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Tretinoin and retinoids- toxicity and safety

Reviewed by Marta March 24, 2013 100 Comments

When Junko told us about her trip to an eye doctor resulting in a stern warning to stop using a tretinoin cream (commonly prescribed by dermatologists for the treatment of acne, age spots and wrinkles) on the grounds that it is a toxin, it gave us all a scary jolt.  I have been doing as much research as possible and this post is a little long as I’ve tried to be thorough. So for those who want to cut to the car chase, tretinoin is indeed a toxin, a possible side effect is blurred vision and Junko should absolutely give up all non-dietary forms of vitamin A until her symptoms clear up.

Now for the detail. (Please note that I am continuing to add and update this post as I come across additional research).

Vitamin A and its natural and synthetic analogs are referred to as retinoids. There are several forms of retinoids: retinal (aldehyde); retinoic acid, which is also known as tretinoin (acid); and retinol (alcohol). Vitamin A is acquired through the diet and is ingested through animal sources as retinyl esters and through plant sources as carotenoids, and converted to retinol. Retinoids control normal cell growth, cell differentiation, and cell death during embryonic development and in certain tissues later in life.  These effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors).

The toxicity of retinoids and, in particular, tretinoin is well known – and has been understood by scientists for well over a decade. Research (which I go into below) has extensively been conducted on cancer patients (mostly oral doses of tretinoin) and pregnant animals, looking at topical dosage effects. It is important to note that the absorption of tretinoin is systemic. The condition caused by vitamin A toxicity is called hypervitaminosis A (source). It is caused by overconsumption of preformed vitamin A, not carotenoids. Tretinoin (Retin-A) "because of the potential for systemic absorption of topical tretinoin" is not recommended during pregnancy (source).

Retinoids are relatively new types of anti-cancer drugs. Tretinoin is given orally in capsule form to patients – typically when other forms of treatment have failed. This option of last resort is because of, as the US Institutes of Health points out, the side effects of toxicity.

It is not at all a stretch of the imagination to associate an eye condition with tretinoin reactions. First, as the Linus Pauling Institute explains, the eyes are geared towards taking in, storing and processing vitamin A. Inadequate retinol available to the retina results in impaired dark adaptation, known as "night blindness." Neurologic symptoms include headache, drowsiness, blurred vision (source).

A study on three topical retinoids, reported that “despite their differing capacities to stimulate skin repair and cell growth, all of the agents were cytotoxic for fibroblasts and epithelial cells over the same range of concentrations (0.6 – 3  10-5 M). A fairly recent 6-year trial on over 1,000 veterans set out to discover if tretinoin could be used to treat skin cancer. It was stopped six months before the scheduled end because of a high number of deaths in the tretinoin group. The concentration used was 0.1%. "We report the halting of the VATTC Trial intervention 6 months before its scheduled end date because mortality in the tretinoin-treated group was higher than in the vehicle control group, and our evaluation of this potentially causal association between tretinoin therapy and increased mortality," the study authors wrote.

Meanwhile, pregnant women shouldn’t go anywhere near tretinoin or other retinoids. Used topically, it is “a potent teratogen following exposure in early pregnancy” (source) (a teratogen is an agent that can disturb the development of an embryo or fetus). A 1997 study on rabbits, using 10 times the amount humans would typically use of the tretinoin cream, Renova. The rate of abortion was increased significantly compared with the control group. Dosage-dependent increases in incidence and severity of skin reactions occurred in groups administered the vehicle and the two dosages of tretinoin. Similar results occurred in another study with a dose of 10 mg/kg daily.

Management of vitamin A toxicity includes ensuring that all vitamin A products are discontinued, including multivitamins and topical creams. Consumption of large amounts of dietary carotenoids will not contribute to vitamin A toxicity since efficiency of absorption decreases with dosage, and conversion to the vitamin is not rapid enough to contribute to toxic levels (source).

The following Tretinoin side effects are common (occurring in greater than 30%) for patients taking Tretinoin:

Typical retinoid toxicity include symptoms that are similar to those found in patients taking high doses of vitamin A: Headache, fever, dry skin, dry mucous membranes (mouth and nose), bone pain, nausea and vomiting, rash, mouth sores, itching, sweating, eyesight changes. Plus: Flu-like symptoms, bleeding problems, infections, swelling of feet or ankles, pain (bone and joint pain, chest discomfort), abdominal pain.

The following are less common Tretinoin side effects (occurring in 10-29%) for patients receiving Tretinoin: Weight increase, heart rate irregularities (arrhythmias - see heart problems), flushing, poor appetite, weight loss, earache or feeling of fullness in the ears, diarrhea, dizziness, constipation, numbness and tingling in hands and feet, anxiety, heartburn, low blood pressure, insomnia, depression, high blood pressure, confusion (source).

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  • March 8, 2017

    by Sue

    I am slightly shocked by the realisation that the retinol (over the counter) cream I have bee using has given me quite bad side-effects. I have been using a small amount every night on my face. I had a severe dizzy attack a couple of weeks ago, and suffered on and off for about a week, and remained in a 'spaced-out' state. I tried to go through everything that might be causing it - and finally researched the cream I was putting on my face. I stopped it immediately and felt better the following morning after not applying it the night before. I had been having difficulty focusing to read, and my tinnitus was very bad; both these symptoms have improved and my tinnitus is back to what it normally is. I am pretty horrified by this. I am sensitive to things I take or put on me, but this has slightly shaken me.

  • February 23, 2017

    by grace

    I also had been using Tretinoin 1% . for about 2 weeks. Even though I was using a pea size amount
    I began to feel headaches after a few days, then dizziness, confusion and nausea. There was no
    physical or psychological reason for this. Shortly after I stopped applying it altogether, I was back
    to feeling well again. Why it affects a minority of people and not others , makes me wonder why!

  • October 3, 2016

    by Naomi

    I don't think anyone has answered this question so I would really appreciate it if someone could. Could 1% retinol, not retin -A, cause the blurry vision. The product I'm using states it converts to 0.025% retinoic acid on the skin.

  • October 2, 2016

    by Nikki

    Hello everyone,

    I have to start off by saying that I cannnot emphasize enough how much relief, even if short lived, this article has brought me. I am a 31 year old male and in desperate need of all of your help. I am happily married with two beautiful little girls. I have always had bad facial skin and I recently started using three products: Tretinoin 0.05% gel, clindamycin phosphate 1% foam and an over the counter 10% benzoyl peroxide face/body wash. I started them about three and a half weeks ago. Initially, I was using it sporadically, maybe every other day or every two days. This sporadic use was for no other reason than a super busy work schedule and my forgetting to apply it before bed after a long day at work. While my job requires long hours and is stressful, I have always managed well and even have awards to prove it. I'd also like to add that I have absolutely no psychiatric history. Nothing.

    So here is where it gets a bit tricky and basically where my life has been flipped upside down. My job, which happens to be in the medical field, occasionally requires me to switch over to nights. It is the hardest part of my job, but everyone has to do it. They are long 16-18 hour shifts back to back for 5 days in a row, followed by a short two day break and another 5 days in a row. All of my colleagues hate it and everyone agrees it is the hardest part of our current year. We have to do it a total of 4-5 times this year, but then we're done for the next two years. I have already completed two weeks of it earlier this year in July. Well, I was up for another two weeks of nights about 3 weeks ago (1/2 a week after starting the medication). I was concerned that it would interrupt my use of the topical medications, so I made sure I consistently applied the tretinoin every day before going to bed after a long night shift. My skin began to show great improvement. It was wonderful. However, toward the end of my first week of nights (two and a half weeks ago), I began to notice I was having mild chest pain and anxiety at work. My wife and I attributed it to the lack of sleep since I was averaging about three and a half hours of sleep between shifts. We did not think too much of it at first. However, by the time I hit the second week it was happening regularly. It was not only at work now, but I started to experience it on my drive to work. It was pretty bad. It felt like adrenaline, but without my heart necessarily racing. I felt it shooting down my arm, too. Worst of all, it began to affect my emotions. I was very emotional. I would have episodes of crying and overwhelmed with guilt of not being home with my daughters. My wife and I again attributed it to being over worked and sleep deprived. It did not make sense to me though, because I had already completed two weeks of nights back in July that were extremely difficult (harder than this time around) and I never developed these types of symptoms. However, I gave it the benefit of the doubt and figured since it was starting on my drive to work and while at work that perhaps it did have something to do with being overworked during nights and maybe I was developing some sort of aversion to night call. Then it got worse. I ended up having a full-on panic attack at work and locked myself in the bathroom so no one would see me crying my eyes out. I literally wanted to run away and never come back. The thing is, it was basically unprovoked. The night was slow and there wasn't too much going on. I called a friend in desperation who wanted me to go to the Emergency Room, but I knew my career would be over if I left my shift. I don't know how, but I managed to finish the shift. After that day, I began to continue having symptoms almost all day long. On my way to work, at work, on my way home, at home. It was affecting my sleep and filling me with more anxiety because I couldn't take advantage of the short amount of sleep I was already being limited to. Again, I attributed this to being on nights, even though I had to try hard to convince myself of this since it did not make sense given my work history. Keep in mind that I was applying tretinoin daily throughout this entire experience. Finally, when nights came to an end a little over a week ago, I expected all of these symptoms to be turned off like a light switch. Boy was I wrong. They have burdened me beyond anything I can describe. I am overwhelmed with anxiety, panic and depression every day. Completely unprovoked. It has become difficult to enjoy time with my family and I am losing interest in participating in events because I know I cannot enjoy them feeling this way. Now being back on day shifts, I continue to have constant unending anxiety and depression. It is absolutely unbearable. Along with these symptoms, however, I have also lost 10 pounds over the last three weeks, which I have attributed to the extreme anxiety that prevents me from having an appetite. Additional symptoms have also included constant dry mouth, irritable stomach, occasional but rare dizziness and headaches.

    I started to become overwhelmed with fear that I have developed an anxiety disorder that has caused depression and would have to live with it for the rest of my life. Until a couple days ago, I started to think about anything new in my life that could be causing this. It finally dawned on me that those three products were the only new things that I had introduced into my life and I had started them right around the onset of symptoms. I had not really thought about it before since it was a topical cream and seemed very unlikely to me that it could cause systemic symptoms. I finally pieced it all together and looked up the side effects, which seemed to be minor and superficial in nature with the topical product. However, the more I dug, the more stories I came across of people experiencing similar symptoms.

    I have stopped using all three products 48 hours ago. I am hoping to receive some support from people who discovered the same thing and were able to fully recover. I am overwhelmed with fear that this is something I will have to deal with the rest of my life. I am hoping I have discovered the culprit and after speaking to a medical profession, she agreed with me that it is very likely the source considering I am experiencing other systemic side effects such as the dry mouth, headaches and dizziness. Those of you that experienced anxiety and/or depression while on this medication and got off of it, how long did it take you to notice improvement? What about to fully recover? I know it has less to do with the product half life and moreso to do with how much vitamin A was built up so these periods of recovery could vary, but any feedback would be extremely helpful during this time in my life. I spend my day helping people, it is unusual for me to reach out like this. I am hoping for helpful responses. Thank you everyone for reading this extraordinary long post!

  • September 17, 2016

    by Leslie

    Hi, I have been using retin a .025 for about a week. Starting last night and throughout today, I am seeing double. Absolutely the cream has not touched my eyes, but I'm wondering if I'm getting too close to them. I never use anything larger than a pea-size dollop.

    Has anyone experienced this? If so, please tell me it goes away. Also, I am very reluctant to discontinue use, so am hoping its Temporary like the peeling and redness.

    Thank you.

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