Can LDN make acne worse? Integrative Functional Medicine in Champaign, Iowa City, Columbia
- John Kim
- 3 days ago
- 3 min read
Low-dose naltrexone (LDN) is recognized for its immune-modulating properties, which may influence acne severity in certain individuals. While LDN generally exhibits anti-inflammatory effects, reports of acne exacerbation during treatment warrant examination through the lenses of Toll-like receptor 4 (TLR4) inhibition and T helper 1 (Th1)/T helper 2 (Th2) balance modulation.
Regarding TLR4 inhibition, LDN antagonizes TLR4 signaling on immune cells, such as microglia and keratinocytes, thereby attenuating the production of pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). In acne pathogenesis, TLR4 activation by Cutibacterium acnes (formerly Propionibacterium acnes) triggers inflammatory cascades, contributing to lesion formation and severity. Although TLR4 inhibition might theoretically mitigate this inflammation, it could paradoxically lead to initial worsening by disrupting established immune responses, potentially allowing transient bacterial proliferation or altered cytokine dynamics before equilibrium is restored. This flare phenomenon has been observed in some patients, where symptoms intensify temporarily as the immune system adapts.
With respect to Th1/Th2 balance modulation, LDN promotes immune homeostasis by restoring equilibrium between Th1 (pro-inflammatory, cell-mediated) and Th2 (anti-inflammatory, humoral) responses, often favoring Th2 dominance or reducing Th1/Th17 hyperactivity. Acne vulgaris is characterized by a Th1/Th17-dominant immune profile, with elevated Th1 cytokines driving inflammation and minimal Th2 involvement. This imbalance exacerbates lesion development. LDN's shift toward Th2 predominance may initially disrupt this Th1-skewed state, resulting in a transitional flare as cytokine profiles recalibrate, potentially worsening acne before long-term benefits emerge. Patient experiences support this, with some noting temporary aggravation of skin symptoms upon initiation.
In summary, acne worsening on LDN may reflect an adaptive phase wherein TLR4 inhibition and Th1/Th2 rebalancing temporarily intensify inflammation prior to stabilization. Individual responses vary, and consultation with a healthcare provider is recommended for personalized assessment.
Yoon Hang Kim MD
References
AgelessRx. (2024, August 27). LDN: Why do symptoms sometimes get worse before getting better? https://agelessrx.com/why-do-ldn-symptoms-get-worse/
Anonymous. (2024, November 27). Any experience with LDN causing acne? [Reddit post]. r/LowDoseNaltrexone. https://www.reddit.com/r/LowDoseNaltrexone/comments/1h1ejw5/any_experience_with_ldn_causing_acne/
Cant, R., Dalgleish, A. G., & Allen, R. L. (2017). Naltrexone inhibits IL-6 and TNFα production in human immune cell subsets following stimulation with ligands for intracellular toll-like receptors. Frontiers in Immunology, 8, 809. https://doi.org/10.3389/fimmu.2017.00809
Carvalho, J. F. de, & Skare, T. (2023). Low-dose naltrexone in rheumatological diseases. Mediterranean Journal of Rheumatology, 34(1), 1–6. https://doi.org/10.31138/mjr.34.1.1
Dara, P., Farooqui, Z., Mwale, F., Choe, C., van Wijnen, A. J., & Im, H.-J. (2023). Opiate antagonists for chronic pain: A review on the benefits of low-dose naltrexone in arthritis versus non-arthritic diseases. Biomedicines, 11(6), 1620. https://doi.org/10.3390/biomedicines11061620
Erdei, L., Bolla, B. S., Bozó, R., Tax, G., Urbán, E., Kemény, L., & Szabó, K. (2018). TNIP1 regulates Cutibacterium acnes-induced innate immune functions in epidermal keratinocytes. Frontiers in Immunology, 9, Article 2155. https://doi.org/10.3389/fimmu.2018.02155
Huang, L., Yang, S., Yu, X., Fang, F., Zhu, L., Wang, L., Zhang, X., Yang, C., Qian, Q., & Zhu, T. (2024). Association of different cell types and inflammation in early acne vulgaris. Frontiers in Immunology, 15, Article 1275269. https://doi.org/10.3389/fimmu.2024.1275269
Kwiecien, K., Zielińska, D., & Rzepkowska, A. (2021). Cutibacterium acnes: The urgent need to identify diagnosis markers. Infection and Immunity, 89(4), e00753-20. https://doi.org/10.1128/iai.00753-20
McKenzie-Brown, A. M., Boorman, D. W., Ibanez, K. R., Agwu, E., & Singh, V. (2023). Low-dose naltrexone (LDN) for chronic pain at a single institution: A case series. Journal of Pain Research, 16, 1993–1998. https://doi.org/10.2147/JPR.S389957
Noh, H. H., Shin, S. H., Roh, Y. J., Moon, N. J., Seo, S. J., & Park, K. Y. (2022). Particulate matter increases Cutibacterium acnes-induced inflammation in human epidermal keratinocytes via the TLR4/NF-κB pathway. PLoS ONE, 17(8), e0268595. https://doi.org/10.1371/journal.pone.0268595
Sardana, K., & Verma, G. (2017). Propionibacterium acnes and the Th1/Th17 axis, implications in acne pathogenesis and treatment. Indian Journal of Dermatology, 62(4), 392–394. https://doi.org/10.4103/ijd.IJD_483_16
Timoney, L., & Bunker, C. B. (2021). Prurigo excoriée treated with low dose naltrexone. BMJ Case Reports, 14(11), e243773. https://doi.org/10.1136/bcr-2021-243773
Wu, S., Zhang, X., Wang, Y., Zheng, H., & Zhu, M. (2023). Lipid metabolism reprogramming of immune cells in acne: An update. Clinical, Cosmetic and Investigational Dermatology, 16, 2391–2398. https://doi.org/10.2147/CCID.S424478
Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33(4), 451–459. https://doi.org/10.1007/s10067-014-2517-2