Summary
Background. —
A major cause of blindness in older persons is age-related macular degeneration (AMD). Cigarette smoking is one of the major risk factors for AMD. In the present study, we analyzed UK Biobank data to determine whether smoking cannabis, like cigarettes, might be related to AMD.
Methods. —
Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with AMD and cannabis smoking information. The diagnosis of AMD was ascertained based on the 10th Revision of the International Classification of Diseases (ICD10), H35.3. Age at time of diagnosis of AMD was obtained from data field 5923. Cannabis information was recorded in UKB category 143, data field 20453, ever taken cannabis. A touch screen posed the question, “Have you taken CANNABIS (cannabis, grass, hash, ganja, blow, draw, skunk, weed, spliff, dope), even if it was a long time ago?” Possible answers were no, yes, 1–2 times, yes 3–10 times, yes, 11–100 times, yes, more than 100 times.
Results. —
Subjects who had used marijuana more than 100 times had a significantly reduced risk of AMD, compared to subjects who had never used marijuana, and use of marijuana every day was associated with less AMD than use of marijuana less than once a month. But subjects who used cannabis 100 times or more were significantly younger (8 years) when they developed AMD than subjects who never used cannabis.
Conclusion. —
Drusen, deposits of lipids, proteins, and cellular debris, accumulate in Bruch’s membrane, limiting transport between the retinal pigment epithelium and the vasculature, triggering an inflammatory reaction. Marijuana can retard the inflammatory process because it is a powerful anti-inflammatory agent. Therefore, marijuana could reduce the risk of AMD. At the same time, blood vessels in the choriocapillaris below Bruch’s membrane become more sparse with age. This phenomenon is believed to be a starting point for AMD. Marijuana can accelerate the loss of blood vessels due to its anti-angiogenic properties. Therefore, marijuana use might cause AMD to develop sooner in younger people.
Keywords: Cannabis, Tar, Retina, Toxicity
Résumé
Contexte. —
Une cause majeure de cécité chez les personnes âgées est la dégénérescence maculaire liée à l’âge (DMLA). Le tabagisme est l’un des principaux facteurs de risque de DMLA. Dans la présente étude, nous avons analysé les données de la UK Biobank pour déterminer si le fait de fumer du cannabis, comme les cigarettes, pouvait être lié à la DMLA.
Méthodes. —
Notre application UK Biobank a été approuvée en tant que projet UKB 57245 (S.L., P.H.R.). Notre analyse a inclus tous les sujets avec des informations sur la DMLA et le tabagisme. Le diagnostic de DMLA a été établi à l’aide de la 10e révision de la classification internationale des maladies (CIM10), H35.3. L’âge auquel la DMLA a été diagnostiquée provenait du champ de données 5923. Les informations sur le cannabis ont été enregistrées dans la catégorie UKB 143, champ de données 20453, ayant déjà consommé du cannabis. Un écran tactile posait la question : « Avez-vous pris du CANNABIS (cannabis, herbe, hasch, ganja, blow, draw, skunk, weed, spliff, dope), même si c’était il y a longtemps ? » Les réponses étaient non, oui, 1 à 2 fois, oui 3 à 10 fois, oui, 11 à 100 fois, oui, plus de 100 fois.
Résultats. —
Les sujets qui avaient consommé de la marijuana plus de 100 fois présentaient un risque significativement réduit de DMLA, par rapport aux sujets qui n’avaient jamais consommé de marijuana, et la consommation de marijuana chaque jour était associée à moins de DMLA que la consommation de marijuana moins d’une fois par mois. Mais les sujets qui ont consommé du cannabis 100 fois ou plus étaient significativement plus jeunes (8 ans) lorsqu’ils ont développé une DMLA que les sujets qui n’ont jamais consommé de cannabis.
Conclusion. —
Les Drusen, ou dépôts de lipides, protéines et débris cellulaires, s’accumulent dans la membrane de Bruch, limitant le transit entre l’épithélium pigmentaire rétinien et le système vasculaire, déclenchant une réaction inflammatoire. La marijuana peut retarder le processus inflammatoire car elle est puissamment anti-inflammatoire. Par conséquent, la marijuana pourrait réduire le risque de DMLA. Dans le même temps, les vaisseaux sanguins de la choriocapillaire sous la membrane de Bruch deviennent plus clairsemés avec l’âge. Ce phénomène est considéré comme un point de départ pour AMD. La marijuana peut accélérer la perte de vaisseaux sanguins car elle est anti-angiogénique. Par conséquent, la consommation de marijuana pourrait accélérer le développement de la DMLA chez les jeunes.
MOTS CLÉS: Cannabis, Goudron, Rétine, Toxicité
A major cause of blindness in older persons is age-related macular degeneration (AMD). The disorder involves retinal degeneration, and the risk of having it increases dramatically after middle age. According to one estimate, nearly one in every twelve persons between the ages of 45 and 85 in the world suffers from AMD [1].
The underlying causes of AMD are unknown, although they include core biological factors like age and heredity, as well as lifestyle factors like smoking and unhealthy food. The production of drusen, or deposits of cellular debris in the macula, is linked to the early stages of AMD. Drusen expand in size as AMD progresses, causing an inflammatory and physiologically dysfunctional environment in the macula [1].
Cigarette smoking is one of the major risk factors for AMD. Although population-based studies have found high cross-sectional connections between smoking and AMD, prospective data on the smoking-AMD relationship is relatively new. The Beaver Dam Eye Study was the first large population-based study to look at the long-term links between smoking and incident AMD and found a small but significant link between smoking and early but not late AMD [2]. After adjusting for age, sex, and other characteristics, the Blue Mountains Eye Study reported that current smokers had a 4-fold higher risk of late AMD than never smokers [3].
Cannabis smoke, like tobacco smoke, contains a comparable variety of carcinogenic and toxic compounds. Concerns about the respiratory effects of inhaling cannabis smoke are heightened by awareness of the harm caused by tobacco smoke and the various ways in which cannabis is smoked. When compared to tobacco, cannabis requires a longer and deeper inhalation, as well as a shorter butt length and a higher combustion temperature. Cannabis inhalation causes a fivefold rise in carboxyhemoglobin concentration, a fourfold increase in tar inhaled, and a one-third increase in tar retention in the lower airway [4]. But little is known of the effects of cannabis on the retina [5].
In the present study, we analyzed UK Biobank data to determine whether smoking cannabis, like cigarettes, might be related to AMD.
Methods
The UK Biobank is a large prospective observational study of men and women. Participants were recruited from across 22 centers located throughout England, Wales, and Scotland between 2006 and 2010 and continue to be longitudinally followed for capture of subsequent health events [6]. This methodology is like that of the ongoing Framingham Heart Study [7], with the exception that the UKB program collects postmortem samples, which Framingham did not.
Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with AMD and cannabis smoking information. AMD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10), H35.3. Age when AMD diagnosed was from data field 5923. Cannabis information was recorded in UKB category 143, data field 20453, ever taken cannabis. A touch screen posed the question, “Have you taken CANNABIS (cannabis, grass, hash, ganja, blow, draw, skunk, weed, spliff, dope), even if it was a long time ago?” Answers were no, yes, 1–2 times, yes 3–10 times, yes, 11–100 times, yes, more than 100 times.
Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used the UK Biobank Data Parser (ukbb parser), a python-based package that allows easy interfacing with the large UK Biobank dataset [8]. Statistical analysis was done with SPSS 25 and R.
Results
Age of subjects was 56 ± 8 (mean ± SD), 54% were female, 46% were male, 95% were white British. Two subjects who had never taken marijuana had died, a woman 76.2, and a man 77.9. No subject who used marijuana had died as of June 2021. More demographic data are in the tables.
Cannibis use and age at AMD diagnosis of 419 subjects are shown in Fig. 1. The variability is significant (P < 0.001, one way ANOVA). Subjects who used cannabis 100 times or more were significantly younger (8 years) when they developed AMD than subjects who never used cannabis (P = 0.05, Tukey B post-hoc test). Multivariate linear regression was performed, age at AMD diagnosis dependent variable, cannabis use and pack years cigarettes smoked independent variables. The effect of cannabis use on age at AMD diagnosis was significant (unstandardized regression coefficient B = −2.4, P < 0.001) and unrelated to pack years cigarettes smoked (B = 0.008, P = 0.832).
Figure 1.
Cannabis use versus age at age-related macular degeneration (AMD) diagnosis in 419 subjects, mean + SD. The variability was significant (P = 0.001, one way ANOVA). Subjects who used cannabis more than 100 times were diagnosed at a significantly younger age than subjects who never used cannabis (P = 0.05, Tukey B post-hoc range test). Number of cases in each group is to right of error bar.
Years between last cannabis use and enrollment in study shown in Fig. 2. On average, subjects had not smoked cannabis for 24 ± 11 years (mean ± SD).
Figure 2.
Years between last cannabis use and enrollment in study. On average, subjects had not smoked cannabis for 24 ± 11 years (mean ± SD).
Ever taken marijuana versus age-related macular degeneration (AMD), no or yes, is in Table 1. The variability was significant (P < 0.001, two-sided Chi2 test). Subjects who had used marijuana more than 100 times had a significantly reduced risk of AMD, compared to subjects who had never used marijuana.
Table 1.
Ever taken marijuana versus age-related macular degeneration (AMD), no or yes. The variability was significant (P < 0.001, two-sided Chi2 test). Subjects who had used marijuana more than 100 times had a significantly reduced risk of AMD, compared to subjects who had never used marijuana.
| AMD | AMD | Total | ||
|---|---|---|---|---|
| Ever taken | No | Yes | ||
| No | Count | 120,590 | 1870 | 122,460 |
| % within ever taken | 98.5% | 1.5% | 100% | |
| 1–2 times | Count | 14,683 | 165 | 14,848 |
| % within ever taken | 98.90% | 1.10% | 100% | |
| 3–10 times | Count | 8515 | 86 | 8601 |
| % within ever taken | 99.0% | 1.0% | 100% | |
| 11–100 times | Count | 6948 | 48 | 6996 |
| % within ever taken | 99.3% | 0.70% | 100% | |
| More than 100 times | Count | 4183 | 23 | 4206 |
| % within ever taken | 99.5% | 0.50% | 100% | |
| Total | Count | 154,919 | 2192 | 157,111 |
| % within ever taken | 98.6% | 1.40% | 100% |
Frequency of marijuana use versus AMD, no or yes, is shown in Table 2. Variability was significant (P = 0.05 two tail Fisher exact test). Use of marijuana every day was associated with less AMD (0.5%) than use of marijuana less than once a month (1%).
Table 2.
Frequency of marijuana use versus age-related macular degeneration (AMD) (no or yes). Variability was significant (P = 0.05 two tail Fisher exact test). Use of marijuana every day was associated with less AMD (0.5%) than use of marijuana less than once a month (1%).
| AMD | AMD | Total | ||
|---|---|---|---|---|
| Frequency | No | Yes | ||
| Less than once a month | Count | 21,508 | 216 | 21,724 |
| % within frequency | 99.00% | 1.0% | 100% | |
| Once a month | Count | 4011 | 33 | 4044 |
| % within frequency | 99.2% | 0.8% | 100% | |
| Once a week | Count | 5512 | 45 | 5557 |
| % within frequency | 99.2% | 0.8% | 100% | |
| Every day | Count | 2302 | 11 | 2313 |
| % within frequency | 99.5% | 0.5% | 100% | |
| Total | Count | 33,333 | 305 | 33,638 |
| % within frequency | 99.1% | 0.9% | 100% |
Table 3 shows logistic regression, 95% confidence intervals L.B. (lower bound), U.B. (upper bound); age-related macular degeneration (no, yes) dependent variable, ever taken marijuana, pack years cigarettes smoked, independent variables. Marijuana use was associated with an AMD O.R. 0.719. Each pack year of cigarettes smoked was associated with an AMD O.R. 1.011.
Table 3.
Logistic regression, 95% confidence intervals L.B. (lower bound), U.B. (upper bound); age-related macular degeneration (AMD) (no, yes) dependent variable, ever taken marijuana, pack years cigarettes smoked, independent variables. Marijuana use was associated with an AMD odds ratio (O.R.) 0.719. Each pack year was associated with an AMD O.R. 1.011.
| 95% L.B. | O.R. | 95% U.B. | P-value | |
|---|---|---|---|---|
| Ever taken | 0.663 | 0.719 | 0.779 | <0.001 |
| Pack years | 1.007 | 1.011 | 1.015 | <0.001 |
Discussion
At first glance, our results would seem to be contradictory.
Marijuana reduces risk of AMD: Subjects who had used marijuana more than 100 times had a significantly reduced risk of AMD, compared to subjects who had never used marijuana, and use of marijuana every day was associated with less AMD than use of marijuana less than once a month. The risk of AMD in marijuana users was not lower because marijuana users die sooner. As noted above, no subject who used marijuana had died as of June 2021.
Marijuana accelerates onset of AMD: subjects who used cannabis 100 times or more were significantly younger (8 years) when they developed AMD than subjects who never used cannabis.
The apparent contradiction between A and B can be resolved with an understanding of the pathology of AMD and the multiple physiologic effects of marijuana.
Drusen, or deposits of lipids, proteins, and cellular debris, accumulate in Bruch’s membrane, limiting transit between the retinal pigment epithelium and the vasculature, triggering an inflammatory reaction. This process can be accelerated by genetic factors and smoking. But marijuana can retard the inflammatory process because it is anti-inflammatory [9]. Therefore, marijuana could reduce the risk of AMD. Multivariate analysis in Table 3 demonstrates that the favorable effect of marijuana on AMD was independent of cigarettes smoked.
The retinal pigment epithelium and the retinal vasculature are separated by Bruch’s membrane, which controls the flow of oxygen, nutrients, and metabolites. Blood vessels in the choriocapillaris below Bruch’s membrane become sparser with age. This phenomenon is believed to be a starting point for AMD [10]. Marijuana could accelerate the loss of blood vessels because it is anti-angiogenic [11]. Therefore, marijuana use could cause AMD to develop sooner in younger people.
A weakness in our analysis is that we were unable to distinguish between the dry and wet forms of AMD. Wet and dry AMD begin in similar ways, but the pathologies of the two conditions ultimately diverge. UK Biobank entries do not differentiate between wet and dry.
While high-dose antioxidants and zinc supplements impede progression of age-related macular degeneration [12], the effects of marijuana appear to be much more complex. Further study is warranted.
Acknowledgement
This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was also supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Ethics approval
UK Biobank has approval from the Northwest Multi-center Research Ethics Committee (MREC), which covers the UK. It also sought the approval in England and Wales from the Patient Information Advisory Group (PIAG) for gaining access to information that would allow it to invite people to participate. PIAG has since been replaced by the National Information Governance Board for Health & Social Care (NIGB). In Scotland, UK Biobank has approval from the Community Health Index Advisory Group (CHIAG).
Disclosure of interest
The authors declare that they have no competing interest.
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