Topics > Depression > Postpartum Depression

Key Insights

• Postpartum depression (PPD) is a distinct condition from major depressive disorder, affecting 10-20% of mothers worldwide and characterised by emotional disconnection from self, baby, and support systems, with both biological and psychosocial origins.
• Ketamine and esketamine have shown promising initial results in preventing postpartum depression (PPD), with one study showing that esketamine reduces the major PPD risk to 7% compared to 25% in the placebo group. However, more research is needed on optimal dosing and safety during breastfeeding.
• Several companies are actively advancing psychedelic treatments for PPD, with Reunion Neuroscience developing RE104 (a short-duration psilocybin analogue) and GH Research studying GH001 (inhalable 5-MeO-DMT), both showing encouraging preliminary results in clinical trials.

Author: Chiara Corpetti. This page was made possible by Chiara Corpetti, PhD, in Pharmacology and Toxicology.

Postpartum Depression 

Postpartum depression (PPD) is a prevalent depressive disorder affecting individuals in the period following childbirth. While it typically emerges after delivery, it can manifest during pregnancy. Distinguished from temporary ‘baby blues’, PPD is characterised by prolonged major depressive episodes and represents a significant public health concern [1].

Although PPD shares commonalities with major depressive disorder (MDD), emerging research indicates its distinctive nature, particularly regarding the mother-infant dynamic. The hallmark of PPD lies in its profound emotional disconnection from self, infant, and support networks, creating a unique therapeutic challenge.

The condition manifests through several key symptoms: persistent low mood, depleted energy levels, compromised infant bonding, diminished concentration, and difficulties with self-care. Despite affecting 10-20% of mothers worldwide, PPD frequently remains undiagnosed [2]. Its gradual onset often masks its development, while societal misconceptions lead to consistent underestimation of its severity. Depression affects 4% of the general population, with women, particularly those of reproductive age, showing higher susceptibility than men [3].

Mechanism of Post-Partum Depression

Postpartum depression develops through a mix of biological and social factors working together. While it shows up as a mental health condition, its root causes include changes in the body, brain chemistry, hormones, and social circumstances. Understanding how these different factors interact helps doctors identify individuals who may be at risk and develop more effective treatments.

One of the main biological triggers is the sharp drop in hormones after giving birth, especially a hormone called allopregnanolone. This hormone helps regulate mood by interacting with specific brain receptors, known as GABA receptors. When hormone levels fall, they can disrupt the body’s stress-response system, known as the hypothalamic-pituitary-adrenal (HPA) axis, particularly in the first six to eight weeks after birth. Not everyone develops PPD, which suggests that genetic makeup and how sensitive someone is to hormone changes play important roles.

Recent studies have shown that pregnancy alters the brain’s structure, including the reduction of some areas. These changes can impact how new mothers manage their emotions and regulate their mood. Scientists have also found that certain brain chemicals become imbalanced, particularly two key ones: GABA and glutamate. Women with PPD often have higher levels of glutamate, which might explain why they have trouble managing their emotions [4].

Outside of body chemistry, life circumstances and stress play a big role, especially when they occur alongside the biological changes. Things like problems in relationships, not having enough support from family and friends, or experiencing stress during pregnancy can increase the risk of developing PPD. This shows us that PPD isn’t caused by just one thing—it’s the result of many factors in the body, brain, and environment working together. This is why doctors need to look at the whole picture when helping someone with PPD.

Standard treatments 

For women experiencing depression during and after pregnancy, talk therapy (psychotherapy) is usually the first recommended treatment. When symptoms are moderate to severe, doctors often prescribe antidepressant medications alongside therapy. While these treatments are based on those used for general depression, they don’t always work as well for PPD, and some women don’t respond to them at all.

The most commonly prescribed medications are antidepressants that work by adjusting levels of brain chemicals called neurotransmitters. These include:

• SSRIs (selective serotonin reuptake inhibitors), which increase serotonin levels
• SNRIs (serotonin-norepinephrine reuptake inhibitors), which increase both serotonin and norepinephrine levels

Over the past five years, two new medications have been specifically developed and approved for PPD: Brexanolone and Zuranolone. These drugs work differently from traditional antidepressants by targeting brain receptors called GABA receptors. This new approach offers two key advantages: they start working more quickly, and they treat depression through different pathways in the brain compared to standard antidepressants [5].

Psychedelics in Postpartum Depression

Because current treatments for PPD don’t work well enough for many mothers, researchers are looking into new approaches. One promising area is psychedelic-assisted therapy, which combines carefully controlled psychedelic substances with professional therapeutic support. A recent review suggests that psychedelics could be particularly valuable in PPD by fostering emotional ‘reconnection’ – helping mothers improve their mood while strengthening their emotional bond and sensitivity towards their infant.

Trials over the last few years have shown encouraging results using psychedelics to treat various types of depression and other mental health conditions. These early studies have shown that when used properly, these treatments can be both safe and effective. Based on these positive findings, scientists have now started trials to investigate whether similar treatments might help women with PPD. 

They are particularly interested in three main substances: ketamine and esketamine (related medicines already used in medical settings), psilocybin (the active compound found in magic mushrooms), and new, laboratory-made (second-generation) versions of these substances specifically designed to work more effectively as medicines.

Mechanisms of Action of Psychedelics

To understand how psychedelics might help with PPD, we need to look at how these substances affect the brain. While different psychedelic compounds work in slightly different ways, they all seem to help the brain form new connections and reset emotional responses. Scientists have identified two primary mechanisms by which these substances function in the brain [6,7].

The first important mechanism involves substances like ketamine and esketamine, which work by blocking specific brain receptors known as NMDA receptors. When these receptors are blocked, a chain reaction is initiated in the brain, leading to the release of another neurotransmitter, glutamate. This process enables brain cells to form new connections and repair existing ones. For mothers with PPD, these changes could help restore healthy brain patterns, particularly in areas that control mood and maternal behaviour. These improvements might help stabilise emotions during the challenging postpartum period [5,7].

The second method involves substances like psilocybin, which primarily affect the brain’s serotonin system by activating specific serotonin (5-HT) 2a receptors. Studies of people with depression have shown that psilocybin can help people feel emotionally “reconnected” – both with themselves and with others. This could be particularly valuable for mothers with PPD, as it might help strengthen the emotional bond with their baby and help them feel more confident in their role as a mother [4,8].

Current Research on Ketamine and Esketamine

Ketamine and its left-handed enantiomer (one of a pair of molecular entities which are mirror images) esketamine were originally used as anaesthetics, but have recently gained attention for their ability to treat depression rapidly. Esketamine may work more effectively on certain brain receptors, specifically NMDA receptors, compared to regular (racemic; both pairs) ketamine. In recent years, researchers have studied both substances for various mental health conditions, including treatment-resistant depression (TRD), major depression (MDD), and now PPD.

Esketamine (sold under the brand name Spravato) is already approved for treating depression that hasn’t responded to other treatments. Researchers are now interested in whether it might prevent or reduce PPD symptoms. Early studies have also looked at low doses of ketamine, given during or after caesarean sections, to try to prevent PPD.

Initial trials using 35mg/70kg of ketamine showed short-term improvements in mood and fewer cases of ‘baby blues’. The benefits were most noticeable in the first two to four weeks after giving birth, and most women tolerated the treatment well. Some studies found that fewer women developed PPD when given ketamine (12.8% compared to 19.6% in untreated groups), and fewer experienced baby blues (11.9% compared to 18.3%) [10].

However, the research findings haven’t all shown the same results. This variability in results was highlighted in a large clinical trial with 330 participants that found no significant benefit of low-dose ketamine (17.5mg/70kg) for preventing PPD when given during caesarean section. The study found that while ketamine reduced PPD symptoms in the first week after birth, these benefits didn’t last at the four-week follow-up. More women in the ketamine group experienced vomiting, although overall side effects were similar between the treated and untreated groups. The research suggested that giving ketamine continuously through a pump for 48 hours after birth worked better than a single dose during delivery.

However, a comprehensive meta-analysis of multiple studies found that a higher dose of 35mg/70kg ketamine did significantly reduce PPD symptoms in the first week after birth, though these benefits weren’t maintained after 4 weeks.

The promising results with ketamine have led researchers to study esketamine as a potential PPD prevention treatment. Since esketamine is already approved for treatment-resistant depression and has some advantages over ketamine, there’s growing interest in using it as a quick-acting treatment during the perinatal period.

Building on these findings, recent trials have assessed low-dose esketamine (0.7–17.5 mg/70kg) for PPD prevention [11]. A 35mg/70kg intravenous dose administered after childbirth significantly reduced the risk of major postpartum depression at 42 days, with only 6.7% of treated participants affected compared to 25.4% in the placebo group. Depressive symptoms were also lower at 7 and 42 days postpartum. While nearly half of the esketamine group experienced transient neuropsychiatric effects, none required intervention. Other studies using 17.5mg/70kg reported no antidepressant benefit but noted reduced motor pain [12-14]. 

Esketamine can help reduce anxiety and provide mild sedation without making patients unconscious, which could be useful during surgical deliveries. However, we don’t yet have studies directly comparing ketamine and esketamine. The main differences noticed so far are in side effects: esketamine tends to cause dizziness, while ketamine more often causes vomiting [15].

A crucial concern is whether it’s safe to use ketamine or esketamine while breastfeeding. This involves understanding how much of the drug passes into breast milk, how much the baby might receive, and any effects on the baby or milk production.

Research has shown that both ketamine and its breakdown product (active metabolite), norketamine, do appear in breast milk after the mother receives the treatment (either by injection into muscle or through a vein). The levels peak in milk about 1 to 3 hours after treatment and then decrease significantly over the next 12 to 24 hours. The amount of drug transferred to milk depends on factors such as the percentage of the drug that binds to proteins in the blood (10-50%) and the rate at which the body removes it (typically 2-4 hours) [16, 17].

We need larger and more thorough trials to determine the best dose, timing, and safety of ketamine and esketamine for preventing PPD. Future studies should also investigate how these treatments work in various populations and provide clearer guidance on their safe use during breastfeeding.

Current Research on Psilocybin and Related Compounds

Scientists are investigating psilocybin (the active compound in magic mushrooms) and similar substances that affect the brain’s serotonin system as potential new treatments for PPD. This interest comes from promising results in treating general depression, where psilocybin has shown it can quickly improve mood and help people feel emotionally reconnected, effects that could be particularly helpful for new mothers struggling with PPD and bonding with their babies.

Although no clinical trials had tested psilocybin specifically for PPD as of 2025, studies of general depression have shown that psilocybin can be used safely when given under careful medical supervision with psychological support. Researchers have suggested ways to make these treatments possible for new mothers, such as temporarily pausing breastfeeding during treatment. These early findings suggest that studying psilocybin for the treatment of PPD is worth pursuing.

A company called Reunion Neuroscience is developing a new version of psilocybin, designated as RE104. This modified compound is designed to work more quickly, with effects lasting only 3 to 4 hours instead of the usual 6 to 8 hours of traditional psilocybin. This shorter duration could make the treatment more practical for new mothers [18].

In initial safety testing (Phase I trials), RE104 was found to be generally safe at doses up to 44 mg. Side effects were usually mild and included feeling sick, headaches, a faster heart rate, and restlessness. When given at 33 mg, people reported similar experiences to traditional psilocybin but for a shorter time. These results suggest that RE104 might work quickly enough to be a practical treatment option for PPD [18].

Reunion is now conducting a larger trial (called RECONNECT) to assess the effectiveness of RE104 for PPD. They are comparing two different doses—1.6 mg and 33 mg—to determine which might be most effective [18, 19].

Psychedelic Industry and Future Research

Given that current PPD treatments don’t work well enough for many mothers, researchers are exploring new options. One promising area is psychedelic-assisted therapy, which might help both mothers recover and strengthen the crucial bond between mother and baby.
Companies with Ongoing Studies

Two companies are currently conducting important research into psychedelic treatments for PPD:

Reunion Neuroscience is developing a new medicine called RE104, which is similar to psilocybin but works more quickly. RE104 creates psychedelic effects that last about 4 hours, making it potentially more practical for new mothers than traditional psychedelics. The company plans to initiate testing of RE104 for moderate to severe PPD in mid-2024, with results anticipated in 2025. Initially, they won’t include breastfeeding mothers in their studies, but plan to test the treatment’s safety for breastfeeding women in future research [20, 21].

GH Research is working on a novel approach with its treatment, called GH001. This is an inhaled form of a substance called mebufotenin, which creates very short but powerful psychedelic effects lasting only 15-30 minutes. This brief duration could make it especially practical for new mothers. They’re currently testing GH001 in women with moderate to severe PPD who have given birth within the past year. The treatment involves giving three increasing doses (6 mg, 12 mg, and 18 mg) all on the same day, without requiring additional therapy sessions. Early results have been encouraging – women have shown improvements as quickly as two hours after treatment, and the medicine has been well tolerated. Most impressively, all participants in the study recovered from their depression by day 8 [22, 23].

Current and Future Research

While therapy remains essential for treating PPD, it’s often difficult for new mothers to attend regular sessions due to their demanding schedules, tiredness, and childcare needs. Researchers face additional challenges when studying new treatments for PPD: there are fewer potential participants compared to studies of general depression, and new mothers face unique obstacles to joining research trials. We also need more long-term studies to understand the effectiveness of these treatments over time and to determine the optimal ways to utilise them.

Research into psychedelic treatments for depression is moving quickly, particularly for TRD and MDD. Currently, only esketamine is officially approved as a psychedelic treatment, though it can be used either alone or with other treatments. Several companies are testing other substances in clinical trials: psilocybin-based treatments are in final testing stages, while 5-MeO-DMT, LSD, and ketamine are in middle-stage trials. However, most of this research focuses on general depression rather than PPD specifically.

Ketamine and esketamine are currently the most studied psychedelic treatments for PPD, particularly when used in low doses. Researchers are carefully examining how these substances work in the body, their effectiveness, and most importantly, their safety for both mothers and babies. This is especially crucial during breastfeeding, when any treatment could potentially affect the baby.

Recent guidelines from Canadian experts (CANMAT) suggest using ketamine as a second choice for treating depression and a third choice for bipolar disorder. However, they don’t recommend using ketamine during pregnancy or the postpartum period yet, as we don’t have enough evidence about its safety [24].

Meanwhile, researchers are exploring other options. One ongoing trial is looking at MDMA-assisted therapy for mothers who developed post-traumatic stress disorder (PTSD) and opioid addiction after childbirth. This study will help determine whether this treatment is safe and practical for new mothers. The treatment involves three therapy sessions using MDMA, with follow-up checks after four weeks and six months.

Future Research Directions

While early research into psychedelics for PPD shows promise, particularly with ketamine and esketamine after caesarean births, significant gaps in our knowledge remain. Current medical guidelines still recommend against using ketamine during pregnancy due to limited safety data. The key challenges ahead include determining how these treatments might affect babies, both during pregnancy and through breastfeeding, which requires large, well-designed studies across diverse groups of mothers.

We need to determine the optimal doses and the timing of these treatments. Future research should explore whether higher doses might work better for women at higher risk of PPD or those who aren’t breastfeeding. While ketamine-based treatments are furthest along in development, researchers are also studying other psychedelics. For example, the RECONNECT trial is testing RE104 (a modified form of psilocybin) for non-breastfeeding mothers with moderate to severe PPD.

To move forward, we need more rigorous clinical trials that follow mothers for longer periods, employ proper scientific controls, and account for other factors that may affect the results, such as birth interventions and sleep quality. These high-quality studies will help doctors make evidence-based decisions about using psychedelic treatments for PPD.

External References for Postpartum Depression and Psychedelics

All resources available on Blossom are directly linked on this topic page. Find even more background about this topic with these external references.

1. Carlson K, Mughal S, Azhar Y, et al. Perinatal Depression. [Updated 2025 Jan 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519070/

2. NHS-Overview – Postnatal depression. Available online, https://www.nhs.uk/mental-health/conditions/post-natal-depression/overview/ 

3. Khadka N, Fassett MJ, Oyelese Y, et al. Trends in Postpartum Depression by Race, Ethnicity, and Prepregnancy Body Mass Index. JAMA Netw Open. 2024;7(11):e2446486. https://doi.org/10.1001/jamanetworkopen.2024.46486

4. Paternina-Die, M., Martínez-García, M., Martín de Blas, D. et al. Women’s neuroplasticity during gestation, childbirth and postpartum. Nat Neurosci 27, 319–327 (2024). https://doi.org/10.1038/s41593-023-01513-2

5. Moore Simas TA, Whelan A, Byatt N. Postpartum Depression—New Screening Recommendations and Treatments. JAMA. 2023;330(23):2295–2296. https://doi.org/10.1001/jama.2023.21311

6.  Li, S., Zhou, W., Li, P., & Lin, R. (2024). Effects of ketamine and esketamine on preventing postpartum depression after cesarean delivery: A meta-analysis. Journal of affective disorders, 351, 720–728. https://doi.org/10.1016/j.jad.2024.01.202 

7. Darwish, M.Y., Helal, A.A., Othman, Y.A. et al. Efficacy and safety of ketamine and esketamine in reducing the incidence of postpartum depression: an updated systematic review and meta-analysis. BMC Pregnancy Childbirth 25, 125 (2025). https://doi.org/10.1186/s12884-025-07186-y

8. Parsaei, M., Hasehmi, S. M., Seyedmirzaei, H., Cattarinussi, G., Sambataro, F., Brambilla, P., Barone, Y., & Delvecchio, G. (2024). Perioperative esketamine administration for prevention of postpartum depression after the cesarean section: A systematic review and meta-analysis. Journal of affective disorders, 361, 564–580. https://doi.org/10.1016/j.jad.2024.06.080

9. Ma, J. H., Wang, S. Y., Yu, H. Y., Li, D. Y., Luo, S. C., Zheng, S. S., Wan, L. F., & Duan, K. M. (2019). Prophylactic use of ketamine reduces postpartum depression in Chinese women undergoing cesarean section. Psychiatry research, 279, 252–258. https://doi.org/10.1016/j.psychres.2019.03.026

10. Alipoor, M., Loripoor, M., Kazemi, M., Farahbakhsh, F., & Sarkoohi, A. (2021). The effect of ketamine on preventing postpartum depression. Journal of medicine and life, 14(1), 87–92. https://doi.org/10.25122/jml-2020-0116

11. Frivaldszky, L., Lőrincz, K., Hoferica, J., Hegyi, P., Ács, N., Melczer, Z., Fehérvári, P., & Keszthelyi, M. (2025). Esketamine reduces the risk of postpartum depression in women undergoing cesarean section: A systematic review and meta-analysis. Journal of psychiatric research, 183, 164–173. https://doi.org/10.1016/j.jpsychires.2025.02.021 

12. Shen, J., Song, C., Lu, X., Wen, Y., Song, S., Yu, J., & Sun, J. (2023). The effect of low-dose esketamine on pain and post-partum depression after cesarean section: A prospective, randomized, double-blind clinical trial. Frontiers in psychiatry, 13, 1038379. https://doi.org/10.3389/fpsyt.2022.1038379

13. Xu, S., Yang, J., Li, J., Zhang, M., Sun, J., Liu, Q., & Yang, J. (2024). Esketamine pretreatment during cesarean section reduced the incidence of postpartum depression: a randomized controlled trail. BMC anesthesiology, 24(1), 20. https://doi.org/10.1186/s12871-023-02398-1

14. Wang, S., Deng, C. M., Zeng, Y., Chen, X. Z., Li, A. Y., Feng, S. W., Xu, L. L., Chen, L., Yuan, H. M., Hu, H., Yang, T., Han, T., Zhang, H. Y., Jiang, M., Sun, X. Y., Guo, H. N., Sessler, D. I., & Wang, D. X. (2024). Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ (Clinical research ed.), 385, e078218. https://doi.org/10.1136/bmj-2023-078218

15. Nayyer, M. A., Khan, S. M., Umer, M., Imran, H., Khalid, S., Murtaza, H., Sarfraz, A., Atiq, N., Rasool, H., & Fatima, M. (2024). Efficacy and safety of peri-partum Esketamine for prevention of post-partum depression in women undergoing caesarian section: A meta-analysis and systematic review of randomized controlled trials. Asian journal of psychiatry, 97, 104090. https://doi.org/10.1016/j.ajp.2024.104090

16.  Ketamine – Drugs and Lactation Database (LactMed®) – NCBI Bookshelf, https://www.ncbi.nlm.nih.gov/books/NBK500566/

17. Pharmacokinetics of ketamine transfer into breastmilk: a case series – Texas Tech University Health Sciences Center https://www.ttuhsc.edu/medicine/medical-education/documents/Ketamine_Poster.pdf 

18. Reunion Neuroscience, Poster. Available online: https://reunionneuro.com/wp-content/uploads/2023/06/23-RNR-3851_ASCP23_RE104_Poster_M1-3.pdf 

19. Reunion Neuroscience, Press-release. Available online: https://reunionneuro.com/2024/07/23/reunion-neuroscience-inc-announces-first-patient-dosed-in-phase-2-clinical-trial-of-re104-for-the-treatment-of-postpartum-depression/

20. Alexander R. et al., RE104: A Novel, Fast-Acting Psychedelic for Postpartum Depression. June 26, 2024. Available online: https://hsc.unm.edu/research/centers-programs/bbhi/assets-aig-rpt/rpt-documents/ppdarticle.pdf

21. Reunion Neuroscience, webpage. Available online, https://reunionneuro.com/science/ 

22. GH Research, pipeline. Available online, https://www.ghres.com/our-work/pipeline 

23. GH Research clinical trials. Available online, https://www.ghres.com/our-work/clinical-trials 

24. Swainson J. (2025) Ketamine and Perinatal Mental Health: Problems and Potentials. The Canadian Journal of Psychiatry. https://doi.org/10.1177/07067437251331514