This review (2022) makes the case for using psychedelics in the treatment of postpartum depression (PDD). The effects we see in other clinical trials with psychedelics may translate to PPD such as ‘reconnection.’ This effect in PPD, by fostering a sense of ‘reconnection’ for the mother, may allow for improved mood and maternal sensitivity towards the infant, which can positively impact maternal role gratification and the mother-infant relationship.

Abstract

“Background: Postpartum depression (PPD) is a major public health concern and has, at its core, a sense of maternal ‘disconnection’ – from the self, the infant, and the support system. While PPD bears similarities with MDD, there is increasing evidence for its distinct nature, especially with the unique aspect of the mother-infant relationship. Current treatment modalities for PPD, largely based on those used in major depressive disorder (MDD), have low remission rates with emerging evidence for treatment resistance. It is, therefore, necessary to explore alternative avenues of treatment for PPD.

Objective: In this narrative review, we outline the potential therapeutic rationale for serotonergic psychedelics in the treatment of PPD, and highlight safety and pragmatic considerations for the use of psychedelics in the postpartum period.

Methods: We examined the available evidence for the treatment of PPD and the evidence for psychedelics in the treatment of MDD. We explored safety considerations in the use of psychedelics in the postpartum period.

Results: There is increasing evidence for safety, and encouraging signals for the efficacy, of psilocybin in the treatment of MDD. Psilocybin has been shown to catalyse a sense of ‘reconnection’ in participants with MDD. This effect in PPD, by fostering a sense of ‘reconnection’ for the mother, may allow for improved mood and maternal sensitivity towards the infant, which can positively impact maternal role gratification and the mother-infant relationship.

Conclusion: Psychedelic assisted therapy in PPD may have a positive effect on the mother-infant dyad and warrants further examination.”

Authors: Chaitra Jairaj & James J. Rucker

Summary

Introduction

The transition to motherhood, termed ‘matrescence’, is a transformative life event involving both positive and negative emotional processes. Postpartum depression (PPD) is a significant public health concern, and brexanolone is the only drug approved for the treatment of PPD in the United States.

Research into the use of classic psychedelics has resumed since 2000. Early phase clinical trial evidence suggests safety and feasibility of psilocybin given with psychological support in the treatment of depression, end-of-life distress, and substance use disorders.

Postpartum depression

Perinatal depression is a common illness, with prevalence rates ranging from 10% to 20%, and higher incidence across some cultures and in socially disadvantaged populations. It is associated with negative foetal and neonatal outcomes, impaired infant neurodevelopment and attachment, and increased risk of developing depression during adulthood.

Postpartum depression (PPD) is a major public health concern. This narrative review explores the potential therapeutic rationale for serotonergic psychedelics in the treatment of PPD, and highlights safety and pragmatic considerations for the use of psychedelics in the postpartum period.

PPD has a heterogeneous presentation with high comorbidity with anxiety, including pervasive low mood, impaired sleep, appetite, and concentration, feelings of inadequacy or guilt, and a sense of detachment from the infant.

PPD is thought to be multifactorial, with hormones, neurotransmitters, inflammation, genetics, and environmental risk factors all playing a role. Low allopregnanolone levels are thought to underlie the pathophysiology of PPD in some women.

There are several significant differences between perinatal depression and major depressive disorder, including aetiology, genetic risk factors, decreased activation in reward-related regions, and associations with early life and chronic psychosocial stress.

PPD is thought to be caused by hormonal factors, the change in role to motherhood, and the responsibility of caring for a dependent infant. Infant-related symptoms are distinct to PPD.

PPD is associated with a blunted amygdala response to negative stimuli, and decreased activation of corticolimbic circuitry involved in emotional salience and threat processing, which may explain the decreased maternal sensitivity and increased self-reported hostility towards the infant seen in PPD.

PPD has similar therapeutic needs to MDD, but additional goals of improving maternal care and the quality of the mother-infant interaction. Current treatments for PPD are based on those used in the general adult population, and there is little evidence of efficacy for antidepressant treatment specific to PPD.

Brexanolone, administered as an intravenous infusion over a 60-h period, has shown promise in clinical trials for the treatment of PPD. However, the high cost and prolonged period of admission required for brexanolone treatment are barriers to its accessibility and generalisability.

Postpartum maternal mental disorders can affect infant development and future well-being, in part due to adverse effects on mother-infant interaction and attachment. Parent-infant psychotherapy can improve health outcomes in the parent-infant dyad, including management of maternal postpartum psychological symptoms and improving infant attachment security.

PPD has distinct features to MDD, including dampened corticolimbic circuitry and amygdala response, and can negatively impact the mother-infant relationship. Current treatment options ignore these differences, leading to poor efficacy and treatment resistance.

Overview of psychedelic research

There is a long history of ritualistic use of psilocybin and ayahuasca, and some encouraging results were achieved with the use of classic psychedelics in the 1950s and 1960s. However, concerns about serious adverse effects arose, and their use was prohibited.

Since the turn of the millennium, clinical research with classic psychedelics has resumed, and has been successful. No long-term impairment or abuse has been reported, and dysphoric experiences (‘bad trips’) have been minimised by ensuring rapport with the guides or therapists and providing a safe environment for the session.

Serotonergic psychedelics act through numerous serotonin receptors (5-HTR), with psilocybin and LSD acting as partial agonists at the 5-HT2AR. The 5-HT2AR is thought to be necessary (but not sufficient) for subjective psychedelic effects.

Serotonergic psychedelics enhance amygdala activity and reduce default mode network (DMN) and salience network connectivity. These effects are not specific to classic psychedelics, and may be important for the therapeutic benefits of psychedelics.

Psychedelic trials in depression

A systematic review of pre-prohibition studies of classic psychedelics in cases classed as ‘depressives’ found that clinician-judged improvement occurred in 79.2% of patients.

In an open-label study of six patients with recurrent depression, ayahuasca significantly reduced depression scores by day 7 after dosing, and the effect lasted up to day 21. No adverse events were reported in either open-label study, and a randomised placebo-controlled trial was conducted in 29 participants with treatment-resistant depression.

In an open-label study, 12 patients with moderate to severe treatment-resistant depression received oral psilocybin for 7 days. After one week, 67% of patients achieved complete remission, and at 3-month follow-up, 58% of patients maintained response and 42% remained in complete remission.

A single centre trial of psilocybin-assisted therapy in 27 participants with MDD showed that depression scores reduced rapidly on day 1 and remained low at 4 weeks. Psilocybin may produce a rapid antidepressant response with sustained remission up to 4 weeks after dosing.

In a phase 2, double-blind RCT, 59 participants with moderate-to-severe MDD received psilocybin or escitalopram. The mean change in QIDS-SR-16 scores from baseline to week 6 was similar in the psilocybin and escitalopram groups, with a between-group difference of two points (95% CI: 5.0 to 0.9).

Psilocybin was reported to have a well-tolerated safety profile in a multi-centre phase IIb trial in 233 participants with treatment-resistant depression. Psilocybin therapy appeared to have similar rapid reduction in depression scores, with enduring response at 6 months.

Psychedelics postpartum

There are no studies on psychedelics postpartum, particularly in breastfeeding. Evidence for their safety is largely based on case reports.

Breast milk drug concentration is found to be concordant with maternal plasma drug concentration. Psilocin, the active metabolite of psilocybin, is less likely to pass into breast milk than psilocybin, as it has a pH of 5.2 and is therefore less likely to diffuse into breast milk.

Low molecular weight drugs, such as psilocin, can cross readily into breast milk, and psilocybin can transiently increase prolactin levels, but leave no effect on breast milk production.

The age of the infant is another factor determining the risk of infant adverse effects through drug exposure in breast milk.

Psilocybin and psilocin are not yet examined in clinical trials, but current knowledge suggests that they may pass into breast milk. However, maternal plasma concentration of psilocin may be the most useful indicator of breast milk concentration.

Therapeutic rationale for the use of psychedelics in the treatment of PPD

PPD is associated with a profound sense of maternal ‘disconnection’ from the self, from the infant, and from the support network, as well as lower maternal sensitivity towards the infant, which can impact on infant development, behaviour and mental health in later years.

Psychedelics induce altered states of consciousness and can elicit mystical-type experiences, which are associated with enduring improvements in depression and anxiety outcome measures.

Qualitative studies of psychedelic experiences in participants with mental ill-health have revealed a number of themes that bear relevance to PPD, including increased self-compassion, a greater insight into one’s relationship with others, and a transition from emotional avoidance to acceptance.

LSD is associated with an increase in oxytocin levels in healthy participants, and this increase may be mediated through 5-HT2AR agonism. This may help improve maternal sensitivity and the mother-infant relationship.

Psychedelic-assisted therapy involves preparation sessions with the therapist before the dosing session, support during the dosing session, and integration sessions after the dosing session. ACT is a third-wave behavioural therapy that emphasises acceptance of internal events.

Psychedelic therapy can improve the mother-infant relationship through increased sense of connectedness, improved maternal self-compassion and role gratification, and increased oxytocin levels.

Discussion

PPD is a distinct disorder to MDD in aetiology and neurobiology, with poor response to conventional MDD treatment.

Psilocybin, with its positive effects on mood and openness, may be a useful adjunct in the treatment of postpartum depression. It can promote a sense of connection between mother and infant, improve maternal mood and maternal role gratification.

Psilocybin appears to have little teratogenic potential in healthy participants and those with MDD, but little research has been done on the safety of psilocybin in the perinatal period.

There is no research into the safety of psilocybin in breast-feeding women, but there has been a shift from systematic exclusion of breastfeeding women from clinical drug trials towards a more reasoned approach of inclusion while taking infant safety into consideration.

Psilocybin may have a role in the treatment of PPD, particularly in promoting reconnection of the mother to herself, her infant, and her support structures, and positive enduring changes in the mother-infant relationship.

Safety considerations

There are no studies of psilocybin use in breastfeeding. Women may be advised to abstain from breastfeeding for 48 h after psilocybin administration to reduce infant exposure to psilocybin and allow breastfeeding women to participate in psilocybin trials.

Limitations

The evidence on psychedelics in the treatment of MDD is limited to single-centre phase 2 trials with small sample sizes. Larger multi-centre RCTs are awaited.

Conclusion

Psychedelic-assisted therapy may be beneficial in treating maternal loss of connection with herself and her infant, and promote positive changes for the mother-infant dyad.