olfactory receptor cells in the nose.

The loss of smell and taste after onset of COVID-19 is relatively rapid, and because of that some researchers have concluded that the incidence of olfactory impairment is a good indicator of the spread of the virus. (See article: Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness – link opens in new window). By determining how many new cases of olfactory impairment there are in a population, it is possible to estimate how many new infections exist. An ongoing concern has been the spread of the infection among those who do not get tested but are infected. These patients may report changes to their smell and taste but do not have other symptoms.

Risks of Olfactory Dysfunction

Besides the obvious detrimental effects – not being able to enjoy food or scents – there are other risks of olfactory dysfunction that may not immediately come to mind. A loss of smell leaves people vulnerable to dangers such as food poisoning and fire. In a study that was published in 2014 before the pandemic, patients with olfactory dysfunction were given a questionnaire with 5 questions:

• Have you had any incidents while cooking which were caused by your smell disturbance? Specifically, have you burnt pots and/or pans or
• have you started a fire while cooking?
• Were you ever unable to smell smoke from a fire?
• Have you had any incidents in which natural gas was leaking and you were unable to smell it?
• Have you ingested any spoiled foods or swallowed any toxic substances?

The study found that individuals with olfactory impairment had 3 times the risk of experiencing a smell-related hazardous event compared to individuals with normal smell function. (Risk Factors for Hazardous Events in Olfactory-Impaired Patients – JAMA Otolaryngology- Head & Neck Surgery – link opens in new window). Hazardous events experienced included burning pots or pans, ingesting spoiled food, not detecting smoke from a fire, not detecting a gas leak, and starting a fire while cooking.

Another possible consequence of olfactory impairment is vitamin deficiency from avoiding certain foods or avoiding food altogether because it is unpalatable. Individuals who do not completely lose their smell or taste but instead have an altered smell and taste often report that some foods that used to taste good now taste unpleasant. This could lead to drastic changes in a person’s diet and their nutritional balance.

Steroids and Smell Training

Steroids and smell training are the two most commonly used treatments for smell loss after recovering from COVID-19 right now. Oral corticosteroids in combination with smell training were shown to be more effective than smell training alone in one study. However other researchers have concluded that the use of corticosteroids should be avoided and is not effective for treating smell loss following COVID-19.  

Most researchers and clinicians agree however that smell training is at least somewhat helpful and has no side effects. Smell training often involves smelling at least 4 different scents twice per day. In studies, this has included scents like eucalyptus, lemon, rose, cinnamon, chocolate, coffee, lavender, honey, strawberry and thyme. Any scent could be chosen however, and it is good to start with some that are familiar. The scents do not necessarily even need to be “good” scents like spices but could also be something like an extinguished candle. Over time this process allows a “re-training” of the sense of smell. This therapy requires persistence – results tend to be noticed gradually, but there are few downsides.

Theophylline Intranasal

One of the most promising treatments for loss of smell is the drug theophylline. A phase II clinical trial is underway to study the effectiveness of intranasal theophylline in treating anosmia and dysgeusia in patients who have recovered from COVID-19. (Smell in Covid-19 and Efficacy of Nasal Theophylline (SCENT2) – opens in new window). The ultimate goal of this and other recent trials is to have an FDA-approved treatment indicated for loss of smell. The trial utilizes an intranasal formulation, which has been the preferred method of treatment in recent studies.

Trials have been ongoing for years that tested theophylline for patients with anosmia. Initial studies mostly focused on the use of oral theophylline, showing that it effectively improved sense of smell as long as treatment was continued (See article: An Open-Label Controlled Trial of Theophylline for Treatment of Patients With Hyposmia – opens in new window). The Taste and Smell Clinic in Washington, D.C. has been studying smell and taste disorders for decades, and first published research in 2008 regarding the use of theophylline for loss of smell (See article: For Some Who Have Lost Their Sense Of Smell, A Once Popular Asthma Drug Could Help – opens in new window). With COVID-19 came a greater prevalence of olfactory issues which made this research especially relevant. The researchers studying theophylline for intranasal use now have significant funding to pursue clinical trials with the intent of gaining FDA approval.

Intranasal Theophylline vs. Oral Theophylline

It has been demonstrated that intranasal theophylline is safer and more effective than oral theophylline. (See article: Intranasal Theophylline Treatment of Hyposmia and Hypogeusia: A Pilot Study – opens in new window) Oral theophylline can result in restlessness, gastrointestinal tract discomfort, sleep difficulties, tachycardia, and other symptoms. Intranasal theophylline has few side effects and is generally well tolerated. More importantly, administration directly to the nose has been shown to be more effective than oral administration in treating loss of smell.

How Does Theophylline Work?

Theophylline treats loss of smell and taste caused by low levels of two proteins called cAMP and cGMP. A low level of these proteins in nasal mucus inhibits the production of olfactory receptor cells. Theophylline is a phosphodiesterase inhibitor that can increase levels of cAMP and cGMP to improve sense of smell and sense of taste. The nasal spray may also help reduce inflammation that can be a contributing factor in loss of smell and taste.

Compounded Intranasal Theophylline

Theophylline is pharmacologically similar to theobromine and caffeine. It is actually found in tea (in small amounts) and cocoa (sometimes in large amounts). As an approved drug, it has been used mostly for treating COPD and asthma. Its use for treating loss of smell is currently considered “off-label” whether it is an FDA approved drug being used for this purpose or a compounded drug. Since there is currently no commercially available intranasal version, it must be made by a compounding pharmacy. A compounding pharmacy can make medications using bulk pharmaceutical ingredients that are not commercially available.

Theophylline can be compounded in the form of an atomized nasal spray. The drug is compounded in capsules which are added by the patient to a saline rinse and applied to the nasal passages with an atomizer. An atomizer is device with a motor that sends a fine mist of medicated solution into the nasal passages where it can act locally on the nasal surfaces.