Does cannabis alleviate tinnitus? A review of the current literature

1 INTRODUCTION

Tinnitus is the perception of sound that results exclusively from activity within the nervous system without any corresponding mechanical, vibratory activity within the cochlea, and not related to external stimulation of any kind.¹ These perceived sounds can manifest a variety of symptoms, such as ringing, buzzing, whirring, humming, whooshing, static, insects, and hissing sounds. Most tinnitus is subjective, perceived only by the patient as a phantom sound. In contrast, objective tinnitus refers to the perception of acoustic, vibratory activity generated mechanically within the body, that can be heard by the patient and the examiner. Objective tinnitus is a rare entity and is not the focus of this review. Tinnitus has been reported to affect approximately 1 in 10 US adults, with a prevalence as high as 30% amongst adults over 50, making it one of the most common chronic conditions.^2-5 In the veteran population, tinnitus and hearing loss are the #1 and #2 most prevalent service connected disabilities with 1 971 201 veterans listed as service connected for hearing loss and 1 228 936 veterans listed as service connected for tinnitus.⁶

Even if patients learn to ignore these perceived sounds, tinnitus can negatively impact quality of life.⁷ Survey data suggests that half of adults who experience tinnitus approach a physician for a medical consultation, and approximately 15% try any type of treatment.^{2, 8} Persistent symptoms can be debilitating and incur considerable psychological distress.^9-11 In the veteran population, it has been described that 71.9% of those with tinnitus suffer from anxiety, 59.3% with tinnitus suffer from depression, and 58.2% with tinnitus suffer from both anxiety and depression.¹² Overall, patients with tinnitus suffer increased rates of depression and anxiety by almost 3-fold.² Patients who experience tinnitus are also at increased risk for insomnia and its sequalae as well as suicidal ideation.^13-16 These relationships are likely bidirectional as reduction in tinnitus symptoms has been observed after pharmacologic treatment of mood disorders with anxiolytics and antidepressants.^{15, 17, 18} Head trauma, concussion, hypertension, smoking, and ototoxic medications have been associated with tinnitus.^{3, 19} However, by far the most common contributing risk factor is hearing loss, either due to acoustic trauma or presbycusis.^{20, 21} Literature suggests that 90% of tinnitus patients report comorbid hearing loss.²¹ Furthermore, tinnitus is a predictable consequence after surgical transection of the auditory nerve during the excision of acoustic neuromas.²² The burden of hearing loss is expected to grow with an aging population, which may be compounded by a growing prevalence of adolescents with hearing loss,²³ likely increasing the prevalence of tinnitus over the coming years.

The exact pathophysiology of tinnitus is not yet fully understood. Tinnitus appears to be caused by mechanisms that involve both the peripheral and central components of the auditory system,²⁴ initially triggered by trauma to the cochlea.^{25, 26} A commonly accepted hypothesis for the development of tinnitus is that of neuronal hyperactivity.²² After trauma to cochlea, damage to the auditory nerve fibers synapsing with the inner hair cells undergo maladaptive neural plasticity to compensate for damage to the cochlear cells.²¹ A decrease in inhibition or an increase in excitation leads to an excitatory-inhibitory imbalance that can cause neural hyperexcitability. Multiple regions of the auditory pathway become more active and neurons fire synchronously, introducing aberrant activity that creates the sensation of sound perceived as tinnitus. This neuronal hyperactivity has been observed in multiple parts of the auditory pathway, including the dorsal cochlear nucleus (DCN), ventral cochlear nucleus (VCN), the inferior colliculus, the medial geniculate body (MGB) and the auditory cortex.^27-32

Several pharmacological and non-pharmacological approaches for the treatment of tinnitus have been studied. For patients who have concurrent significant hearing impairment, hearing aids or cochlear implants may rescue auditory sensation and prevent the progression of neuroplastic changes that contribute to tinnitus. Masking, a type of sound therapy, uses external auditory stimuli to reduce the patient's awareness of tinnitus.^{33, 34} Neurophysiological and cognitive behavioral therapies have also been shown to be effective against tinnitus, as these techniques attempt to modulate the patient's response or experience of tinnitus, by both reducing distress and cultivating coping strategies and distraction skills. Cognitive behavioral therapy is the best-established treatment to date for tinnitus.^{35, 36} Based on the evidence that tinnitus is associated with neuronal hyperactivity in the auditory brain regions, several studies have investigated the efficacy of anti-epileptic drugs, including carbamazepine,³⁷ gabapentin,^38-40 and lamotrigine⁴¹ in the treatment of tinnitus. However, pre-clinical evidence supporting the use of antiepileptic drugs in tinnitus is limited and contradictory, and are unlikely to be beneficial when compared to placebo.⁴²

Given the limitations of existing therapies for the treatment of tinnitus, there is an increasing interest in exploring other pharmacotherapy. As a result of recent legislative changes, changing societal perceptions, and recent advances in the field, the potential of cannabis in the treatment of tinnitus is explored in this review article. With some evidence supporting that cannabinoids can suppress epileptiform and seizure activity in animals,^43-45 cannabinoid drugs may be a good candidate for the treatment of tinnitus by potentially reducing neuronal hyperactivity. In the context of otolaryngology, the role of cannabinoid drugs has been studied across various subspecialties,⁴⁶ especially in the setting of palliative care and management of chronic, cancer pain.⁴⁷

2 CANNABIS BIOLOGY AND RECEPTOR DISTRIBUTION

Cannabis, also known as marijuana, is a generic term for the psychoactive drug derived from plants of the Cannabis family, including Cannabis sativa and Cannabis indica. Cannabis contains over 400 different chemicals. The biologically active molecules unique to cannabis are known as phytocannabinoids; approximately 120 different phytocannabinoids have been identified, many of which directly modulate the endogenous cannabinoid system. Two of the phytocannabinoids that predominate in literature and by far the most well-understood are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the principal psychoactive constituent of cannabis, associated with the euphoric feeling users experience. It also possesses antiemetic, anti-inflammatory, analgesic and anti-oxidant properties.⁴⁸ CBD is a non-psychoactive cannabinoid, and associated with anticonvulsant, anxiolytic and sedative effects.^{49, 50} There is also a growing body of evidence for the use of THC and CBD, both individually and in combination sprays (Nabiximol), for the management of chronic pain, in the setting of multiple sclerosis,^{51, 52} spinal cord injury-related neuropathic pain,⁵³ and refractory advanced cancer-related pain.^54-56

Two classes of cannabinoid receptors have been identified, CB₁ and CB₂ receptors, which are part of the endocannabinoid system. CB₁ receptors are mainly expressed within the central nervous system,^{57, 58} whereas the CB₂ receptors are localized within the peripheral nervous system and the immune system.^{59, 60}). In the brain, endogenous cannabinoids are released postsynaptically and act in a retrograde manner on presynaptic CB₁ receptors and are thought to inhibit calcium influx at the presynaptic terminals, inhibiting neurotransmitter release.⁴³ In mouse and rat models of epilepsy, endocannabinoids have been shown to oppose excitatory signals during seizures, by activating GABA_A receptors.^{44, 45, 61-63} As the most widely accepted hypothesis for the pathophysiology of tinnitus is that of neuronal hyperexcitability, a mechanism that has been long observed in epilepsy, there is a potential role of cannabinoids in the management of tinnitus through its anticonvulsant effects.

3 CB₁/CB₂ RECEPTOR EXPRESSION IN COCHLEAR NUCLEUS

Herkenham et al. first identified CB₁ receptors in the cochlear nucleus (CN) in early autoradiographic studies in a rat model.⁶⁴ The spatial distribution of CB₁ receptors in the cochlear nucleus was further elucidated by Zheng et al. utilizing immunohistochemistry studies and cell counting procedures to quantify CB₁ receptor expression.⁶⁵ The group identified high levels of CB₁ receptor expression in the DCN and VCN, suggesting a role of CB₁ receptors in auditory function, hypothesized to be likely modulating synaptic plasticity in the auditory nucleus.^{66, 67} Zhao et al. further demonstrated that specialized cells within the DCN expressed diacylglycerol (DAG) α and β, two enzymes necessary for the production of the endocannabinoid, 2-arachidonyl glycerol (2-AG).⁶⁷ These endocannabinoids were shown to regulate CB₁ receptor activation in the absence of exogenous cannabinoid drugs. Baek et al also reported expression of CB₂ receptor labeling in the cochlear nucleus⁶⁸; however, conflicting data exists regarding CB₂ expression in the cochlear nucleus and still remains unclear.⁶⁹ Based on these studies, there is considerable evidence for an endocannabinoid system within the cochlear nucleus, which may be important for the development of tinnitus. These cannabinoid receptors may be targeted by exogenous drugs for the treatment of tinnitus.

4 ANIMAL STUDIES

Literature on the effects of cannabinoid drugs on tinnitus is sparse, with only a few experimental studies performed in animal models. Zheng et al. investigated the expression of CB₁ receptors in the DCN and VCN in the salicylate model of tinnitus in rats, based on Jastreboff's tinnitus model.⁶⁵ In this model, salicylate injections was used to induce tinnitus, which was then confirmed using behavioral testing that determines whether the rats subjectively “hear” sounds in the quiet.⁷⁰ During the study, rats were water deprived, and then placed in a chamber with access to water and conditioned to drink water during episodes of silence. This was achieved by pairing a mild electric foot shock (the unconditioned stimulus) with discrete periods of silence (the conditioned stimulus) in a continuous background noise, resulting in reduced licking behavior, or decreased water consumption. The animals learnt the association between silence and the electric foot shock. After the conditioning period, control rats refrained from licking water when they were presented with silence only. On the other hand, after the injection of salicylic acid, rats who perceived tinnitus continued to lick water during periods of silence. Using immunohistochemical studies, the authors found that compared to controls, rats with tinnitus-related behavior possessed significant lower of CB₁ receptor expression in neurons in the VCN. Downregulation of CB₁ receptors was not seen in the DCN. The findings suggested that CB₁ receptors in the cochlear nucleus may have a functional role in auditory processing and may contribute to the pathophysiology of tinnitus.

Based on this evidence, Zheng et al. further explored the relationship of cannabinoid receptors and tinnitus, by investigating the effect of tinnitus with two different CB₁ non-selective, receptor agonists, WIN55,212-2 and CP55,940.⁷¹ In this experiment, both receptor agonists at different concentrations were injected in the salicylate-induced tinnitus rat model and in controls. Neither WIN55,212-2 (at 3 mg/kg) or CP55,940 (at 0.1 mg/kg or 0.3 mg/kg) significantly reduced the conditioned behavior associated with tinnitus in the rat model. On the contrary, injection of WIN55,212-2 at 3 mg/kg, and CP55,940 at 0.3 mg/kg in control animals significantly increased tinnitus-related behavior, suggesting that cannabinoids may induce tinnitus. The association between cannabinoid receptors in rats and tinnitus-like behavior was further elucidated by using the acoustic trauma-induced tinnitus rat model, which is believed to be more closely related to human tinnitus than the salicylate rat model since noise trauma is one of the more common causes of tinnitus in humans.^{72, 73} In a follow up study, Zheng et al. investigated the effect of delta-9-THC and CBD in a 1:1 to ratio, equivalent to Nabiximols (Sativex), used in the treatment of spasticity and chronic pain in multiple sclerosis,⁷⁴ in an acoustic-trauma induced tinnitus rat model.⁷⁵ Tinnitus was induced by unilateral acoustic trauma applying a 16 kHz pure tone with an intensity of 115 dB, and tinnitus-related behavior observed using the conditioned lick suppression paradigm.^{76, 77} Zheng et al found that the administration of delta-9-THC and CBD significantly increased tinnitus-related behavior compared to controls. Following a 2-week washout period, the tinnitus-related behavior decreased in the experiment group. The cannabinoid agonists used in both studies were non-selective and it has been hypothesized that they may have interacted with opioid, vanilloid, or muscarinic receptors, obscuring the interpretation of the results.^78-80

Berger et al. investigated the effects of a highly selective, potent CB₁ receptor agonist, arachidonyl-2′-chloroe- thylamide (ACEA), on a salicylate-induced and noise-induced tinnitus model in guinea pigs.⁸¹ Following administration of ACEA, the group found no significant reduction or reversal of tinnitus-like behavior in guinea pigs. Interestingly, the group found that ACEA seemed to reverse the decrease in auditory brainstem-evoked response amplitudes induced by salicylate, compared to the control group, suggesting that ACEA may be potentially otoprotective. Overall, using both the salicylate-induced tinnitus model and acoustic trauma-induced tinnitus model, it appears that cannabis may reversibly exacerbate or induce tinnitus.⁸² Based on animal models, there is no evidence that cannabis or cannabinoid drugs can alleviate tinnitus.

5 SURVEY AND CLINICAL STUDIES

At present, there are no systematic studies or randomized controlled trials in humans that have examined the effects of cannabinoids on tinnitus. Although cannabis for medical use is legal in 33 states in the US (Figure 1), cannabis remains as a Schedule I controlled substance at the federal level.^{83, 84} This status requires researchers to face several, strict regulatory barriers, such as obtaining licensure from three different federal entities as well as obtaining appropriate state permissions, to undertake research.⁸⁵ As a result, research on the health effects of cannabis and cannabinoids has been limited in the US.

To date, the only FDA approved cannabis-derived or cannabis-related products for medical use are Epidiolox (cannabidiol), used for seizures in rare epileptic syndromes, Marinol and Syndros (THC dronabinol formulations) for anorexia in AIDS patients, and Cesamet (nabilone, a THC analog) for treating chemotherapy-associated nausea.^86-88 Nabiximol is currently available in Canada for cancer pain management, but not in the US.⁸⁸ Some states have passed legislation allowing the prescription of cannabis products for certain conditions (Figure 2).^{84, 85} Tinnitus, however, is not among commonly approved conditions, which contributes to the challenges of conducting relevant investigative clinical studies.

Nevertheless, some epidemiological studies have examined associations between recreational cannabis use and tinnitus in a non-controlled setting.^{89, 90} Table 1 illustrates an overview of animal and human studies investigating the relationship of cannabis and tinnitus. Qian et al. recently published a cross-sectional study evaluating the association between cannabis use and occurrence of tinnitus utilizing the National Health and Nutrition Examination Surgery (NHANES) survey.⁹⁰ NHANES is an ongoing, nationally representative series of cross-sectional health surveys of the US non-institutionalized civilian population designed to provide estimates of health and nutritional status.⁹¹

An association was reported between the regular use of cannabis (at least once per month over the previous 12 months) and the experience of tinnitus during that 12-month period (P < .001). No significant dose-response relationship was observed with the frequency (P = .716) or quantity (P = .560) of cannabis consumed and frequency of tinnitus. The association was present after controlling for other variables in multivariate analysis (OR = 1.75, 95% CI 1.02-3.01, P = .043). However, the presence of hearing loss, history of work noise exposure, and anxiety were also found to be associated with prevalent tinnitus; these variables had a stronger correlation to the presence of tinnitus than cannabis use.⁹⁰

Although this study describes a statistically significant association between tinnitus and cannabis use in humans, large survey databases such as NHANES surveys must be interpreted with caution. A major limitation of the study is that both key variables examined, cannabis use and presence of tinnitus, are self-reported variables and may be subject to recall bias. Literature suggests patients tend to underreport cannabis use, and inaccurately estimate the quantity of cannabis consumed.^92-95 The NHANES surveys also lack data on the potency, specific cannabis strain, and lifetime cannabis use of individuals. The survey also presents insufficient data on the characterization of tinnitus; no data on the severity of tinnitus and the impact on quality of life were assessed, making comparisons between participants difficult. Furthermore, an inherent weakness of the study design is the inability to determine directionality or causal pathways of the findings observed. The study found that anxiety was strongly associated with tinnitus and cannabis use. Several studies have shown mood disorders to be correlated with both tinnitus perception and cannabis use.^96-98 Due to the cross-sectional design, the study cannot exclude the possibility of tinnitus leading to increased cannabis use as a mechanism for this association. The lack of standardization of cannabis use, the insufficient information of the severity of tinnitus and the cross-sectional nature of the study, limits the ability to draw major conclusions from this study.

A similar epidemiological, cross-sectional study was undertaken by Han et al. investigating the association of illicit drug use with different health conditions, including tinnitus, utilizing data from the National Surveys on Drug Use and Health (NSDUH).⁸⁹ The study investigated the lifetime use of cannabis and other illicit drugs of 29 195 participants between the age of 35 and 49. After controlling for confounding factors, no statistically significant associations were found between tinnitus and cannabis use. Similar to other cross-sectional surveys, the study is subject to recall bias and causative conclusions are unable to be made due to the design of the study.

Noyes et al. first described an association between cannabis and tinnitus in 1975,⁹⁹ where the group performed a double-blinded cross-over study evaluating the analgesic effects of different doses of THC and codeine in patients with cancer. 11 patients from a total of 34 patients from the study cohort reported tinnitus as an adverse event after the administration of 10 mg or 20 mg of THC, compared to 3 patients reporting tinnitus in the placebo group. The data also show a likely dose-response relationship, with patients who received the higher concentration THC reporting tinnitus more frequently. Since the objective of the study was to assess the analgesic effects, no statistical analyses were performed comparing the tinnitus and non-tinnitus group, nor the severity of tinnitus characterized. Despite the small sample size, the study is one of the first studies in literature that provides objective data on the adverse side-effect profile of THC in humans in a controlled environment.

The first published study using a cannabinoid for the treatment of tinnitus was undertaken by Raby et al. The group presented a case report describing the use of dronabinol, a CB₁ receptor agonist (synthetic delta-9-THC), in a patient with long-standing, symptomatic, idiopathic intracranial hypertension (IIH).¹⁰⁰ The patient had previously reported symptom control of IIH when smoking cannabis, but wanted to seek an alternative medication to minimize the psychoactive effects related to it. Treatment with dronabinol, 5 mg twice daily, increased to 10 mg twice a day after 7 days, resulted in the resolution of her headaches and decreased perception of tinnitus. She remained free of symptoms over 30 months with a maintenance dosage of 5 mg twice a day. Resolution of her IIH-related symptoms was also objectively correlated with improvement of papilledema on fundoscopic exam. Although an improvement of tinnitus was observed, the pathophysiology of objective tinnitus in this patient, caused by increased turbulent, venous flow secondary to intracranial hypertension,¹⁰¹ differs to that of “subjective” tinnitus. Objective tinnitus may be considered as a separate disease entity, with different treatment algorithm to subjective tinnitus.^{102, 103} In addition, it is difficult to draw any considerable conclusions from the case report given that the evidence is anecdotal in nature.

6 CONCLUSION

Based on the findings from animal studies, there is evidence of an endocannabinoid system, mediated chiefly by CB₁ receptors, that plays a role in the auditory pathway. The relationship between CB₁ receptors and tinnitus is likely complex, and not fully understood. At present, there is no compelling data either from animal or human studies for the use of cannabinoids to alleviate tinnitus. On the contrary, evidence suggests that cannabinoids may induce or worsen tinnitus.^{71, 79, 90, 99} As high quality prospective research for the effect of cannabis on tinnitus is lacking, evidence can neither support nor refute the use of cannabis in controlling symptoms of tinnitus. Once we overcome restrictive regulatory barriers for undertaking cannabis research in the US, future prospective trials may help provide data to further elucidate the association between cannabis and tinnitus.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

Vishal Narwani, Alexandra Bourdillon, Keerthana Nalamada, R. Peter Manes, Douglas M. Hildrew: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. Vishal Narwani, Alexandra Bourdillon, Keerthana Nalamada, R. Peter Manes, Douglas M. Hildrew: Drafting the work or revising it critically for important intellectual content. Vishal Narwani, Alexandra Bourdillon, Keerthana Nalamada, R. Peter Manes, Douglas M. Hildrew: Final approval of the version to be published. Vishal Narwani, Alexandra Bourdillon, Keerthana Nalamada, R. Peter Manes, Douglas M. Hildrew: Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.