Introduction

Cannabis is currently the most used drug worldwide, with an estimated 219 million users in 2021,¹ and refers to a group of plants that includes Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

Studies have reported the therapeutic efficacy of cannabinoids in treating chronic pain, alleviating spasticity in multiple sclerosis, and serving as an antiemetic.² Research into cannabinoids’ applications to treat ocular conditions have revealed its potential in treating blepharospasm^3–8 and lowering intraocular pressure in glaucoma.^9–30 Animal studies demonstrate anti-inflammatory and analgesic properties, corneal regenerative effects,^31–40 and retinal neuroprotective effects of cannabinoids.^41–54

Several unwanted effects of medical and recreational cannabis use are described in the scientific literature, including nausea, somnolence, and hallucinations.² Other reports have suggested more substantial effects, including its contribution to the incidence of psychotic disorders.⁵⁵ As for its effects on the eye, adverse ocular effects of cannabinoids and cannabis reported in contemporary literature include eyelid tremor,^56–60 ptosis,^61–68 corneal opacification,^69,70 reduced corneal endothelial cell count,⁷¹ reduced corneal revascularization,⁷² neuroretinal dysfunction,^73–84 retinal vasculature abnormalities,^47–52 and impaired extraocular motility.^85–101 As ongoing research explores the therapeutic benefits of cannabinoids, the understanding of its adverse effects continues to evolve. Given the growing clinical and non-clinical uses of cannabis and cannabinoids, this article aims to identify adverse ocular effects and assess the emerging potential of cannabinoids in ocular therapeutics.

Brief Historical Context

The growing movement towards the decriminalization and legalization of cannabis^1,102,103 necessitates a comprehensive understanding of its physiological effects. In the last decade, there has been a 23% increase in global users:¹ a growth rate more rapid than both opiates and cocaine.¹⁰⁴ As of 2023, cannabis, commonly referred to as marijuana, pot, weed, grass, or herb, is legal in several countries,¹⁰² and 23 states in the United States.¹⁰³

The use of cannabis for medical purposes has occurred for millennia, with the first historical documentation of its medical use appearing nearly 5000 years ago in Ancient Chinese texts.¹⁰⁵ There has been a resurgence of interest in the uses of cannabinoids, the chemical compound in cannabis, to treat several medical conditions in the last few decades.^2,106,107

Method of Literature Search

A systematic literature search of Ovid MEDLINE, Ovid Embase, and Scopus from inception of the databases to June 25, 2023, was conducted to identify relevant papers. The search strategy was developed and validated for each database with an academic librarian using both controlled vocabulary (ie, MeSH and Emtree terms) and free-text terms. The search terms used to identify relevant articles across databases are shown in Supplementary Box 1. We further reviewed reference lists of published reviews identified through our search to ensure comprehensive coverage of relevant studies that may have been missed in the initial search. This study was exempt from requiring ethics review by the University of British Columbia Behavioural Research Ethics Board (BREB) given the use of publicly available information, as per TCPS (Article 2.2).¹⁰⁸ To enhance accessibility for non-eye care professionals, we have included a brief glossary of relevant ophthalmologic and pharmacologic terms for reference in Supplementary Box 2.

Inclusion and Exclusion Criteria

Studies were included if they discussed adverse ocular effects or therapeutic applications of cannabis or cannabinoids. All forms of cannabinoids were considered, including CBD, THC, as well as synthetic cannabinoids (eg, HU-308, UR-144, XLR-11, Nabilone, Dronabinol, Levoantradol, SR 141716A, WIN55,212–2, GAT211, GAT228, HU211). Any route of administration could be utilized (eg, oral, sublingual, topical). Study abstracts must be written in English, and all study designs were accepted. Observational and experimental studies on human participants were prioritized, while laboratory and animal studies were also considered for supplementation. Studies were excluded if they were not relevant to the research topic, not in English, or not peer reviewed.

Screening and Extraction

Abstracts were screened for relevance by two independent reviewers (MB, LL), and conflicts were resolved through discussion with a third reviewer (AXN). Data extraction of relevant studies was conducted descriptively, and articles were organized by topic, relevance, and conclusions through a collaborative, iterative process.

Pharmacological Effects of Cannabinoids

The cannabis plant species contains approximately 540 natural compounds, over 100 of which are classified as phytocannabinoids (plant-derived cannabinoids) based on their chemical structure.¹⁰⁹ The most extensively studied phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which are the predominant psychotropic and non-psychoactive ingredients, respectively.¹⁰⁹ The C. sativa plant has multiple chemotypes that vary in their relative composition of THC and CBD.¹¹⁰

Chemically, phytocannabinoids are a diverse group of isoprenylated resorcinol polyketides. Phytocannabinoids are categorized based on their affinity to the two main cannabinoid receptors: Cannabinoid receptor type 1 (CB₁) and Cannabinoid receptor type 2 (CB₂).¹¹⁰ CB₁ and CB₂ receptors belong to a well-known family of G protein-coupled receptors (GPCR), which plays a central role in the endocannabinoid system. CB1 and CB2 are coupled through G proteins, particularly G i/o (inhibitory G protein), to inhibit adenylate cyclase and influence mitogen-activated protein kinase signaling in some contexts.¹¹¹ CB₁ receptors are also coupled through G proteins to various calcium and potassium channels, promoting neuron hyperpolarization.¹¹¹

Cannabinoid Receptors

The localization of CB₁ and CB₂ receptors has been delineated using several strategies, each providing unique insights.¹¹² These include messenger RNA in situ hybridization, immunocytochemistry, and quantitative autoradiography.¹¹³ CB₁ receptors are mainly localized to the brain and central nervous system, while CB₂ receptors are predominately localized to the peripheral nervous system and immune system.^111,114,115

Most CB₁ receptors are located on the pre-terminal axonal segments of neuronal axons, with fewer on other parts of the neuron.¹¹⁶ CB₁ receptors can also be found on CCK-positive basket cells,¹¹⁶ on many glutamatergic terminals in the brain,¹¹⁷ and within some peripheral tissues, including the liver,¹¹⁸ pancreas,¹¹⁹ skeletal muscle,¹²⁰ and adipocytes.¹²¹ CB₂ receptors are expressed on immune cells,¹¹⁵ neuronal cells,¹²² as well as cells involved in bone mass regulation.¹²³

The human body produces endogenous cannabinoids called endocannabinoids.¹¹² The endocannabinoid system consists of cannabinoid receptors and the enzymes responsible for the synthesis and degradation of endocannabinoids.¹¹² Endogenous cannabinoids include arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG).¹¹¹ These endogenous cannabinoids activate CB₁ and CB₂ receptors, amongst other GPCRs and ion channels.¹²⁴ The simple conceptual framework of agonists and antagonists is not enough to understand the complex pathways within the endocannabinoid system,¹¹² with a complete understanding requiring an understanding of partial agonism,¹²⁵ functional selectivity,¹²⁶ and inverse agonism.¹²⁷

Safety Considerations

The psychoactive cannabinoid, THC, produces many of the adverse effects of cannabis, while the non-psychoactive CBD is credited for its therapeutic effects.^107,128 Non-medical cannabinoid products have differences in their relative concentrations of CBD and THC.¹¹⁰ Retailers who sell cannabinoids are not subject to the same strict regulations as medical prescriptions.¹²⁹ CBD preparations of these products are often inaccurate,^130,131 with CBD and THC concentrations often mislabeled.^132,133 Individuals who use cannabis for self-medication report treating pain, anxiety, depression, headache/migraine, nausea, and muscle spasticity.¹³⁴ The CBD concentrations from retail products are often lower levels than those used in clinical trials and may even contain THC levels that exceed legal limits.¹³⁰ Meanwhile, medical-grade cannabinoids, both synthetic or plant-derived, have more accurate concentrations of THC and CBD.¹²⁹ Plant-derived or synthetic CBD have no pharmacological differences when tested in vitro.¹³⁵

Information on cannabinoid drug interactions is scarce,¹³⁶ which raises safety concerns. The mechanisms of these drug interactions include CBD’s inhibition of drug transport,¹³⁷ enzyme inhibition,¹³⁸ and enzyme induction.¹³⁹ Cannabis and cannabinoids can have adverse psychiatric effects, such as the increased risk of psychotic disorders, anxiety or panic attacks in naïve users, structural and functional alterations to the brain, mood disturbances and depression, and risks of lung cancer when smoked.¹⁴⁰ Consequently, medical cannabis is contraindicated in patients with unstable cardiovascular or respiratory disease, and those with a personal or strong family history of psychosis.¹⁴¹

Cannabinoids and the Ocular Response

The primary mechanism of action of cannabinoids on the eye is through CB₁ and CB₂ receptors.¹⁴² These GPCRs are part of the extensive endocannabinoid system throughout the body.¹⁴³ Both receptors play a crucial role in modulating the release of neurotransmitters¹⁴³ and represent a nuanced interplay between the endocannabinoid system and neuronal health.

CB₁ receptors are located in the central nervous system, including the eyes, and have been shown to provide neuroprotection to retinal cells, particularly in reducing excitotoxicity, inflammation, and oxidative stress.¹⁴² CB₁ receptors are also located on the corneal epithelium and endothelium.¹⁴⁴ While activation of CB1 receptors has been associated with neuroprotective effects, chronic or excessive CB1 activation, often with the use of exogenous cannabinoids like THC, can potentially cause neurotoxicity.

While some studies suggest CB2 expression in the eyes,¹⁴⁵ this topic remains controversial.¹⁴² They have been shown to mediate immune and inflammatory responses and contribute to aqueous humor turnover, which can ultimately also promote neuroprotection by suppressing inflammation and immune-mediated damage.^22,40,146

Barriers to Ocular Drug Delivery to the Eye

On the ocular level, topical administration of drugs is preferred as it can reduce adverse effects from systemic routes of administration.¹⁴⁷ However, only 3–5% of the administered dose reaches the eye due to structural and dynamic barriers.¹⁴⁸ When drugs are administered orally, only 1–2% reach the eye,¹⁴⁹ and they present with greater systemic adverse effects. Furthermore, orally administrated drugs must pass through the gastrointestinal tract, traverse the bloodstream, and cross the uve-ocular barriers.¹⁴⁹ The eye is considered immune privileged due to these blood-ocular barriers, which consist of the blood-aqueous barrier (BAB) in the anterior segment and the blood-retinal barrier (BRB) in the posterior segment of the eye.¹⁵⁰ Intravenous and intramuscular routes of administration must overcome the BRB to reach therapeutic targets in the eye.

With topical drug delivery to anterior eye segment structures, only about 3–5% of the applied dose is effective due to protein interactions in the tear film, tear turnover rate, and drug removal through the blinking reflex.¹⁵¹ Physiological barriers present additional challenges for therapeutic targets in the anterior segment, as drugs must pass through several layers. After administration, a drug interacts with the lacrimal fluid (tears), forming a tear film that consists of a lipophilic external, aqueous middle, and mucin inner layer containing electrolytes, lipids, and proteins, which can partially hydrolyze the drug and thus reduce bioavailability.¹⁵² The tear turnover rate and blinking reflex result in a short contact time of the drug with ocular surface tissue. Loss of ophthalmic solution via nasolacrimal drainage or systemic absorption via the conjunctiva is a dynamic barrier to drug delivery.¹⁵² The corneal epithelial layer comprises a single layer of basal cells and several layers of stratified squamous epithelial cells held together by tight junctions. These cells serve as a barrier against drug penetration via paracellular and transcellular transport pathways.¹⁵² Once reaching the anterior chamber, drugs may bind to melanin pigments in the uvea, thus reducing bioavailability in the anterior chamber.¹⁵³ Topical administration is favorable in the treatment of conjunctivitis, blepharitis, glaucoma, or anterior uveitis.¹⁵⁴ When drugs targeting the anterior chamber are delivered systemically, they must overcome the BAB, which consists of the endothelium of the iris/ciliary blood vessels and the non-pigmented ciliary epithelium.¹⁵⁵

Drug administration to the posterior segment of the eye occurs via intravitreal, transscleral, subretinal, and topical modes of administration, with the latter being less suitable due to the anatomical specificities of the eye.¹⁵⁶ Topical ocular administration targeting structures in the posterior segment must cross the tear film, conjunctiva, cornea, aqueous humor, and vitreous humor. For this reason, posterior segment targets typically require intravitreal and subretinal administration.¹⁴⁹

Ocular Teratogenic Effects

A study using pregnant mice found that prenatal exposure to cannabis smoke for 5 minutes each day during gestation resulted in 17% thinner retinas in young adulthood, but this result normalized in older adulthood.¹⁵⁷ A longitudinal cohort study of 794,099 infants in Quebec, Canada revealed that prenatal substance exposure was significantly associated with childhood eye disorder hospitalization.¹⁵⁸ Exposure to illicit drugs in utero, including smoked cannabis, was also shown to result in reduced visual acuity, nystagmus, and delayed visual maturation in a case series of 20 patients.¹⁵⁹ However, these findings were not specific to cannabis exposure, as many participants in the study were known users of other illicit substances (including benzodiazepines and opiates),¹⁵⁹ making cannabis-related effects inconclusive.

Adverse Ocular Effects — Anterior Segment

Red Eyes in Cannabis Users

Smoked cannabis causes acute, transient conjunctival injection, or red eye, among users.^100,160 Hence, this is one of the most sensitive objective signs of cannabis use, with one study reporting that 94% of drug-impaired drivers with a positive THC blood sample have red eyes.¹⁰⁰ THC induces vasodilation through binding cannabinoid receptors in the eye. These on-target effects increase blood flow to the conjunctiva, leading to conjunctival redness. Animal models suggest the degree of THC-induced vasodilation is dose-dependent.¹⁶¹

Dry Eyes and Cannabis

A study on THC’s role in aqueous deficiency dry eye (ADDE) found that CB₁ receptors are expressed in cholinergic neuronal axons innervating lacrimal gland cells.¹⁶² CB₁ activation by THC reduced tearing in male mice, but this was not seen in female mice.¹⁶² Other studies on mice have implicated endocannabinoid receptors’ multi-factorial role in dry eye disease (DED).¹⁶³. A theoretical benefit of cannabis to treat DED through THC-mediated pain relief and CBD-mediated anti-inflammation has been proposed.¹⁶³ In contrast, dry eye symptoms have been reported by cannabis users in several studies. In a study on medical cannabis users, 8.7% reported dry eyes.¹⁶⁴ In a randomized control trial of smoked cannabis for chronic neuropathic pain, dry eyes were one the most common drug-related adverse reactions in the group that received the 9.4% THC formulation.¹⁶⁵ A study of orally administered nabilone, a synthetic cannabinoid, also reported dry eyes as a side effect.¹⁶⁶

Decreased Corneal Endothelial Cell Density in Cannabis Users

As discussed earlier, CB₁ receptors are predominantly located in the corneal epithelium and endothelium.¹⁴⁴ A study on cannabis users found a decreased corneal endothelial cell density among chronic users,⁷¹ likely due to cannabinoid toxicity as CB₁ receptors are prominent in the anterior eye segment.

Topical THC Eyedrops Cause Corneal Opacification in Animal Studies

Experimental studies on the topical application of THC eyedrops in animal studies have demonstrated corneal opacification following administration in cats,^69,70 as shown in Table 1. This is thought to occur due to decreased corneal hydration, as activated CB₁ receptors inhibit corneal endothelial cell pumping action, attenuating aqueous humor removal from the cornea, which is needed to maintain corneal transparency.^70,167.

Table 1 Summary of Studies on the Effects of Cannabis on the Cornea

Cannabis Effects on Pupils

Cannabis’ effects on pupil size are conflicting. Several studies suggest acute cannabis smoking causes pupillary constriction.^169–171 Meanwhile, other studies report pupillary dilation following acute cannabis smoking,^100,160,172 likely mediated by sympathetic stimulation.¹⁷² A study of 39 synthetic cannabinoid UR-144 users found pupillary dilatation and, less commonly, pupillary constriction.⁵⁶ Other studies found that smoking cannabis promoted abnormal pupillary reactions to light,^160,171 including a decrease in contraction velocity after a light stimulus,¹⁶⁹ or more simply reported as a “decreased” pupillary light reflex.^160,171

Adverse Ocular Effects — Posterior Segment

Scotopic Vision

GPR55 is expressed in rod photoreceptors and has been implicated in mediating scotopic night vision in animal models.¹⁷³ The cellular mechanism by which this occurs was delineated using tadpoles, whereby CB₁ receptor activation improved visual contrast sensitivity under low-light conditions.¹⁷⁴ Several reports describe anecdotal evidence of improvements in night vision after smoking cannabis,^175–177, a strategy fishermen use.¹⁷⁵ A study in nature evaluating self-reported vision changes after smoked cannabis found that 68% of participants had worsened glare and halos, and 74% felt smoking cannabis diminished their ability to drive at night.¹⁷⁸ Similarly, a study of 64 healthy volunteers found reductions in night vision when measured at 20 minutes after smoking cannabis.¹⁷⁹ With limited and conflicting evidence, whether cannabis transiently improves night vision in humans remains inconclusive.

Visual Acuity

The effects of cannabis on static visual acuity are not fully elucidated. Ortiz-Peregrina et al found a reduction in static vision following smoking cannabis,¹⁷⁸ while Adams et al found no differences in low and high-contrast conditions after smoking cannabis.⁸⁷ Brown et al demonstrated that cannabis use produces dose-dependent reductions in dynamic visual acuity.¹⁸⁰ At an oral dose of 20 mg, while THC provided mild analgesic effects, it also led to blurred vision in cancer patients.¹⁸¹ As for long-term effects, one study demonstrated visual acuity deficits in chronic (>10 years) cannabis users.¹⁷² A case-control study found delayed ganglion cells action potential transmission in regular cannabis smokers.⁷⁴

Reduced Contrast Sensitivity

Contrast sensitivity is another visual function measure. A 30% reduction in binocular and nearly 50% reduction in monocular contrast sensitivity has been demonstrated following smoking cannabis,^178,179 even after consideration of the potential contributions of attention and vigilance.¹⁸² Another study found contrast sensitivity reductions in cannabis users only in low luminance conditions.⁹⁸

Neuroretinal Dysfunction in Cannabis Users

Neuroretinal dysfunction was a documented effect of cannabis on the retina through several studies involving humans. Hallucinogen Persisting Perception Disorder (HPPD), a condition whereby users of hallucinogens continue to experience perceptual disorders for months to years after discontinued drug use, has been reported following heavy cannabis smoking⁷³ (Table 2). One study reported relative and absolute scotomas in five subjects measured through campimetry, as well as pathological changes identified on visual evoked potential (VEP) and electroretinogram (ERG) testing in individuals with polysubstance use disorders.⁷⁵ However, in addition to using cannabis, most study participants also used cocaine, and all used heroin.⁷⁵ Another case report found transient alternations in photoreceptor function on ERG following acute cannabis inhalation.⁷⁶ In a case report of a 25-year-old chronic cannabis smoker with unilateral blurred vision and several subretinal blebs, subretinal blebs resolved after cannabis smoking cessation.⁷⁷ It is difficult to ascertain whether this was due to the cannabis smoking, as the patient was not re-challenged to see if the blebs reappear if cannabis use was reinitiated.⁷⁷ A study that involved 60 former synthetic cannabinoid users found no significant retinal changes on OCT.⁷⁸

Table 2 Summary of Studies on the Effects of Cannabis on the Retina and Retinal Vasculature

Pattern and flash ERGs have helped investigate synaptic transmission abnormalities in cannabis users. Case-control studies of long-term cannabis smokers have reported ganglion cell dysfunction through delayed action potential transmission,^74,80 which was found to occur at the central retinal level⁸² (Table 2). A later study found the degree of this dysfunction to be associated with the quantity of cannabis smoked.⁸³ In addition, other studies have found sustained abnormal visual transmission through decreased amplification by amacrine cells in long-term cannabis smokers.⁷⁹ Delayed bipolar cell neuroretinal processing has also been delineated,^80,81 and confirmed to be due to On and Off pathway dysfunction in cannabis smokers⁸¹ (Table 2). Furthermore, a study on mice found functional loss and increased apoptosis in photoreceptor cells following 1 or 2 mg/kg intraperitoneal THC exposure daily for two months.⁸⁴

Retinal Vasculature Abnormalities in Cannabis Users

Several case reports have proposed associations between cannabis use and abnormalities in retinal vasculature. One case report demonstrated central retinal vein occlusion only minutes following cannabis smoking in an otherwise health 18-year-old male.⁴⁸ Another case reported branch retinal artery occlusion and acute maculopathy in a 21-year-old man, and suggested this may be due to long-term heavy cannabis smoking¹⁸³ (Table 2). A case report of monocular vision loss following hemorrhagic macular infarction in a 55-year-old man was suggested as being associated with his long-term cannabis smoking³³; however, the event seems to be more temporally related to his pregabalin and alcohol overdose in a suicide attempt the previous night.⁴⁷ Given the lack of observational studies or larger case series to substantiate these findings, the proposed associations between cannabis use and retinal vascular abnormalities should be interpreted cautiously until more robust, population-based research is available.

Animal studies have demonstrated the dose-dependent effects of abnormal cannabidiol (abn-CBD), a synthetic CBD, through pre-contracted retinal arteriole vasodilation.^51,184 This is consistent with a cross-sectional study of 8 participants, whereby an oral dose of 7.5 mg dronabinol, a synthetic cannabinoid and THC derivative, significantly decreased retinal arteriovenous passage time.⁵² This effect was further verified in a randomized clinical trial of 24 individuals, which found increased optic nerve head blood flow following 5 mg oral administration of dronabinol.⁵⁰ An observational study on 106 young adults found that mean arteriolar diameter was significantly wider amongst frequent cannabis smokers compared to controls,⁴⁹ which may represent residual vasodilatory effects from cannabis smoking or impaired autoregulation resulting from chronic cannabis use⁴⁹ (Table 2).

Adverse Ocular Effects — Adnexal Structures

Cannabis and Cannabinoids May Cause Transient Eyelid Tremors

Several studies have reported transient eyelid tremors as a physical symptom after synthetic cannabinoid^56,59 and cannabis use^58,59 (Table 3). Eyelid tremor is an umbrella term referring to involuntary and intermittent eyelid muscle spasms.⁶¹ While both blepharospasm and eyelid tremor involve abnormal eyelid movements, they are different in their underlying causes, associated symptoms, and clinical presentation.⁶¹ These reports do not provide clinical detail about the cannabis and cannabinoid related eyelid tremors and may instead refer to temporary tremors distinct from true blepharospasm,^56–59,61 as demonstrated in Table 3. One study of 302 participants noted eyelid tremors in 86.1% of subjects with THC blood levels greater than 1 μg/L by a drug recognition expert (DRE) examination,⁵⁹ while another study demonstrated 6 out of 18 individuals in driving cases who tested positive for synthetic cannabinoid XLR-11 had eyelid tremors.⁵⁷ In a study of drug-impaired driving cases, 39 participants with UR-144 concentrations ranging from trace levels to 17 ng/mL, eyelid tremors were among the most reported signs⁵⁶ Stress and fatigue are common causes of eyelid tremors,¹⁸⁶ which may be a confounder to the presence of eyelid tremors in the drug-impaired drivers within these studies.^56–59

Table 3 Summary of Studies on the Effects of Cannabis on the Eyelids

An interventional study of 5 patients with dystonic movement disorder received oral CBD at doses starting at 100 mg/day, up to 600 mg/day over 6 weeks and found dose-related improvement of dystonia, with maximal improvement ranging from 20–50%⁴ (Table 3). Benign essential blepharospasm (BEB) is a bilateral focal dystonia characterized by episodic contraction of the eyelid protractor muscles that causes progressive spasms. In a retrospective study of 5 patients with Benign Essential Blepharospasm (BEB) refractory to botulism toxin injections (defined by the researchers as patients with residual symptoms despite being on long-term botulinum toxin therapy), participants received varying doses of oral CBD (5 to 47.5mg) and THC (2.5 to 25 mg) and all but one patient discontinued treatment due to cost, side effects, or lack of treatment efficacy.⁶ A case report of a woman with severe BEB refractory to botulism toxin injections received oral dronabinol 25 mg for several weeks and reported improved pain and functional status.⁸ More recently, a randomized controlled trial involving 6 patients with blepharospasm demonstrated the efficacy of 3.2% THC and 0.1% CBD containing drops administered sublingually in the treatment of blepharospasms, as a second-line therapeutic option in patients who repeatedly fail (eg, showed no improvement) first-line treatment using botulinum toxin injections⁷ (Table 3).

Cannabinoids May Result in Ptosis or Droopy Eyelid

Ptosis, also known as droopy eyelid or blepharoptosis, is characterized by an abnormally low upper eyelid margin position, which may cause visual disturbances or lead to cosmetic concerns.¹⁸⁷ Ptosis in the setting of cannabinoid use is classified as having an acquired etiology, as opposed to congenital or involutional causes. One human study of impaired drivers found that 85.6% of blood THC-positive drivers had ptosis identified on field sobriety tests¹⁰⁰ (Table 3). This study did not define how ptosis was measured or defined.

Animal model studies have demonstrated ptosis resulting from intraperitoneal Anandamide,⁶³ intraperitoneal SR 141716A,⁶² as well as cannabinoids administered intravenous or intramuscularly^65,67,68 (Table 3). Meanwhile, others have reported ptosis as part of cannabinoid withdrawal.^64,66 While most of these studies defined ptosis, whether this effect is chronic, or transient has not been described. Similarly, murine models demonstrated that ptosis resulted from intraperitoneal anandamide, an endogenous cannabinoid.^63,66 In a study of non-human primates, rhesus monkeys developed ptosis following acute exposure to intravenous Δ-9-THC but not Δ-11-THC.^65,68 Another study on cynomolgus monkeys treated with intramuscular levonantradol, a synthetic THC analog, at doses ranging from 0.01 to 0.03 mg/kg experienced ptosis, but this did not reach statistical significance.⁶⁷ Overall, animal studies have demonstrated strong evidence that cannabinoids may be associated with ptosis. Observational studies on cannabinoids and cannabis users may provide further insight into potential unwanted effect in humans.

Topical THC Eyedrops and Eyelid Swelling

One study exploring whether topical 1% THC eyedrop administration can decrease intraocular pressure (IOP) reported that 4 out of 28 participants dropped out due to acute burning sensation and “lid swelling”.¹⁴ However, 3 out of 4 participants who dropped out were in the control group that received light mineral oil, not THC.¹⁴ Based on these findings, it cannot be concluded that THC drops cause acute eyelid swelling.

Table 4 Summary of Studies on the Effects of Cannabis on Extraocular Muscle Functioning

Oculomotor Control

Cannabis and cannabinoid effects on extraocular motility have been examined in the context of intoxication from recreational use and as side effects following medical uses^85–101 (Table 4). Early investigations compared the impact of smoked cannabis and drinking alcohol on ocular movements, and found that alcohol impaired saccades and smooth pursuit, while cannabis did not.^85,86,191 Long-term heavy cannabis use may influence static visual acuity, potentially affecting visual performance and promoting changes in psychomotor performance, including ocular motor control.⁹⁶ Long-term studies by Huestegge et al investigated inhaled cannabis’ persistent effects on oculomotor function and eye movement control during reading in a cross-sectional study. In the study, 20 long-term cannabis users (without acute THC intoxication) had prolonged fixation time, increased text revisiting, and longer word viewing times compared to non-users, suggesting that even subtle deficits in essential oculomotor control can impact reading performance^89,90 (Table 4). Potential sustained alterations, including increased fixation time, delayed response times, altered saccadic amplitudes, extended text recheck, and elongation of word visualization were also identified in chronic cannabis users.^89,90

Stereopsis

A reduction in three-dimensional vision following smoking cannabis was demonstrated through a deterioration in stereoacuity^178,179 (Table 4), defined as the ability to detect differences in the depth of field.¹⁷⁸ Other studies have shown a reduction in binocular depth inversion, a sensitive measure of impaired visual information processing, for up to 192 hours after cannabis resin at a dose of 3.0–4.0 mg/kg in seven healthy volunteers¹⁹² and permanent reductions in chronic cannabis smokers when measured using a random-dot stereogram.¹⁹³ As cannabinoids’ effects on extraocular motility implicate a complex interplay with various aspects of visual functioning, including ocular tracking, gaze stability, and nystagmus, further research is needed to investigate these effects.

Gaze Stability and Nystagmus

Beyond gaze stability, cannabinoids have been associated with eye deviation,⁹¹ possibly due to alterations of neural pathways involved in eye movement coordination and control.^91,93 One case reported conjugate dextrodeviation of the eyes from cannabis intoxication after inadvertent ingestion, with effects lasting six weeks⁹¹ (Table 4). Several studies of impaired drivers found horizontal gaze nystagmus a common sobriety examination finding,^58,189 which was later tested on 44 human participants, 43 (98%) of which exhibited HGN after smoking cannabis within the three-hour impairment window¹⁹⁰ (Table 4).

Thyroid Storm

A case was reported on a 25-year-old man with Graves’ disease who passed away following a thyroid storm, which was thought to have been triggered by smoking synthetic cannabinoids the morning of his presentation to the hospital.¹⁹⁴ No other cases have been reported.

Therapeutic Applications of Cannabis and Cannabinoids

Corneal Anti-Inflammatory Properties in Animal Studies

Studies have demonstrated potential therapeutic effects through acute ‘cannabinoid-associated anti-inflammatory, analgesic, and regenerative effects on the cornea,^31–40,168 as summarized in Table 1. These include topical cannabinoid receptor agonist WIN55,212-2.^34–36,168 Furthermore, in vitro human and in vivo animal studies have demonstrated reduced corneal neovascularization through CB₁ receptor antagonism.^72,195 Additional studies investigating these potential therapeutic effects are needed.¹⁹⁶

Pterygium

Cannabinoid receptor differential expression in patients with pterygium, a wedge-shaped fibrovascular outgrowth that originates in the conjunctiva and extends into the cornea,¹⁹⁷ has been reported. This may imply a potential role of cannabinoid targets in the understanding of pterygium.¹⁹⁷

Retina Neuroprotective Effects in Animal Studies

The therapeutic potential of cannabinoids on the retina has been explored through several animal studies. A 2008 study that claimed neuroprotective and anti-inflammatory CBD effects on the retina was retracted in 2014 by the journal editors as the findings were not supported by the presented research data.¹⁹⁸ Rat model glaucoma studies have demonstrated that intravenous THC or synthetic cannabinoid HU-211 injections significantly reduce retinal ganglion cell (RGC) death,^42,43 likely mediated by IOP reduction⁴² (Table 2). Topical administration of cannabinoid receptor agonist WIN 55212-2 has demonstrated similar neuroprotective effects in rat ischemic models of retinal ganglion cell loss.⁴⁴ Two studies demonstrated the neuroprotective effects of intraperitoneal synthetic cannabinoid HU-211 injections in rats following optic nerve crush injuries, including a metabolic and electrophysiological deficit reduction,⁴⁵ and regenerative growth following injury⁴⁶ (Table 2). Accordingly, while cannabinoid retinal neuroprotective effects have been illustrated in animal studies, this has yet to be demonstrated in the human retina.

Retinal ischemia plays a role in various ocular pathologies, including diabetic retinopathy and glaucoma.¹⁸⁵ One study demonstrated that the TRPA1 receptor is a critical element in cell death following the early stages of ischemia.¹⁸⁵ By using synthetic cannabinoid receptor agonists, a decrease in lactate dehydrogenase (LDH) was demonstrated in chick retinal models.¹⁸⁵ LDH was used as a cell death marker in the study.¹⁸⁵ The therapeutic potential of cannabinoids in retinal degenerative etiologies has been explored using animal models. A mouse model study utilizing the CB₁ agonist SR141716A found photoreceptor loss recovery following degeneration⁴¹ (Table 2).

Applications in Diabetic Retinopathy

Differential expression of endocannabinoids in the ocular tissues of diabetics has been documented, including differences in endocannabinoid concentrations in diabetic patient aqueous humor¹⁴⁶ and higher endocannabinoid (AEA and 2-AG) levels in specific anatomical locations within ocular tissue in the post-mortem eye tissue of diabetic retinopathy patients.¹⁸⁸ Differential levels of endocannabinoids in the aqueous humor of diabetic and non-diabetic patients may offer a novel therapeutic target for diabetic retinopathy. Given previous studies suggesting endocannabinoids may offer neuroprotection through anti-inflammatory activity, elevated levels of endocannabinoids may be a mechanism for counteracting inflammation in diabetic retinopathy.¹⁸⁸

Applications in Glaucoma

Glaucoma is a heterogenous group of irreversible diseases characterized by damage to the optic nerve.¹⁹⁹ Therapies focused on reducing IOP are still the primary strategy to prevent disease progression, as IOP remains one of the few modifiable risk factors for glaucoma management.¹⁹⁹ Therapeutic and adverse effects of cannabinoids on IOP have been researched by nine groups involving a total of 112 individuals,^9–30 with most studies focusing on primary open-angle glaucoma (Table 5).

Table 5 Studies on the Effects of Cannabis on Intraocular Pressure

Cannabinoids have been shown to promote an IOP decrease in animal and clinical investigations which date back to the 1980s. In 1976, Cohen described a 30% drop in IOP levels for 4–5 hours following smoking of a mean of 103 mg THC in 7 out of 11 individuals with open-angle glaucoma.¹⁰ In 1977, a prospective study with 10 subjects receiving intravenous (mean 1.5 or 3.0 mg), weight-adjusted THC experienced a 51% IOP-reduction from baseline.¹¹ It was later found that the BW146Y chemical derivative exhibited a noteworthy independent reduction in intraocular pressure, while BW29Y did not effectively lower intraocular pressure, with both compounds showing mild side effects¹⁹ (Table 5).

Subsequent studies have supported short-term THC IOP-reducing effects, thought to occur through aqueous humor outflow mechanisms and trabecular meshwork cell signaling.³⁰ In 2018, an animal study indicated that THC lowers IOP by activating CB₁ and GPR18 receptors, whereas CBD was found to potentially interfere with the IOP-related effects of THC¹⁶ (Table 5). Altinsoy et al also investigated cannabinoids’ potential counter-benefits in rabbits through the impact of anandamide on endotoxin-induced uveitis.²⁵ The authors eventually concluded that this endogenous cannabinoid ligand can exacerbate uveitis despite the background IOP-reducing benefit.²⁵ While THC has been shown to lower IOP, the effects of other cannabinoids (eg, CBD) and endogenous ligands (eg, anandamide) require further investigation.

Synthetic cannabinoids have also been tried in patients with glaucoma who have not achieved adequate IOP control (<22 mmHg) despite being on two or more topical pharmacotherapies, suggesting a potential therapeutic role in refractory cases.¹⁷ Particularly, the synthetic cannabinoid WIN55212-2 was shown to help decrease IOP in the eyes of 8 patients with glaucoma. In 2006, Tomida et al conducted a pilot study administering sublingual CBD or THC and found a short-term reduction in IOP reduction following 5 mg THC, which was well tolerated in patients.²⁰ No IOP reduction was seen with 20 mg CBD, while short-term increased IOP was demonstrated with 40 mg CBD²⁰ (Table 5).

Given the limited evidence of long-term efficacy in treating glaucoma,^200–202 cannabinoids are considered ineffective or suboptimal therapeutic options.^203,204 This is because of their short duration of action and the incidence of undesirable psychotropic and systemic side effects.^201,203,204 Similarly, according to the National Academies of Science (NAS) report on the health effects of cannabis and cannabinoids, it was concluded that given the lack of evidence of continual IOP reducing effects, cannabinoids show limited potential in the treatment of glaucoma.²⁰⁵

Notably, a study of 18 patients with glaucoma inhaled THC led to increased heart rates and lowered intraocular and blood pressure, with hypotensive effects becoming evident after 60 to 90 minutes of use, generally followed by a reduction in intraocular pressure.¹⁵ Until cannabinoids can be demonstrated to work at least as effectively and with fewer side effects as current glaucoma therapies, cannabis and cannabinoids have yet to be considered a reliable option for treating glaucoma.^203,204 In summary, the long-term efficacy of cannabinoids in disease control have yet to be determined.^201,202,205

Cannabinoids in the Treatment of Blepharospasms

A childhood genetic idiopathic generalized epilepsy, Jeavons Syndrome (JS), is partially characterized by eyelid myoclonia. Oral CBD oil seemed to exacerbate eyelid myoclonus in two individuals with JS and poorly controlled seizures when trialed at 4 mg thrice daily, or 5–10mg/kg/day.⁶⁰ A double-masked randomized control trial using a single dose of 0.03 mg/kg oral nabilone, a cannabinoid receptor agonist, did not demonstrate any significant acute reduction in blepharospasm when compared to placebo⁵ (Table 3). Meanwhile, other studies have demonstrated that cannabis and cannabinoids may be a potential medical treatment for patients with blepharospasms who showed no improvement following repeat treatments with conventional, first-line treatment using botulinum toxin injections^3,4,6,8 (Table 3).

Applications in Pendular Nystagmus

A case reported a 30% reduction in nystagmus at the primary position and improved visual acuity after acute smoking 10 mg cannabis in a patient with congenital horizontal nystagmus.⁹⁴ Another study reported suppressed pendular nystagmus and improved visual acuity in an individual with multiple sclerosis after smoking cannabis, but not with nabilone tablets or THC- containing capsules (trialed up to 40 mg THC per day).¹⁰¹

Limitations and Future Directions

The authors recognize that this review, by focusing on the ocular therapeutic and side effects, may have left unanswered components of cannabis’ complex mechanism of action on the eye. We also recognize that less researched cannabinoids, such as cannabigerol, cannabinol, and cannabichromene, as well as terpenes, including myrcene, limonene, and pinene, were also not discussed due to the large breadth of the topics. Cannabis and cannabinoid molecular targets, active components, and functions in the eye should continue to be explored.

Future studies should consider exploring the following research areas to address current gaps in the scientific literature:

Conclusions

Cannabinoids are not currently considered a first-line treatment option for any ocular conditions. Cannabinoids may cause eyelid tremors and ptosis, while paradoxically demonstrating therapeutic potential as a second-line agent for treatment-refractory blepharospasm. Several animal studies have demonstrated cannabinoids’ anti-inflammatory and regenerative effects on the cornea. Meanwhile, dry eye symptoms are a common side-effect of cannabis use. Cannabinoid retinal neuroprotective effects have only been demonstrated in animal studies. Neuro-retinal dysfunction has been substantiated in cannabis smokers, with evidence of partial reversibility with cannabis smoking cessation. Case reports have alluded to retinal vasculature abnormalities with heavy cannabis smoking. Cannabis and cannabinoids may decrease intraocular pressure in the short-term. There is insufficient evidence to support the use of cannabis and cannabinoids in glaucoma treatment given the absence of long-term therapeutic benefit, neurocognitive and systemic side-effects, and the present availability of more effective therapies. Studies have documented that cannabis and cannabinoids disrupt extraocular motility, including smooth pursuit, gaze stabilization, ocular motor control, fixation time, and eye deviation. Case reports demonstrate suppressed pendular nystagmus following smoking cannabis in individuals with multiple sclerosis.