Isotretinoin for Severe Acne: How It Works, Birth-Defect Risk and Mood Research

Table of Contents

1. What Isotretinoin Is
2. How It Works on the Oil Glands
3. Who the Label Covers and What the Guideline Says
4. Clearing and Long-Term Remission in the Trials
5. Low-Dose and Intermittent Regimens
6. The Birth-Defect Risk and the 1985 Study
7. The Boxed Warning and the iPLEDGE Program
8. Mood, Depression and Suicide Research
9. Other Label Warnings and Common Side Effects
10. What Is Not Known
11. Key Research Papers
12. Connections
13. Featured Videos

What Isotretinoin Is

Isotretinoin is 13-cis-retinoic acid. Vitamin A from food (retinol) is turned in the body into retinoic acid, the form that switches genes on and off in skin and many other tissues. The usual natural form is called all-trans-retinoic acid; isotretinoin is a synthetic isomer of it, the same atoms arranged in a slightly different shape. The 1979 report that first showed its effect on acne described it in exactly those terms: "a synthetic isomer of naturally occurring all-trans-retinoic acid". Medicines in this family are called retinoids.

The drug is taken by mouth as a capsule. Some basic facts from the United States label, in plain terms:

• The capsules come in strengths from 10 mg to 40 mg.
• After a single 40 mg dose, the blood level peaked about 2.9 hours later on an empty stomach and about 6.4 hours later with food.
• The half-life (the time for the blood level to fall by half) is about 18 hours for isotretinoin itself and about 38 hours for its main breakdown product, 4-oxo-isotretinoin. The label's pregnancy rules run until one month after the last dose.
• Because it is so close to vitamin A, the label lists allergy to vitamin A as a reason not to use it, and advises against taking vitamin A supplements at the same time, since the two together may add up to vitamin A-type side effects.

The Vitamin A page explains the vitamin itself, and how the body regulates the amount it turns into retinoic acid.

How It Works on the Oil Glands

Acne starts in the hair follicle and the oil gland attached to it (the sebaceous gland). Four things drive it: too much oil (sebum), skin cells that clump and plug the follicle opening, bacteria that grow in the trapped oil, and inflammation. Most acne treatments act on one or two of these. Isotretinoin acts mainly on the first one, at its source.

The label states that the exact way isotretinoin clears severe acne is unknown. What it does say is that the drug "inhibits sebaceous gland function and keratinization" (keratinization is the process by which skin cells mature and harden). Clinical improvement goes along with a drop in oil output, and that drop reflects a reduction in the size of the oil glands and a block on how the gland cells mature. The label adds that the fall in oil output depends on the dose and the length of treatment, and that it is temporary.

The authors of the 1979 report already suspected "a direct inhibitory effect of the drug on the sebaceous gland". A 2008 study gave a more detailed picture. Researchers took skin biopsies from 7 people with acne before treatment and after one week on isotretinoin. Staining showed that the drug caused apoptosis, a planned self-destruction of cells, inside the oil glands. In the patients' skin and in human oil-gland cells grown in the laboratory, one of the genes most strongly switched on by the drug was lipocalin 2, which makes a protein called neutrophil gelatinase-associated lipocalin. In cultured oil-gland cells, this protein on its own triggered apoptosis, and blocking the gene reduced the cell death caused by isotretinoin. The authors concluded that this protein carries out the drug's cell-killing effect in the oil glands. The gene-blocking part of that work was done in cells, not in people.

Shrinking the oil glands explains two things about the drug: why it can work after other treatments have failed, and why so many of its side effects are dryness, of the lips, skin, eyes and nose, where oil and mucus normally protect the surface.

Who the Label Covers and What the Guideline Says

The United States label approves isotretinoin capsules for one use: "severe recalcitrant nodular acne" in people who are not pregnant, aged 12 and older, with multiple inflamed nodules 5 mm across or larger. Nodules are deep, painful lumps under the skin; "recalcitrant" means the acne has not responded to other treatment. The label adds that, "because of significant adverse reactions", the drug is reserved for severe nodular acne that has not responded to conventional therapy, including antibiotic tablets.

The doses, as the label states them:

• 0.5 to 1 mg per kilogram of body weight a day, split into two doses, for 15 to 20 weeks.
• Adults whose disease is very severe, with scarring or mainly on the trunk, may need up to 2 mg per kilogram a day.
• The safety and effectiveness of once-a-day dosing have not been established.
• If the nodule count has fallen by more than 70% before the end of the course, the drug may be stopped early.
• A second course is not started until at least 2 months after the first, because acne may keep improving after the drug is stopped.

Before treatment, the label requires a fasting blood lipid test (including triglycerides) and liver tests for everyone, and documented proof that a patient who can get pregnant is not pregnant.

The 2024 guideline of the American Academy of Dermatology, built on a systematic review of the evidence, makes 18 recommendations. One of its strong recommendations is for oral isotretinoin for acne that is "severe, causing psychosocial burden or scarring, or failing standard oral or topical therapy". That is somewhat wider than the label's wording: the guideline also names acne that causes scarring or emotional burden, not only severe nodular acne. The Acne page lists the guideline's other recommendations.

Clearing and Long-Term Remission in the Trials

What made isotretinoin different from earlier acne treatments was not only that acne cleared, but that in many people it stayed clear after the drug was stopped. The main studies, in the order they appeared:

• 1979, the first report. Fourteen people with treatment-resistant cystic and conglobate acne (a severe form with connected nodules and abscesses) took the drug for four months at an average of 2.0 mg per kilogram a day. Thirteen cleared completely and the fourteenth improved by 75%. All 14 were still in remission at the time of the report, for as long as 20 months after stopping. Side effects were mostly in the skin and mucous membranes, depended on the dose, and went away quickly when the drug was stopped.
• 1984, the dose trial. A double-blind study gave 150 people with treatment-resistant nodulocystic acne one of three daily doses: 0.1, 0.5 or 1.0 mg per kilogram. All three doses produced a highly significant response, and the response did not differ significantly between them. But 42% of the people on the lowest dose needed a second course of the drug. Because side effects and laboratory changes differed only slightly between doses, the authors concluded that the higher doses suited nodulocystic acne better.
• 1993, ten years on. A British group followed 88 people (average age 20.8, average 7.4 years of acne) for up to 10 years after treatment, 9 years on average. Most had needed only 4 months of treatment to reach at least 85% improvement. Sixty-one were still virtually clear. Of the rest, 16% needed further antibiotic treatment and 23% a second course of isotretinoin. Of those who relapsed, 96% did so within 3 years of stopping. Relapse was more common in people with severe acne mainly on the trunk, and in those who had taken 0.5 mg per kilogram a day or a total (cumulative) dose under 120 mg per kilogram. The authors found no long-term side effects in the body or in blood tests.
• The label's trial. The current label describes a randomized trial in 925 people aged 12 to 54 with at least 10 nodules, comparing two versions of isotretinoin capsules over 20 weeks. In the group given the labelled product, the average nodule count of 18.4 at the start fell by an average of 15.68, and 70% of people had at least a 90% drop in nodules.

Two later reviews put this evidence in context. A 2018 systematic review found 11 randomized trials with 760 people, mostly men with moderate to severe acne. In every trial isotretinoin reduced acne lesions by a clinically meaningful amount, and always by more than the comparison, which was placebo in two trials and antibiotic tablets in seven. Side effects were twice as common on isotretinoin (751 events against 388), and more than half were dryness of the skin.

A 2018 Cochrane review was more cautious. It included 31 randomized trials with 3,836 people aged 12 to 55. Pharmaceutical companies funded 12 of them, and all but three had a high risk of bias in at least one area. In three trials comparing isotretinoin with antibiotic tablets plus a skin treatment in moderate or severe acne, there was no difference in the fall in inflamed lesions (risk ratio 1.01), but the reviewers rated this evidence very low quality. Isotretinoin may slightly improve acne severity as judged by the doctor (by about 15%), with a 67% higher risk of minor side effects such as dry lips and skin. The reviewers concluded that the evidence was low quality for most outcomes, and that isotretinoin for acne that has not responded to antibiotics plus skin treatments "needs further assessment". None of the included trials reported birth defects; the trials were not designed to measure them.

Low-Dose and Intermittent Regimens

Because the side effects of isotretinoin depend on the dose, many dermatologists have tried lower daily doses, or "pulsed" regimens where the drug is taken for one week in every four. These regimens are used mostly for moderate acne, which is outside the label's approved use (an off-label use).

A 2011 randomized trial in South Korea compared three regimens in 60 people with moderate acne:

• Group A, the conventional dose: 0.5 to 0.7 mg per kilogram a day for 24 weeks.
• Group B, a low dose: 0.25 to 0.4 mg per kilogram a day for 24 weeks.
• Group C, intermittent: 0.5 to 0.7 mg per kilogram a day for one week out of every four, 6 weeks of drug in all.

The conventional and low-dose groups did about equally well on acne scores and lesion counts. The intermittent group did worse than both. Side effects were more frequent on the conventional dose, and patient satisfaction was highest on the low dose. One year after treatment ended, 2 of 16 people had relapsed in group A, 3 of 17 in group B and 9 of 16 in group C. The authors concluded that, weighing tolerability, effect and satisfaction, the low dose was the most suitable for moderate acne. This was a small trial.

A 2022 systematic review and meta-analysis looked at low-dose isotretinoin for adults with mild to moderate acne. When low daily doses were compared with the conventional dose, the pooled results favoured the conventional dose for response to treatment. When low daily doses were compared with pulsed doses, the low daily dose did better. The authors rated the overall quality of the evidence as low, and wrote that the conventional dose "appears" to improve the odds of a long remission compared with low doses.

The Cochrane review described above came to a similar view on pulsed treatment: daily treatment "may be more effective than treatment for one week each month". Put together, the research suggests a trade-off: lower daily doses tend to cause fewer side effects, while higher total doses are linked to fewer relapses. The evidence on both sides is limited. The label itself states that long-term use of isotretinoin, even at low doses, has not been studied.

The Birth-Defect Risk and the 1985 Study

Retinoic acid was already known to cause birth defects in laboratory animals, and by 1985 a few human case reports had appeared. That year a team led by Edward Lammer published the study that defined the human risk. They investigated 154 pregnancies in which the unborn baby had been exposed to isotretinoin. The outcomes were:

• 95 elective abortions,
• 12 miscarriages (spontaneous abortions),
• 26 babies born without major malformations,
• 21 babies born with malformations.

Thirty-six of these pregnancies were followed from early on, before the outcome was known, which gives a less biased view. Among them there were 8 miscarriages, 23 normal babies and 5 malformed babies.

Exposure to isotretinoin was linked to a relative risk of 25.6 (95% confidence interval 11.4 to 57.5) for a group of selected major malformations. In plain terms, these particular defects were about 25 times more common than expected. The 21 malformed babies showed a recognisable pattern, now called retinoic acid embryopathy, involving the face and skull, the heart, the thymus (a gland in the chest that trains immune cells) and the brain:

• small or missing ears (microtia or anotia): 15 babies,
• central nervous system malformations: 18,
• heart defects of the main outflow vessels and the aortic arch: 8,
• thymus defects: 7,
• a small lower jaw (micrognathia): 6,
• retina or optic nerve abnormalities: 4,
• cleft palate: 3.

The pattern closely matched what retinoids cause in animal studies. The authors suggested, as a possibility, that the drug harms neural crest cells, a group of embryo cells that move out to build much of the face, the outflow of the heart and the thymus. That would explain why these three areas are hit together. The Vitamin A Birth Defects in Pregnancy page explains this biology in more detail, and compares the risk from the drug with the much smaller risk from vitamin A in food and supplements.

The current label lists the same kinds of malformations: of the face, eyes, ears, skull, brain, heart, and the thymus and parathyroid glands, some of them fatal. It also reports cases of IQ scores below 85, with or without other defects, in children exposed before birth, and an increased risk of miscarriage and premature birth.

The Boxed Warning and the iPLEDGE Program

A boxed warning is the strongest warning the United States Food and Drug Administration puts on a medicine label. The isotretinoin label's boxed warning is headed "Embryo-fetal toxicity – contraindicated in pregnancy". It states that there is "an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking any amount of isotretinoin even for short periods of time", that potentially any exposed baby can be affected, and that there is no accurate way to tell before birth whether an exposed baby has been affected.

Because of this risk, the drug is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), a safety system the Food and Drug Administration can require for high-risk medicines. For isotretinoin it is called the iPLEDGE REMS. According to the label, it ties together prescribers, patients, pharmacies and wholesalers:

• Prescribers must be certified, counsel every patient on the risk, check whether each patient can get pregnant, review a negative pregnancy test before each prescription, and report every pregnancy.
• Patients who can get pregnant must enrol, use two forms of contraception at the same time (at least one of them a "primary" form) from 1 month before treatment, throughout it, and for 1 month after the last dose, unless they commit to continuous abstinence or cannot become pregnant for medical reasons. The label states that progesterone-only "minipills" are not an adequate form of contraception here. Patients must show they understand the risk before each prescription and collect the prescription within 7 days of the pregnancy test.
• Pregnancy tests: a screening test and a confirming test before starting, another before each monthly prescription, one at the end of treatment and one 1 month after.
• Patients who cannot get pregnant must also enrol, and must not share the drug or donate blood.
• Pharmacies must be certified, dispense at most a 30-day supply, give out no refills, and hand over a Medication Guide each time.

The label notes that "any birth control method can fail": pregnancies have been reported in people using a single method, including pills, rings, patches and injections, which is why it requires two methods at once. It also asks that any suspected exposure during treatment or in the month after be reported to the Food and Drug Administration and to the iPLEDGE pregnancy registry. Everyone taking the drug, of any sex, is told not to donate blood during treatment and for 1 month after, because the blood could reach a pregnant patient.

How well has the program worked? A 2019 study counted pregnancy reports linked to isotretinoin in the Food and Drug Administration's adverse event reporting system from 1997 to 2017. There were 6,740 pregnancies in all, peaking at 768 in 2006, the year iPLEDGE began, then settling at 218 to 310 reports a year after 2011. The average age of the women was 24.6. Measured against prescribing data, the yearly pregnancy rate among women who could become pregnant ranged from 0.33% to 0.65%. Pregnancies, abortions and birth defects all fell after 2006 but did not stop. The authors listed several possible reasons for the fall, including a national drop in teenage pregnancy, better long-acting and emergency contraception, the iPLEDGE rules, and people simply reporting less over time. They called for research into how well iPLEDGE works and for new ways to lower exposure.

For men, the label reports that in studies of 66 men and of 50 men taking the drug, sperm count and movement did not change significantly. The rules on two forms of contraception apply to patients who can become pregnant.

Mood, Depression and Suicide Research

This is the most debated question about isotretinoin. Severe acne itself can weigh on mood and confidence, and it mostly affects teenagers and young adults, an age when depression and suicidal behaviour often first appear. That makes it hard to tell whether the drug adds a risk of its own.

What the label says

The label states that isotretinoin "may cause depression, psychosis and rarely, suicidal ideation, suicide attempts, suicide and aggressive and/or violent behaviors". In its list of reported reactions it adds that some patients who reported depression found it went away when they stopped the drug and came back when they restarted it. The label instructs prescribers to ask about any psychiatric history before treatment and to check for symptoms of depression, mood change, psychosis or aggression at every visit. If these develop, it instructs patients or caregivers to stop the drug and contact their health care provider, and notes that stopping may not be enough on its own.

What the large studies found

• Swedish cohort, 2010. Researchers linked 5,756 people aged 15 to 49 who had been prescribed isotretinoin in the 1980s to national hospital and death records, and compared their suicide attempts with the number expected for their age, sex and year. In the year before treatment, attempts were already above expected (standardized incidence ratio 1.57, confidence interval 0.86 to 2.63). During treatment and up to 6 months after, the ratio was 1.78 (1.04 to 2.85) for all attempts and 1.93 (1.08 to 3.18) for first attempts. Three years after treatment, attempts were back close to the expected number and stayed there for 15 years of follow-up. The authors estimated that 2,300 six-month treatments a year would be linked to one additional first suicide attempt. They concluded that an increased risk was apparent up to 6 months after treatment, but that because the risk was already rising before treatment, an additional risk due to the drug "cannot be established".
• Depression meta-analysis, 2017. A review of 31 studies found that, in the studies with a comparison group, the change in depression scores did not differ significantly between people taking isotretinoin and people taking another acne treatment. Across studies, the number of people with depression fell after isotretinoin treatment (relative risk 0.588, confidence interval 0.382 to 0.904), and average depression scores went down from the start. The authors noted that none of the studies was a randomized trial and that results varied widely between studies.
• Suicide and psychiatric disorder meta-analysis, 2024. The largest review pooled 25 studies with 1,625,891 participants, average ages 16 to 38. In the first year of treatment, the pooled risks of completed suicide, suicide attempt, suicidal thoughts and self-harm were each below 0.5%, and the risk of depression was 3.83%. Isotretinoin was not linked to a higher risk of psychiatric disorders overall (risk ratio 1.08, confidence interval 0.99 to 1.19). Users were less likely than non-users to attempt suicide 2, 3 and 4 years after treatment (risk ratios 0.92, 0.86 and 0.85; the 2- and 4-year confidence intervals reached 1.00). Studies with more male participants reported a higher one-year risk of completed suicide, and studies with older participants a lower one-year risk of depression. The authors called the findings reassuring at the population level, and still wrote that patients' mental health is to be watched for signs of distress during treatment.

In the 2018 systematic review of randomized trials, depressed mood was one of the side effects that made some participants leave a trial.

Taken together, these studies do not show a rise in depression or suicide across large groups of people treated with isotretinoin, and some show improvement as the acne clears. They cannot rule out that a small number of individuals react badly to the drug, which is what the label's case reports of depression returning on re-treatment describe. The Swedish study also found that the people whose first suicide attempt came within 6 months after treatment were more likely to make further attempts than those whose attempts began before treatment. Suicidal thoughts, talk of self-harm, or sudden severe changes in mood or behaviour are signs that emergency services and hospitals treat as urgent. The Depression page covers the condition more broadly.

Other Label Warnings and Common Side Effects

The most common effects

The label lists the most common side effects (in at least 5% of people) as dry lips, dry skin, back pain, dry eyes, joint pain, nosebleeds, headache, colds, chapped lips, skin inflammation (dermatitis), raised creatine kinase (a muscle enzyme), cheilitis (cracked, inflamed lips), muscle and bone discomfort, upper respiratory infections and reduced sharpness of vision. Cheilitis and high triglycerides were the effects the label describes as dose-related.

Blood fats and the liver

• Blood fats. In clinical trials, marked rises in triglycerides, falls in high-density lipoprotein ("good") cholesterol and rises in cholesterol were seen in 25%, 15% and 7% of people, respectively. The label states these changes reversed after stopping the drug, and that triglyceride levels above 800 mg/dL have been reported. Inflammation of the pancreas (pancreatitis), occasionally fatal, has been reported in people with high or normal triglycerides. The label states that the heart and blood-vessel consequences of the triglyceride rise are unknown, and it names diabetes, obesity, heavy alcohol use and inherited lipid disorders as reasons for closer checking.
• Liver. Mild to moderate rises in liver enzymes were seen in about 15% of people in trials; some returned to normal with a lower dose or even while treatment continued. Clinical hepatitis has been reported.
• How often to test. The label calls for lipid and liver tests before treatment and then periodically until the response is known, which for lipids usually happens within 4 weeks. A 2016 meta-analysis of 26 studies with 1,574 patients found that isotretinoin did shift average values for white blood cells, liver tests and blood fats, but the average changes did not reach levels its authors had defined in advance as high-risk, and the share of patients with abnormal results was low. The authors concluded that their evidence "does not support monthly laboratory testing" for standard doses in the standard patient.

Brain pressure, eyes and ears

• Raised pressure around the brain. Isotretinoin has been linked to cases of intracranial hypertension (also called pseudotumor cerebri), a build-up of fluid pressure inside the skull. Some of these cases involved people also taking a tetracycline antibiotic, such as doxycycline or minocycline. The label advises against using the two together. The early signs it lists are swelling of the optic nerve at the back of the eye, headache, nausea, vomiting and changes in vision. The Idiopathic Intracranial Hypertension page explains the condition, and the Vitamin A Headache and Brain Pressure page describes the same effect from too much vitamin A.
• Night vision. Decreased night vision has been reported, sometimes starting suddenly, and in some cases it lasted after treatment stopped. The label asks prescribers to tell patients about this and to warn them about driving at night. Vitamin A and its relatives are part of the chemistry that lets the retina see in dim light.
• Other eye effects. Dry eyes are common, and people who wear contact lenses may find them hard to wear during and after treatment. Corneal opacities (cloudy spots on the clear front of the eye) have occurred, more often at the higher doses used for other skin conditions; in trials they had cleared or were clearing 6 to 7 weeks after stopping.
• Hearing. Impaired hearing has been reported, in some cases lasting after treatment. The label states that the cause and mechanism have not been established.

Bones and muscles

• Bone density. In a trial of a 20-week course in teenagers, 27 of 306 (9%) had a drop in bone density of 4% or more at the spine or hip (or 5% at the thigh-bone neck), and repeat scans 2 to 3 months later showed no recovery. A separate 2004 study of 217 teenagers aged 12 to 17, who took about 1 mg per kilogram a day for 16 to 20 weeks, found no clinically significant average change: spine density rose 1.4% and hip density fell 0.26%, and no abnormal bone growth (hyperostosis) was seen. Both findings appear in the label. The label states that the effect of long-term use on bone loss is unknown, and that long, high-dose or repeated courses seem to affect bone more than a single course.
• Growing bones. There are case reports of growth plates closing early (premature epiphyseal closure). In a 20-week trial, 9 of 289 teenagers (3%) had changes in bone age on hand X-rays for which a drug effect could not be ruled out.
• Back and joint pain. In a trial of 358 teenagers, 29% developed back pain, severe in 14% of those cases, and 22% had joint pain. Creatine kinase, a muscle enzyme, rose in many people, especially with hard exercise; rare cases of serious muscle breakdown (rhabdomyolysis) have been reported.

Other warnings on the label

• Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, in which the skin blisters and peels, have been reported after the drug went on sale. The 2018 review of trials also lists Stevens-Johnson syndrome among the reasons participants left a trial.
• Inflammatory bowel disease, including ileitis, has been reported in people with no earlier bowel problems, sometimes lasting after the drug was stopped. The label names stomach pain, rectal bleeding and severe diarrhoea as reasons to stop.
• Allergic reactions, including anaphylaxis and inflamed blood vessels (vasculitis).
• Blood sugar. Some patients had trouble controlling blood sugar, and new cases of diabetes have been diagnosed during treatment.
• Sexual function. The label lists abnormal periods and sexual problems, which may continue after treatment, including erectile dysfunction, lower sex drive and vaginal dryness.
• Breastfeeding. There are no data on whether the drug passes into breast milk; the label advises against breastfeeding during treatment and for at least 8 days after the last dose.

Signs that hospitals treat as urgent include severe stomach pain spreading to the back (a sign of pancreatitis), a severe headache with blurred or double vision, blistering or peeling skin with fever, and swelling of the face or throat with trouble breathing.

What Is Not Known

• The exact mechanism. The label states that how isotretinoin clears severe acne is unknown. The oil-gland cell-death pathway described above is supported by a small biopsy study and cell experiments.
• The best dose. Older studies tie higher total doses to fewer relapses; newer small trials suggest lower daily doses work similarly for moderate acne with fewer side effects. Reviews rate the evidence on both sides as low quality, and low-dose use for moderate acne is outside the label.
• How it compares with standard care for less severe acne. The Cochrane review found too little high-quality evidence to say whether isotretinoin beats antibiotics plus skin treatments for moderate acne.
• Mood effects in individuals. Large studies do not show a population-wide rise in depression or suicide, but they cannot identify the individuals, if any, who react badly to the drug, and there are no large randomized trials designed to answer the question.
• Long-term and repeated courses. The label states that long-term use, even at low doses, has not been studied, and that the effects of repeated courses on bone and on growing bones are unknown.
• Lasting effects. Reports of night-vision loss, hearing loss, bowel disease and sexual problems that persist after treatment exist, but how often they occur and whether the drug causes them has not been established.
• The best way to prevent pregnancies. Pregnancies still occur under iPLEDGE, and researchers have called for study of how well the program works.

Decisions about isotretinoin belong with the prescriber and the patient, who weigh the effects of severe acne and scarring against these risks.

Key Research Papers

1. Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. The New England Journal of Medicine. 1985;313(14):837-41. PubMed PMID: 3162101
2. Tan NKW, Tang A, MacAlevey NCYL, Tan BKJ, Oon HH. Risk of Suicide and Psychiatric Disorders Among Isotretinoin Users: A Meta-Analysis. JAMA Dermatology. 2024;160(1):54-62. PubMed PMID: 38019562
3. Al Muqarrab F, Almohssen A. Low-dose oral isotretinoin for the treatment of adult patients with mild-to-moderate acne vulgaris: Systematic review and meta-analysis. Dermatologic Therapy. 2022;35(4):e15311. PubMed PMID: 35000295
4. Reynolds RV, Yeung H, Cheng CE, Cook-Bolden F, Desai SR, Druby KM, et al. Guidelines of care for the management of acne vulgaris. Journal of the American Academy of Dermatology. 2024;90(5):1006.e1-1006.e30. PubMed PMID: 38300170
5. Peck GL, Olsen TG, Yoder FW, Strauss JS, Downing DT, Pandya M, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. The New England Journal of Medicine. 1979;300(7):329-33. PubMed PMID: 153472
6. Strauss JS, Rapini RP, Shalita AR, Konecky E, Pochi PE, Comite H, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. Journal of the American Academy of Dermatology. 1984;10(3):490-6. PubMed PMID: 6233335
7. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for acne vulgaris--10 years later: a safe and successful treatment. The British Journal of Dermatology. 1993;129(3):292-6. PubMed PMID: 8286227
8. Vallerand IA, Lewinson RT, Farris MS, Sibley CD, Ramien ML, Bulloch AGM, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. The British Journal of Dermatology. 2018;178(1):76-85. PubMed PMID: 28542914
9. Costa CS, Bagatin E, Martimbianco ALC, da Silva EM, Lúcio MM, Magin P, et al. Oral isotretinoin for acne. The Cochrane Database of Systematic Reviews. 2018;11(11):CD009435. PubMed PMID: 30484286
10. Lee JW, Yoo KH, Park KY, Han TY, Li K, Seo SJ, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. The British Journal of Dermatology. 2011;164(6):1369-75. PubMed PMID: 21114478
11. Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM. Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells. The Journal of Clinical Investigation. 2008;118(4):1468-78. PubMed PMID: 18317594
12. Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration Reports of Pregnancy and Pregnancy-Related Adverse Events Associated With Isotretinoin. JAMA Dermatology. 2019;155(10):1175-1179. PubMed PMID: 31314041
13. Sundström A, Alfredsson L, Sjölin-Forsberg G, Gerdén B, Bergman U, Jokinen J. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ. 2010;341:c5812. PubMed PMID: 21071484
14. Huang YC, Cheng YC. Isotretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. Journal of the American Academy of Dermatology. 2017;76(6):1068-1076.e9. PubMed PMID: 28291553
15. Lee YH, Scharnitz TP, Muscat J, Chen A, Gupta-Elera G, Kirby JS. Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis. JAMA Dermatology. 2016;152(1):35-44. PubMed PMID: 26630323
16. DiGiovanna JJ, Langman CB, Tschen EH, Jones T, Menter A, Lowe NJ, et al. Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne. Journal of the American Academy of Dermatology. 2004;51(5):709-17. PubMed PMID: 15523348

PubMed Topic Searches

1. PubMed: isotretinoin, acne remission and relapse
2. PubMed: low-dose isotretinoin for acne
3. PubMed: isotretinoin embryopathy
4. PubMed: isotretinoin and iPLEDGE
5. PubMed: isotretinoin, depression and suicide

Other Sources

1. DailyMed: isotretinoin capsules, prescribing label with boxed warning for embryo-fetal toxicity (United States National Library of Medicine), version of August 2026

Connections

• Drugs — every drug page on the site
• Acne — the condition and every treatment option
• Acne: History and Discovery — how isotretinoin changed the understanding of acne
• Vitamin A Birth Defects in Pregnancy — retinoids, food and supplements in pregnancy
• Vitamin A for Skin and Cellular Differentiation — the whole retinoid drug family
• Vitamin A — the vitamin isotretinoin is built on
• Depression — the condition, its signs and treatments
• Idiopathic Intracranial Hypertension — raised pressure around the brain
• Vitamin A Headache and Brain Pressure — the same effect from too much vitamin A

Featured Videos