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Association Between Cannabis and the Eyelids

Cannabis is the most consumed illicit drug worldwide. As more countries consider bills that would legalize adult use of cannabis, health care providers, including eye care professionals (ophthalmologists, optometrists), will need to recognize ocular effects of cannabis consumption in patients. There are only 20 studies on the eyelid effects of cannabis usage as a medical treatment or a recreational drug. These include ptosis induction, an “eyelid tremor” appearance and blepharospasm attenuation. Six articles describe how adequately dosed cannabis regimens could be promising medical treatments for blepharospasm induced by psychogenic factors. Fourteen articles report eyelid tremors in intoxicated drivers and ptosis as a secondary effect in cannabinoid animal experimental models. The exact mechanism of cannabinoids connecting cannabis to the eyelids is unclear. Further studies should be conducted to better understand the cannabinoid system in relation to the eyelid and eventually develop new, effective and safe therapeutic targets derived from cannabis.

1. Introduction

Cannabis is a widely used medical treatment and recreational drug. [1] Despite drooping eyelids being a common side effect, there is little research into cannabis’ effects on the eyelids. [2] Cannabis consumption can lead to reduction of clinically-diagnosed blepharospasm, but can also induce ptosis and eyelid tremors. [3, 4, 5]

Cannabis is increasingly being used worldwide. [6] In 2016, 192 million people have consumed cannabis, commonly referred as grass, herb, marijuana, pot and weed. [1, 7] Approximately half of Americans adults have tried it at least once. [8] Around the world, cannabis has been subjected to a complex history of decriminalization and legalization. Canada became the second country to legalize recreational cannabis with the Cannabis Act in 2018 after Uruguay in 2013. [9, 10] In the United States, more than 20 states have decriminalized the possession of small amounts of cannabis. [11] Due to the increasing widespread use of cannabis, more states and countries are considering bills that would legalize adult use of cannabis.

In this context, it is important that health care providers, including eye care professionals (ophthalmologists, optometrists), general internists and emergency physicians, understand the ophthalmological outcomes of cannabis consumption, since they can expect to see many more patients in the future under the influence of cannabis. This article reviews the cannabinoid impacts on the eyelids, and explores cannabis’ potential as a medical treatment for blepharospasm together with its secondary effects (eyelid tremors and ptosis).

2. Methods of Literature Search

A literature search was performed using NCBI Literature Databases (PubMed/PubMed Central). Reference lists of selected articles were also consulted in order to add unidentified relevant articles according to our selection criteria. Article searches were contained the following MeSH terms: blepharoptosis, blepharospasm, cannabinoids, cannabis, dry eye syndromes, ectropion, entropion, epiblepharon of upper lid, eyelids, eyelid diseases, eyelid neoplasms, marijuana abuse, marijuana smoking, marijuana use, medical marijuana, meige syndrome and myokymia.

2.1. Selection Criteria

The initial search with the MeSH terms and the cross-referencing yielded 47 articles. There was no restriction on the article language. Articles were selected based on their relevance. Twenty seven articles were excluded, as they examined cannabis use and eyelids separately. Because all the articles that were extracted were in English, no abstract translation was required. The dates included in the search range from 1781 (publication date of the oldest article available on PubMed) up to July 2019. A few animal experimental studies examining eyelid tremors as a side effect of cannabinoids were conducted in the 1990s, but this review included a majority of articles that were published recently (during the 21st century). We included all articles mentioning eyelid tremors as a side effect of cannabinoid administration and studies examining to cannabinoid regimens in the treatment of blepharospasm.

2.2. Results

The literature search resulted in 20 articles.

Six studies examined the use of cannabis as a medical treatment for blepharospasm. This included a case report study, [12] a double-blind, randomised, placebo-controlled, crossover study, [13] a retrospective chart review, [3] an open trial [14] followed by an open label evaluation by the same authors, [15] and a systematic review of cannabis use in several neurologic conditions including dystonia. [16]

A drug recognition expert examination, [5] a review article, [17] and driving cases [18, 19] reported eyelid tremors in drivers under the influence of cannabis.

Ten original research articles using animal models noticed ptosis as a secondary effect of cannabis consumption. [4, 20, 21, 22, 23, 24, 25, 26, 27]

3. Cannabis and Cannabinoids

Derived from hybrid cannabis plants, cannabis is a drug whose resin produces psychoactive components known as cannabinoids. [28, 29] Cannabinoids are responsible for cannabis’ medical, physical and psychotropic properties. [29] More than 100 cannabinoids were found in cannabis. These natural cannabinoids, referred as phytocannabinoids, are legally sold in various states and are distinct from endogenous cannabinoids (endocannabinoids) and lab-produced cannabinoids (synthetic cannabinoids) ( Figure 1 ). [30] In the United States, synthetic cannabinoids are unsafe and unregulated, as they are categorized as new psychoactive substances. [31] Cannabinoids can be further classified into types, such as cannabidiol (CBD), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabinol (CBN) and cannabichromene (CBC). [30] CBD is a major compound of cannabis responsible for neurologic and bioactive reactions, but it is not responsible for psychoactivity. Due to its neurologic and bioactive activity, CBD has the potential to treat epilepsy, neurodegenerative diseases and psychiatric disorders. [32] THC is the main psychoactive component of cannabis, responsible for the drug’s mind-altering effects. Cannabinoids are cannabis components responsible for the drug’s properties and its widespread use. [30]

Classification of the Studies According to the Type of Cannabinoid Examined.

Studies included in this review article examined cannabinoids receptors’ reactions to cannabis’ main components (CBD, THC, THCA, CBN and CBC) in different contexts. The source of production of cannabinoids can be either extracorporeal (phytocannabinoids or synthetic cannabinoids) or intracorporeal (endocannabinoids). Cannabinoids that are not produced by the body are often used for medical treatments and recreational purposes.

3.1. Cannabinoid Receptors

Cannabinoids bind to specific receptors in order to trigger different effects. The two main receptors are cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). These two G-protein coupled receptors (GPCRs) are part of the vast endocannabinoid system. GPCRs are responsible of modulating various intracellular signaling pathways. As GPCRs are the largest membrane protein family, they can detect multiple signaling molecules and play a crucial role in the molecular mechanisms of cannabis-signaling in the brain. [30, 33] CB1 and CB2 are highly present in the basal ganglia. [25, 34]

More recently, it has been discovered that non-cannabinoid receptors are involved concurrently with cannabinoid receptors in the modulation of ocular pain and inflammation. [35] These include: transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), [36] transient receptor potential cation channel subfamily M member 8 (TRPM8), [37] the GPCR serotonin 1A receptor (5-HT1A), and peroxisome proliferator-activated receptors (PPARs) ( Figure 2A ). [38] Indeed, some cannabidiol derivatives have antinociceptive and anti-inflammatory properties on the eye due to their affinity as ligands to CB2. [39] THC binding to CB1 also leads to short-term and long-term effects on synaptic transmission. [40] Hence, cannabinoids interact with multiple systems, including the gabaergic, [41] serotonergic, [42] cholinergic [43] and dopaminergic [44] pathways ( Figure 2B ).

Schematic Representations of Cannabinoid-Related Pathways

Figure 2A: Ocular Cannabinoid Receptors and Sensory Pathways [59]

Cannabinoids bind to cannabinoid receptors, which are predominantly found in corneal epithelial cells and the basal ganglia. Non-cannabinoid receptors modulate the cerebral cannabinoid-signaling pathway involved in the regulation of ocular pain and inflammation.

CB1: Cannabinoid receptor 1

CB2: Cannabinoid receptor 1

TRPA1: Transient receptor potential ankyrin 1

TRPM8: Transient receptor potential cation channel subfamily M member 8

TRPV1: Transient receptor potential cation channel subfamily V member 1

Ascending corneal nociceptive regulation

Descending nociceptive regulation

Figure 2B: Schematic Representations of the Four Human Central Systems Affected by Cannabis [60]

I : Gabaergic pathway

II : Serotonergic pathway

III : Cholinergic pathway

IV : Dopaminergic pathway

Four main pathways interact with cannabis-signaling molecules. It has been suggested that the human cannabinoid system involves gamma-aminobutyric acid (GABA) activation, serotonin downregulation, cholinergic neuronal activity and dopamine disregulation. [4,41,42,43,44,52]

4. Cannabis as a Promising Medical Treatment for Blepharospasm

Blepharospasm is an incurable disorder with symptoms that can only be attenuated. [48] This rare idiopathic movement disorder is characterized by progressive, involuntary muscular contractions of the orbicularis oculi and upper facial muscles, which can lead to complete eyelid closure. [49–51] Repeated botulinum toxin injections provide a temporary and safe solution to most patients, but might come with secondary effects (ptosis, dry eye syndromes and tearing). [52] Patients that are resistant to botulinum toxin might consider surgical procedures, such as myectomy, which can provide relief. [53] Other medical treatments have failed to cure this condition. Cannabis might be an effective treatment for blepharospasm.

Six articles examined cannabis as a medical treatment for blepharospasm. 3, 12–16 The preliminary findings from eight subjects are promising, but show equivocal results. Five cannabinoid regiments allowed patients to note subjective symptomatic improvement. Patients’ blepharospasm severity improvement ranged from 25% to 70% and frequency of spasms decreased from 0% to 50%. These patients experienced an initial blepharospasm-severity degree of 75% to 100% (100% being maximal severity) and an approximate symptoms’ improvement of 25%. While all the cannabinoid regimens were given as capsules, the doses (ranging from 5 to 400 mg) and cannabinoids (ie, CBD, THC, nabilone) selected were personalized. The treatment duration also differed from one subject to another, as the clinical stable state was reached at 5 to 12 weeks. The four patients who did not indicate subjective symptomatic improvement with cannabinoid tinctures had either undergone another successful therapy (ie, botulinum injections), did not note any improvement in terms of blepharospasm severity or frequency or experienced important side effects like lightheadedness ( Table 1 ).

Table 1:

Patient, medication history, subjective responses and scale results

Delta-9-THC (Dronabinol) 12 THC & CBD 3 CBD 14,15 Nabilone 13
Patient characteristics Condition Blepharospasm Blepharospasm Blepharospasm Blepharospasm Blepharospasm Blepharospasm Meige syndrome Primary dystonia (15 patients)
Age 56 60 54 61 72 60 42 28 to 63
Sex Female Female Male Female Male Female Male 6 males, 9 females
Daily dose prescribed 1 st script: 10 mg 2 nd script: 30 mg 3 rd script: 10-5-15mg paradigm 5 mg THC, 95 mg CBD 10 mg THC, 10 mg CBD 1 st script: 5 mg THC, 5 mg CBD
2 nd script: 4 mg THC, 1 mg CBD
1 st script: 5 mg THC
2 nd script: 8 mg THC, 2 mg CBD
Up to 10 mg THC, 10 mg CBD 300/400 mg ** Single dose: 0.03 mg/kg to the nearest whole mg
Duration of cannabis use Total duration: 16 weeks 8 weeks 2 weeks 12 weeks 12 weeks 8 weeks 6 weeks NA
Over 2 weeks After 5 weeks, clinical stable state reached
Side effects None Vertigo Reduction of vertigo None Sleep disturbance Sleep disturbance Sporadic headaches Lightheadedness Hypotension
Dry Mouth
Lightheadedness
2/15 patients: hypotension and pronounced sedation
Subjective Symptomatic Improvement (Yes/No) No Yes Yes NA: Patient discontinued the treatment after two weeks. Yes No Yes Yes No: 4/15 patients experienced subjective improvement 2–3 days after administration
Symptom Score a NRS: 8.5–10 NRS: 3–5 Pre
BSDIS: 3
BSDIF: 3
JRF: 10
NA Pre
BSDIS: 3
BSDIF: 3
JRF: 14
Pre
BSDIS: 4
BSDIF: 4
JRF: 13
NA Baseline DS: 29
Max. DS: 120
Maximal improvement: 40%
Median total movement DSs over 180 min placebo:
• 70.5 (range, 11–216) for nabilone
• 81 (range, 8–209) for placebo
Post
BSDIS: 2
BSDIF: 1
JRF: 6
Post
BSDIS: 2
BSDIF: 3
JRF: 12
Post
BSDIS: 4
BSDIF: 4
JRF: 8
Reason for discontinuation NA Costs Success of botulinum therapy NA No improvement noted ER admission twice due to lightheadedness NA 2/15 patients withdrawn due to side effects

Abbreviations of the symptom score scales

• NRS: Numerical Rating Scale (0–10)

• BSDIS: Blepharospasm Disability Index Severity (0–4)

• BSDIF: Blepharospasm Disability Index Frequency (0–4)

• JRS: Jankovic Rating Scale (0–24)

• DS: Dystonia Score following the Burke, Fahn, Marsden dystonia scale

• Pre: Pre-cannabis therapy blepharospasm scale results

• Post: Post-cannabis therapy blepharospasm scale results

Cannabis has originally been used to treat blepharospasm because of its antispasmodic properties. Reports dating from the 19th century mention that cannabis has been specifically used to treat muscular spasms, including blepharospasm. [15] A more recent study by Radke et al examined patients following cannabinoid therapies combining THC and CBD tinctures and capsules. The treatments were tolerated by four out of five patients and out of those four patients, three of them noted a decrease in blepharospasm symptoms ( Table 1 ). [3] However, the exact mechanisms of cannabinoids, especially in dystonic patients, are still unknown. [15] It has been suggested that CBD either activates gamma-aminobutyric acid (GABA) or halts the uptake of serotonin. [4] Another hypothesis is that THC modulates the activity of dopaminergic neurons. [47] In the case report by Gauter et al, the patient’s benign essential blepharospasm might be caused by a problem in the dopaminergic system as emotional burden triggered the symptoms ( Figure 2B ). After an adaptation period to the cannabinoid treatment and the prescription of an adequate quantity of delta-9-THC (Dronabinol), the frequency and severity of attacks were also reduced, compulsive crying ended, dry eye symptoms decreased and the patient’s quality of life improved. It has been hypothesized that this delta-9-THC therapy was successful due to the psychogenic cause of the blepharospasm. [12] The non-psychoactive components of cannabis, CBD, was also tested in an open-label evaluation by Consroe et al, which examined five patients with different forms of dystonia. [15] One patient had Meige’s syndrome (Blepharospasm-oromandibular dystonia) and was previously in Synder and Consroe’s preliminary open trial of CBD. [14] The symptomatic improvement, in this case, was 40% and was dose-dependent. Mild side effects included hypotension, dry mouth and lightheadedness ( Table 1 ). It is important to note that CBD is potentially contraindicated for patients with Parkinson’s disease as the two patients with this syndrome showed increased hypokinesia and resting tremor when they consumed medical CBD. [15] Overall, these studies suggest that cannabis has potential to generate positive outcomes in the treatment of blepharospasm.

These studies also have important limitations, such as small sample sizes, short study times (less than a year), short follow-up times (or absence of follow-up), utilization of different scales to measure symptomatic improvement, varying cannabinoid regimens, limiting study designs and analyses. [3, 12, 14, 15] For instance, the retrospective chart and prospective data gathering by Radke et al. only examined ten patients who were officially authorized to use medical cannabis as a treatment therapy for benign essential blepharospasm. Half of the patients were excluded, as they did not meet other inclusion criteria (verbal consent, formal clinical diagnosis, and ineffective botulinum toxin treatment). Out of the five remaining patients on the medical cannabis regimen, four stopped the treatment either because of the high costs, side effects like severe lightheadedness or no visible improvement. [3] More research should be done in order to determine if medical cannabis could be an effective therapy for blepharospasm because the major limitations of these studies have led to inconclusive results.

Additionally, a double-blind, randomised, placebo-controlled, crossover study was notably inconclusive. This study analysed the effects of nabilone, a synthetic form of delta-9-THC in patients with primary dystonia. [16] A single dosage of nabilone or placebo (0.03mg/kg) was given to fifteen patients with a clinical diagnostic of primary dystonia. [16] Side effects included hypotension and pronounced sedation. Only four patients experienced subjective improvement two to three days after the administration of nabilone ( Table 1 ). Nabilone was ineffective in significantly reducing dystonia, which might be due to the drug’s small quantity and its single administration. The fifteen patients also had different forms of dystonia and were not a homogeneous sample. The fact that the patients were not specifically diagnosed with blepharospasm might also explain the study’s negative results. The current understanding of nabilone’s role in dystonia as a CB1R agonist might also be flawed. [13]

5. Cannabis-Associated Eyelid Tremors

Eyelid tremor is a generic term referring to involuntary and intermittent spasms of the eyelid muscles. [46] The diagnosis of eyelid tremors is difficult because it can refer to eyelid twitches, myokymia (involuntary contractions of a lower eyelid) or blepharospasm.

Although cannabis has potential to alleviate blepharospasm, three reports examining cannabis impairment noted that eyelid tremors are a common physical symptom that is visible after cannabis consumption. These reports, including a drug-recognition examination, might allude to temporary eyelid tremors distinct from true blepharospasm. [5, 17, 18] Furthermore, a murine study suggested that the receptor TRPA1 mediates neural mechanisms responsible for tear deficiency and irritation in dry eye disease. [53] Dry eyes are a common characteristic of the blepharospasm reflex. [45] As a reminder, TRPA1 is actively involved in the peripheral cannabinoid pathway in sensory neurons ( Figure 2A ). [36] Therefore, eyelid tremors associated with cannabis consumption might be caused by the activation of the TRPA1 receptor triggering dry eye symptoms.

6. Cannabis-Associated Ptosis

Ptosis (or blepharoptosis) is a condition where the upper eyelid is drooping or displaced causing a reversible vision loss. Ptosis is assessed with five clinical measurements: levator function, vertical palpebral aperture height, lagophthalmos presence, margin-reflex distance (MRD-1) and upper eyelid crease location. [55] Cannabis-associated ptosis is classified as acquired ptosis.

Ptosis has been noticed as a secondary effect of cannabis consumption in ten original research articles using animal models (rats, mice, rhesus monkeys, cynomolgus monkeys). [4, 19, 20, 21, 22, 23, 24, 25, 26, 27] It is unknown if these ptosis symptoms are temporary or long-lasting.

Cannabis-associated studies based on a murine model have resulted in common findings. Three studies clearly noted ptosis as a side effect of the endogenous cannabinoid anandamide. [19, 22, 26] This further validates one of the hypothesises about the endocannabinoid pathway, which suggests that anandamide regulates the cell signaling of various cortical transmitter systems. [12] Other studies have reported ptosis as part of the cannabis withdrawal syndrome because a CB1 receptor antagonist (SR 141716A) triggered ptosis. According to their scales, ptosis is defined as having at least 50% closure of the eyelids. [23, 25] Additionally, mice treated with THC (20 mg/kg, but not 10 mg/kg) had even higher incidences of ptosis. [23] In another paper, Hutcheson & al. observed that CBD selected doses (60, 120, 240 and 480 mg/kg) correlated with the grades of palpebral ptosis in murine experimental groups. [4] The increasing ptosis has therefore been specified as palpebral ptosis, which is a myogenic form of blepharoptosis due to a reduction in levator muscle function. [54] The other studies, including one exposing mouse blood and tissue to ‘buzz’ smoke, [27] do not specify the ptosis side effect’s subcategory. These findings are interesting as the morphogenesis of human eyelids is comparable to murine models. [55]

Non-human primates have also been used for studies examining cannabinoid pathways. In rhesus monkeys, ptosis can be seen at a much smaller dose of delta-9-THC, but delta-11-THC did not cause ptosis. [21, 22] Another study confirms that cannabinoids generated symptoms of central nervous system depression, such as ptosis, in rhesus monkeys. The rhesus monkeys were periodically injected with one of the two following cannabinoids: levonantradol or nantradol. [25] While rhesus monkeys’ eyelid glands and innervation resemble the human eyelid, [59, 60] cynomolgus monkeys’ eyelid compartmentalization is similar microscopically and macroscopically to the human eyelid. [54] However, Meschler et al found that ptosis was not statistically significant in cynomolgus monkeys treated with levonantradol, which could be due to the small dosage selected. [25] Because their eyelid physiology is similar to the human eyelid, the two types of macaques (rhesus and cynomolgus) are adequate experimental research models ( Table 2 ).

Table 2:

Cannabinoid-Related Non-Human Primate Studies

Type of macaque monkey Cannabinoid regimen (synthetic CB1 agonist) Dose prescribed (mg/kg) Ptosis (Yes/No)
Rhesus 20,21 Delta-9-THC (Dronabinol) 1.0 (or less) Yes
Delta-11-THC 5.0 No
Levonantradol 0.03
0.1
0.3
0.56
Yes
Nantradol 0.2
0.4
Yes
Cynomolgus 24,58 Levonantradol 0.03 No

Since the cannabinoid regimens, the dose prescribed, the number of subjects and the type of animal subjects differ from one study to another, further investigations are required to better understand the association between cannabis and ptosis. To confirm that cannabinoids are ptosis inductors, more detailed studies should be conducted to examine how cannabis causes ptosis. In the future, clinical trials should be conducted to better assess the “ptosis” effect of cannabis in patients.

7. Conclusions

It is important to better understand the cannabinoid system effect on the eyelids to develop new, efficient and safe therapeutic targets. The relationship between cannabinoids and eyelid tremors is still unclear; some studies have shown that cannabis can potentially treat blepharospasm, while others have noted light eyelid tremors and significant ptosis as secondary effects.

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