Association Between Cannabis and the Eyelids
Address correspondence and reprint requests to Albert Y. Wu, MD, PhD, FACS, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive West, Room G3155, Stanford, CA 94303. [email protected], Phone number: (650) 497-0758
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.
Cannabis is a widely used medical treatment and recreational drug.  Despite drooping eyelids being a common side effect, there is little research into cannabis’ effects on the eyelids.  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.  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.  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.  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.
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,  a double-blind, randomised, placebo-controlled, crossover study,  a retrospective chart review,  an open trial  followed by an open label evaluation by the same authors,  and a systematic review of cannabis use in several neurologic conditions including dystonia. 
A drug recognition expert examination,  a review article,  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.  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 ).  In the United States, synthetic cannabinoids are unsafe and unregulated, as they are categorized as new psychoactive substances.  Cannabinoids can be further classified into types, such as cannabidiol (CBD), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabinol (CBN) and cannabichromene (CBC).  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.  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. 
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.  These include: transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1),  transient receptor potential cation channel subfamily M member 8 (TRPM8),  the GPCR serotonin 1A receptor (5-HT1A), and peroxisome proliferator-activated receptors (PPARs) ( Figure 2A ).  Indeed, some cannabidiol derivatives have antinociceptive and anti-inflammatory properties on the eye due to their affinity as ligands to CB2.  THC binding to CB1 also leads to short-term and long-term effects on synaptic transmission.  Hence, cannabinoids interact with multiple systems, including the gabaergic,  serotonergic,  cholinergic  and dopaminergic  pathways ( Figure 2B ).
Schematic Representations of Cannabinoid-Related Pathways
Figure 2A: Ocular Cannabinoid Receptors and Sensory Pathways 
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 
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.  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).  Patients that are resistant to botulinum toxin might consider surgical procedures, such as myectomy, which can provide relief.  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 ).
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
|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
|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
|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.  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 ).  However, the exact mechanisms of cannabinoids, especially in dystonic patients, are still unknown.  It has been suggested that CBD either activates gamma-aminobutyric acid (GABA) or halts the uptake of serotonin.  Another hypothesis is that THC modulates the activity of dopaminergic neurons.  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.  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.  One patient had Meige’s syndrome (Blepharospasm-oromandibular dystonia) and was previously in Synder and Consroe’s preliminary open trial of CBD.  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.  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.  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.  A single dosage of nabilone or placebo (0.03mg/kg) was given to fifteen patients with a clinical diagnostic of primary dystonia.  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. 
5. Cannabis-Associated Eyelid Tremors
Eyelid tremor is a generic term referring to involuntary and intermittent spasms of the eyelid muscles.  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.  Dry eyes are a common characteristic of the blepharospasm reflex.  As a reminder, TRPA1 is actively involved in the peripheral cannabinoid pathway in sensory neurons ( Figure 2A ).  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.  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.  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.  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.  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.  The other studies, including one exposing mouse blood and tissue to ‘buzz’ smoke,  do not specify the ptosis side effect’s subcategory. These findings are interesting as the morphogenesis of human eyelids is comparable to murine models. 
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.  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.  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.  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 ).
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|
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.
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.
Supplemental Table: Diagnosis, Clinical Presentation, Assessment and Treatments
The authors have no financial or conflicts of interest to disclose.
1. World Health Organization [Internet]. Cannabis [cited 2019 June 02]; [about 1 screen]. Available from: https://www.who.int/substance_abuse/facts/cannabis/en/
2. Domino EF, Rennick P, Pearl JH. Dose-effect relations of marijuana smoking on various physiological parameters in experienced male users. Observations on limits of self-titration of intake . Clinical pharmacology and therapeutics . 1974. May; 15 ( 5 ):514–20. PubMed PMID: 4827468. Epub 1974/05/01. [PubMed] [Google Scholar]
3. Radke PM, Mokhtarzadeh A, Lee MS, Harrison AR. Medical Cannabis, a Beneficial High in Treatment of Blepharospasm? An Early Observation. Neuroophthalmology . 2017. October; 41 ( 5 ):253–8. PubMed PMID: 29339959. PMCID: PMC5764009. Epub 2018/01/18. [PMC free article] [PubMed] [Google Scholar]
4. Zuardi AW, Rodrigues JA, Cunha JM. Effects of cannabidiol in animal models predictive of antipsychotic activity . Psychopharmacology . 1991; 104 ( 2 ):260–4. PubMed PMID: 1678894. Epub 1991/01/01. eng. [PubMed] [Google Scholar]
5. Hartman RL, Richman JE, Hayes CE, Huestis MA. Drug Recognition Expert (DRE) examination characteristics of cannabis impairment . Accident; analysis and prevention . 2016. July; 92 :219–29. PubMed PMID: 27107471. Epub 2016/04/25. eng. [PubMed] [Google Scholar]
6. World Health Organization [Internet]. Management of substance abuse: Cannabis [cited 2019 June 02];[about 2 screens]. Available from: https://www.who.int/substance_abuse/facts/cannabis/en/
7. National Institute on Drug Abuse [Internet]. Marijuana [cited 2019 June 02]; [about 2 screens]. Available from: https://www.drugabuse.gov/publications/research-reports/marijuana/what-marijuana
8. Poll Marist [Internet]. Yahoo News/Marist Poll: Weed and the American Family [cited 2019 June 02];[about 1 screen]. Available from: http://maristpoll.marist.edu/yahoo-newsmarist-poll/-sthash.DO4EbP1H.dpbs
9. The Government of Canada [Internet]. The Cannabis Act: The Facts [cited 2019 June 02];[about 2 screens]. Available from: https://www.canada.ca/en/health-canada/news/2018/06/backgrounder-the-cannabis-act-the-facts.html
10. Cerdá M, Kilmer B. Uruguay’s middle-ground approach to cannabis legalization . The International journal on drug policy . 2017; 42 : 118–120. [PMC free article] [PubMed] [Google Scholar]
11. National Conference of State Legislatures [Internet]. Marijuana Overview [cited 2019 July 02]; [about 2 screens]. Available from: http://www.ncsl.org/research/civil-and-criminal-justice/marijuana-overview.aspx
12. Gauter B, Rukwied R, Konrad C. Cannabinoid agonists in the treatment of blepharospasm–a case report study . Neuro Endocrinol Lett . 2004. February-April; 25 ( 1–2 ):45–8. PubMed PMID: 15159681. Epub 2004/05/26. [PubMed] [Google Scholar]
13. Fox SH, Kellett M, Moore AP, Crossman AR, Brotchie JM. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia . Movement disorders : official journal of the Movement Disorder Society . 2002. January; 17 ( 1 ):145–9. PubMed PMID: 11835452. Epub 2002/02/09. [PubMed] [Google Scholar]
14. Snider SR CP. Treatment of Meige’s syndrome with cannabidiol . Neurology . 1984. [Google Scholar]
15. Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders . Int J Neurosci . 1986. November; 30 ( 4 ):277–82. PubMed PMID: 3793381. Epub 1986/11/01. [PubMed] [Google Scholar]
16. Koppel BS. Cannabis in the Treatment of Dystonia, Dyskinesias, and Tics . Neurotherapeutics . 2015. October; 12 ( 4 ):788–92. PubMed PMID: 26271953. PMCID: PMC4604174. Epub 2015/08/15. [PMC free article] [PubMed] [Google Scholar]
17. Porath AJ, Beirness DJ. Predicting categories of drugs used by suspected drug-impaired drivers using the Drug Evaluation and Classification Program tests . Traffic injury prevention . 2019; 20 ( 3 ):255–63. PubMed PMID: 30946603. Epub 2019/04/05. eng. [PubMed] [Google Scholar]
18. Louis A, Peterson BL, Couper FJ. XLR-11 and UR-144 in Washington state and state of Alaska driving cases . Journal of analytical toxicology . 2014. October; 38 ( 8 ):563–8. PubMed PMID: 25217547. Epub 2014/09/14. eng. [PubMed] [Google Scholar]
19. Lichtman AH, Hawkins EG, Griffin G, Cravatt BF. Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo . The Journal of pharmacology and experimental therapeutics . 2002. July; 302 ( 1 ):73–9. PubMed PMID: 12065702. Epub 2002/06/18. eng. [PubMed] [Google Scholar]
20. Beardsley PM, Scimeca JA, Martin BR. Studies on the agonistic activity of delta 9–11-tetrahydrocannabinol in mice, dogs and rhesus monkeys and its interactions with delta 9-tetrahydrocannabinol . The Journal of pharmacology and experimental therapeutics . 1987. May; 241 ( 2 ):521–6. PubMed PMID: 3033218. Epub 1987/05/01. [PubMed] [Google Scholar]
21. Young AM, Katz JL, Woods JH. Behavioral effects of levonantradol and nantradol in the rhesus monkey . J Clin Pharmacol . 1981. August-September; 21 ( S1 ):348S–60S. PubMed PMID: 6271836. Epub 1981/08/01. [PubMed] [Google Scholar]
22. Aceto MD, Scates SM, Razdan RK, Martin BR. Anandamide, an endogenous cannabinoid, has a very low physical dependence potential . The Journal of pharmacology and experimental therapeutics . 1998. November; 287 ( 2 ):598–605. PubMed PMID: 9808686. Epub 1998/11/10. eng. [PubMed] [Google Scholar]
23. Hutcheson DM, Tzavara ET, Smadja C, Valjent E, Roques BP, Hanoune J, et al. Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol . British journal of pharmacology . 1998. December; 125 ( 7 ):1567–77. PubMed PMID: 9884086. PMCID: PMC1565737. Epub 1999/01/12. eng. [PMC free article] [PubMed] [Google Scholar]
24. Meschler JP, Clarkson FA, Mathews PJ, Howlett AC, Madras BK. D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates . The Journal of pharmacology and experimental therapeutics . 2000. March; 292 ( 3 ):952–9. PubMed PMID: 10688609. Epub 2000/02/25. eng. [PubMed] [Google Scholar]
25. Aceto MD, Scates SM, Lowe JA, Martin BR. Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal . The Journal of pharmacology and experimental therapeutics . 1996. September; 278 ( 3 ):1290–5. PubMed PMID: 8819514. Epub 1996/09/01. eng. [PubMed] [Google Scholar]
26. Costa B, Giagnoni G, Colleoni M. Precipitated and spontaneous withdrawal in rats tolerant to anandamide . Psychopharmacology . 2000. April; 149 ( 2 ):121–8. PubMed PMID: 10805606. Epub 2000/05/11. eng. [PubMed] [Google Scholar]
27. Poklis JL, Amira D, Wise LE, Wiebelhaus JM, Haggerty BJ, Lichtman AH, et al. Determination of naphthalen-1-yl-(1-pentylindol-3-yl]methanone (JWH-018) in mouse blood and tissue after inhalation exposure to ‘buzz’ smoke by HPLC/MS/MS . Biomedical chromatography : BMC . 2012. November; 26 ( 11 ):1393–8. PubMed PMID: 22407432. PMCID: PMC3697740. Epub 2012/03/13. eng. [PMC free article] [PubMed] [Google Scholar]
28. National Cancer Institute [Internet]. Cannabis and Cannabinoids: Health Professional Version . [cited 2019 June 02]; [about 1 screen] Available from: https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq
29. SQDC [Internet]. The plant and the main cannabinoids (THC and CBD) . [cited 2019 June 02];[about 2 screens]. Available from: https://www.sqdc.ca/en-CA/learn-about-cannabis/the-plant-and-cannabinoids
30. Ronan PJ, Wongngamnit N, Beresford TP. Molecular Mechanisms of Cannabis Signaling in the Brain . Progress in molecular biology and translational science . 2016; 137 :123–47. PubMed PMID: 26810000. Epub 2016/01/27. eng. [PubMed] [Google Scholar]
31. National Institute on Drug Abuse [Internet]. Synthetic Cannabinoids . 2018. Feb 05 [cite 2019 June 25]; [about 1 screen]. Available from: https://www.drugabuse.gov/publications/drugfacts/synthetic-cannabinoids-k2spice
32. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, … Friedman D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders . Epilepsia . 2014; 55 [ 6 ]:791–802. [PMC free article] [PubMed] [Google Scholar]
33. Zhang D, Zhao Q, Wu B. Structural Studies of G Protein-Coupled Receptors . Mol Cells . 2015; 38 [ 10 ]:836–42. PubMed PMID: 26467290. Epub 2015/10/15. eng. [PMC free article] [PubMed] [Google Scholar]
34. Straiker AJ, Maguire G, Mackie K, Lindsey J. Localization of cannabinoid CB1 receptors in the human anterior eye and retina . Invest Ophthalmol Vis Sci . 1999. September; 40 [ 10 ]:2442–8. PubMed PMID: 10476817. Epub 1999/09/07. eng. [PubMed] [Google Scholar]
35. Vučković S, Srebro D, Vujović KS, Vučetić Č, Prostran M. Cannabinoids and Pain: New Insights From Old Molecules . Front Pharmacol . 2018; 9 :1259-. PubMed PMID: 30542280. eng. [PMC free article] [PubMed] [Google Scholar]
36. Akopian AN, Ruparel NB, Patwardhan A, Hargreaves KM. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation . The Journal of neuroscience : the official journal of the Society for Neuroscience . 2008. January 30; 28 ( 5 ):1064–75. PubMed PMID: 18234885. Epub 2008/02/01. eng. [PMC free article] [PubMed] [Google Scholar]
37. Storozhuk MV, Zholos AV. TRP Channels as Novel Targets for Endogenous Ligands: Focus on Endocannabinoids and Nociceptive Signalling . Current neuropharmacology . 2018. January 30; 16 ( 2 ):137–50. PubMed PMID: 28440188. PMCID: PMC5883376. Epub 2017/04/26. eng. [PMC free article] [PubMed] [Google Scholar]
38. Hind WH, England TJ, O’Sullivan SE. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARgamma and 5-HT1A receptors . British journal of pharmacology . 2016. March; 173 ( 5 ):815–25. PubMed PMID: 26497782. PMCID: PMC4761095. Epub 2015/10/27. eng. [PMC free article] [PubMed] [Google Scholar]
39. Thapa D, Cairns EA, Szczesniak A-M, Toguri JT, Caldwell MD, Kelly MEM. The Cannabinoids ΔTHC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation . Cannabis Cannabinoid Res . 2018; 3 ( 1 ):11–20. PubMed PMID: 29450258. eng. [PMC free article] [PubMed] [Google Scholar]
40. Mackie K. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength . International Journal of Obesity . 2006 2006/April/01; 30 ( 1 ):S19–S23. [PubMed] [Google Scholar]
41. Ativie F, Komorowska JA, Beins E, Albayram O, Zimmer T, Zimmer A, et al. Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity . Frontiers in molecular neuroscience . 2018; 11 :295. PubMed PMID: 30210289. PMCID: PMC6121063. Epub 2018/09/14. eng. [PMC free article] [PubMed] [Google Scholar]
42. Mendiguren A, Aostri E, Pineda J. Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects . Life sciences . 2018. January 1; 192 :115–27. PubMed PMID: 29169951. Epub 2017/11/25. eng. [PubMed] [Google Scholar]
43. Oz M, Al Kury L, Keun-Hang SY, Mahgoub M, Galadari S. Cellular approaches to the interaction between cannabinoid receptor ligands and nicotinic acetylcholine receptors . European journal of pharmacology . 2014. May 15; 731 :100–5. PubMed PMID: 24642359. Epub 2014/03/20. eng. [PubMed] [Google Scholar]
44. Renard J, Norris C, Rushlow W, Laviolette SR. Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments . Neuroscience and biobehavioral reviews . 2017. April; 75 :157–65. PubMed PMID: 28185872. Epub 2017/02/12. eng. [PubMed] [Google Scholar]
45. Bowling B. Facial Spasm: Benign essential blepharospasm . In: Bowling B, ed. Saunders Elsevier 8 : Kanski’s Clinical Ophthalmology. [Google Scholar]
46. American Academy of Ophthalmology. Chapter 11 Periocular Malpositions and Involutional Changes. In: Basic and Clinical Science Course 2018–2019, Section 7 Orbit, Eyelids, and Lacrimal System . San Francisco, CA. [Google Scholar]
47. Defazio G, Hallett M, Jinnah HA, Conte A, Berardelli A. Blepharospasm 40 years later . Movement disorders : official journal of the Movement Disorder Society . 2017. April; 32 ( 4 ):498–509. PubMed PMID: 28186662. PMCID: PMC5941939. Epub 2017/02/12. eng. [PMC free article] [PubMed] [Google Scholar]
48. Defazio G, Abbruzzese G, Livrea P, Berardelli A. Epidemiology of primary dystonia . The Lancet Neurology . 2004. November; 3 ( 11 ):673–8. PubMed PMID: 15488460. Epub 2004/10/19. eng. [PubMed] [Google Scholar]
49. National Institute of Neurological Disorders and Stroke [Internet]. Dystonias Fact Sheet . [cited 2019 June 02];[about 2 screens] Available form: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Dystonias-Fact-Sheet
50. Scott AB, Kennedy RA, Stubbs HA. Botulinum A toxin injection as a treatment for blepharospasm . Archives of ophthalmology (Chicago, Ill : 1960) . 1985. March; 103 ( 3 ):347–50. PubMed PMID: 3977705. Epub 1985/03/01. eng. [PubMed] [Google Scholar]
51. Georgescu D, Vagefi MR, McMullan TF, McCann JD, Anderson RL. Upper eyelid myectomy in blepharospasm with associated apraxia of lid opening . American journal of ophthalmology . 2008. March; 145 ( 3 ):541–7. PubMed PMID: 18191096. Epub 2008/01/15. eng. [PubMed] [Google Scholar]
52. Bloomfield MAP, Ashok AH, Volkow ND, Howes OD. The effects of Δ(9)-tetrahydrocannabinol on the dopamine system . Nature . 2016; 539 ( 7629 ):369–77. PubMed PMID: 27853201. eng. [PMC free article] [PubMed] [Google Scholar]
53. Katagiri A, Thompson R, Rahman M, Okamoto K, Bereiter DA. Evidence for TRPA1 involvement in central neural mechanisms in a rat model of dry eye . Neuroscience . 2015. April 2; 290 :204–13. PubMed PMID: 25639234. PMCID: PMC4359622. Epub 2015/02/03. [PMC free article] [PubMed] [Google Scholar]
54. Clauser L, Tieghi R, Galie M. Palpebral ptosis: clinical classification, differential diagnosis, and surgical guidelines: an overview . The Journal of craniofacial surgery . 2006. March; 17 ( 2 ):246–54. PubMed PMID: 16633170. Epub 2006/04/25. eng. [PubMed] [Google Scholar]
55. Tawfik HA, Abdulhafez MH, Fouad YA, Dutton JJ. Embryologic and Fetal Development of the Human Eyelid . Ophthalmic Plastic & Reconstructive Surgery . 2016; 32 ( 6 ):407–14. PubMed PMID: 00002341–201611000-00001. [PMC free article] [PubMed] [Google Scholar]
56. Stephens LC, Schultheiss TE, Vargas KJ, Cromeens DM, Gray KN, Ang KK. Glands of the eyelids of rhesus monkeys (Macaca mulatta) . Journal of medical primatology . 1989; 18 ( 5 ):383–96. PubMed PMID: 2681785. Epub 1989/01/01. eng. [PubMed] [Google Scholar]
57. Munger BL, Halata Z. The sensorineural apparatus of the human eyelid . The American journal of anatomy . 1984. June; 170 ( 2 ):181–204. PubMed PMID: 6465049. Epub 1984/06/01. eng. [PubMed] [Google Scholar]
58. Cook BEJ, Lucarelli MJ, Lemke BN, Dortzbach RK. The Cynomolgus Monkey Eyelid as an Anatomic Model for Oculoplastic Surgery . Ophthalmic Plastic & Reconstructive Surgery . 2002; 18 ( 3 ):183–9. PubMed PMID: 00002341–200205000-00006. [PubMed] [Google Scholar]
59. Toguri JT, Caldwell M, Kelly ME. Turning Down the Thermostat: Modulating the Endocannabinoid System in Ocular Inflammation and Pain . Front Pharmacol . 2016; 7 :304. PubMed PMID: 27695415. PMCID: PMC5024674. Epub 2016/10/04. eng. [PMC free article] [PubMed] [Google Scholar]
60. Barth C, Villringer A, Sacher J. Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods . Frontiers in neuroscience . 2015; 9 :37. PubMed PMID: 25750611. PMCID: PMC4335177. Epub 2015/03/10. eng. [PMC free article] [PubMed] [Google Scholar]
Getting my Life Back
I have followed the board for some time now, but this is my first posting. A little over a year ago, after sudden onset, an Opthamologist diagnosised me with dry eye syndrome. Fast forward to May of this year and the diagnosis became dry eye desease with low shermer�s scores, MGD, only 2 second tear film and possible ocular rosacea. Then the deep socket eye pain began and almost daily ocular migraines; most painful & miserable.
The Long and short of it is that I have fought my way back, through considerable trial & error to a nearly normal life. If something didn�t work, I was on to researching & trying the next thing.
Confirmed by recent eye dr appts, I now have working oil glands, a normal 10 second tear film and no pain. While reluctant to post, this is what working for me after considerable trial and error. I��m not saying it will work for anyone else & I have no financial gain in any way from mentioning what has worked for me. So here goes:
* without fail . Twice daily . morning & night: dry heat application, followed by Avenova, facial cleanser whipes from Trader Joe�s, one drop each eye of Regener-eyes which has kept Coronas smooth without abrasions. Eye docs were amazed that when my eyes were at worst corneas were healthy & smooth.
* one capsule daily: cbd hemp oil (medical marijuana) for inflammation control. After trying Doxy, Restasis & xiidra (the later of which made me ill from various side effects)), I knew there must be a way to treat inflammation naturally & without side effects. Thanks to products like Charlotte�s Web CBD & Green Mountain CBD, I no longer have eye or head pain as I no longer have inflammation. Hemp oil is legal in all 50 states since contains 27 parts cbd to only 1 part thc. Like product profiled on 60 minutes to halp children overcome chronic seizures.
* Retaine moisturizing drops . down to about twice daily from many times per day earlier on. Found Refresh (even the newer one with flax oil) made my eyes worse. Seem to be allergic to an ingredient in Refresh, but not Retaine.
* IPL treatments . 4 since June to open oil/ membobian glands. Also, CBD has helped to keep inflammation at bay which also helps to keep oil flowing.
in Dec will have lipiflow as doc says since I no longer have much inflammation I am now candidate for procedure. Eye doc says often patients have lipiflow procedure while they have inflammation and that�s why doesn’t� always work.
IPL & CBD have been biggest game changer for me.
Please don��t hesitate to post or message with questions. I too have greatly suffered from this treatable condition.