Key Insights

• Borderline personality disorder affects up to 2.7% of the population and is characterised by profound instability in identity, relationships, and emotional regulation, with no medication consistently improving its core features.
• Psychedelic-assisted therapies (including ketamine and MDMA) show promise for BPD through mechanisms of enhanced neuroplasticity and emotional processing.
• Despite theoretical promise and early positive findings, BPD patients have been systematically excluded from most psychedelic trials due to safety concerns. New studies are beginning to examine the effects of psychedelics for BPD directly.

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

What is Borderline Personality Disorder?

Borderline personality disorder (BPD) is a complex mental health condition characterised by marked instability in identity, interpersonal relationships, and emotional regulation. Individuals with BPD often exhibit impulsive behaviours, episodes of intense anger, chronic feelings of emptiness, suicidal ideation, and self-harm. Acute episodes may involve stress-related paranoid thoughts or severe dissociative symptoms, such as feeling detached from oneself or one’s surroundings [1].

BPD frequently co-occurs with other psychiatric conditions, including mood disorders, anxiety disorders, and substance misuse. Prevalence estimates vary, with studies suggesting that BPD affects between 0.7% and 2.7% of the United States population and approximately 1.8% of adults globally [2]. Diagnosis is typically made using structured or semi-structured clinical interviews conducted by trained mental health professionals. These tools help identify the complex symptom profile and differentiate BPD from other mental disorders [1].  

Mechanism of Borderline Personality Disorder 

BPD arises from a complex interplay of genetic, neurobiological, and environmental factors. Although the relative contributions of these elements remain unclear, current evidence suggests a multifactorial origin involving hereditary traits, neurochemical imbalances, and early life adversity.

Genetic influences appear to play a substantial role, with heritability estimates for BPD reaching approximately 40% [3]. This suggests that inherited traits may predispose individuals to emotional dysregulation and impulsivity, core features of the disorder.

Neurobiological research has pointed to dysregulation in neurotransmitter systems, particularly involving serotonin. Altered serotonin signalling is associated with mood instability, impulsive aggression, and emotional reactivity, and may underlie both depressive symptoms and the characteristic behavioural volatility observed in BPD [4].

Environmental risk factors are also significant. Individuals exposed to early adverse experiences, including emotional neglect, physical or sexual abuse, and inconsistent parenting, appear to have a heightened risk of developing BPD. Broader social influences such as low socioeconomic status, maternal psychopathology, or family substance misuse further increase vulnerability. Longitudinal studies have additionally linked certain childhood temperament traits, such as high emotional sensitivity and impulsivity, to the later emergence of BPD [5,6].

Standard Treatments 

The first-line treatment for BPD is psychotherapy. Despite its efficacy, therapeutic benefits often diminish over time and may no longer be present six months or more after treatment ends.  Earlier clinical guidelines recommended a range of psychiatric medications to manage BPD symptoms, including antidepressants (e.g., fluoxetine), mood stabilisers such as lithium carbonate, antipsychotics, and monoamine oxidase inhibitors [7]. However, recent evidence indicates that no medication class consistently improves the core features of BPD.

Pharmacological interventions are recommended only when treating comorbid conditions such as major depressive disorder or generalised anxiety. In such cases, selective serotonin reuptake inhibitors (SSRIs) may be considered [8, 9]. Current best practices prioritise verbal interventions, such as dialectical behaviour therapy (DBT), mentalisation-based therapy (MBT), or schema-focused therapy. When pharmacological treatment is necessary, short-term use at the lowest effective dose is advised [1]. 

Psychedelics and BPD

Psychedelic-assisted therapy (PAT) has attracted growing interest as a novel approach for a range of mental health conditions. BPD, marked by emotional dysregulation, unstable self-image, and interpersonal difficulties, remains one of the most challenging psychiatric diagnoses to treat effectively. Some researchers have proposed classifying certain presentations of BPD within the broader framework of complex post-traumatic stress disorder (C-PTSD), reflecting overlapping symptoms and treatment challenges [10].

Emerging research suggests that psychedelic therapies may offer potential benefits in addressing core features of BPD, including emotional instability, identity disturbances, and impaired social functioning. Several psychedelic compounds are being investigated for their relevance to BPD, particularly MDMA, psilocybin, ayahuasca, and ketamine.

Most ongoing or planned clinical trials are not targeting BPD directly but rather focus on comorbid conditions frequently associated with it, such as major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), and bipolar disorder (BD). As these disorders often co-occur with BPD, improvements in one domain may indirectly benefit BPD symptoms.

Encouraging outcomes from psychedelic trials in complex psychiatric conditions suggest the potential for broader application to BPD. However, the high rates of diagnostic overlap and the heterogeneity of BPD presentations pose challenges for study design and treatment evaluation. Future research will need to address these complexities to determine whether psychedelic therapies can offer targeted, enduring benefits for individuals with BPD [11].

Mechanisms of Action of Psychedelics

Psychedelics are a class of compounds that induce altered states of consciousness and modulate affect, cognition, and perception. Their mechanisms of action vary by compound, but most classical psychedelics exert their effects through the serotonergic system.

Classic psychedelics such as psilocybin, LSD, and DMT (also found in ayahuasca) act primarily as agonists at the 5-HT2A receptor. Activation of this receptor alters brain network connectivity, enhances cognitive flexibility, promotes neuroplasticity, and shifts patterns of thought and awareness. These effects are thought to underlie many of the therapeutic benefits observed in psychedelic-assisted therapy [12].

Not all compounds classified as psychedelics share this mechanism. For example, MDMA (also classified as an entactogen) presents an activation of different levels of alteration as serotonin, dopamine, and norepinephrine, leading to heightened emotional openness, empathy, and reduced fear responses. Ketamine, while often included in the broader category of psychedelics due to its dissociative and therapeutic effects, acts through a different mechanism. It is a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor and is associated with rapid-acting antidepressant effects.

Together, these diverse mechanisms suggest multiple potential pathways through which psychedelics may benefit individuals with BPD, particularly by modulating emotional reactivity, enhancing self-awareness, and promoting neural adaptability.

Ketamine and BPD

Ketamine, along with its S-enantiomer esketamine, has emerged as a promising treatment for various psychiatric conditions, particularly TRD, which frequently co-occurs with BPD. Comorbidity rates between BPD and MDD are high, ranging from 71% to 83%, and significantly impact prognosis and treatment outcomes. 

Originally approved as a general anaesthetic by the U.S. FDA in the 1970s, ketamine has since been investigated for its rapid-acting antidepressant effects. Building on these findings, esketamine was approved by the FDA in 2019 as a nasal spray for use in adults with TRD, either as monotherapy or in combination with oral antidepressants.

Ketamine and esketamine show promise as a treatment for individuals with BPD, particularly for co-occurring depression, suicidal ideation, and anxiety, with emerging evidence for its impact on BPD symptoms themselves.

In the context of BPD, ketamine’s action on glutamate receptors may help address dysregulated glutamatergic signalling implicated in emotional instability and impulsivity. By enhancing neuroplasticity, ketamine may contribute to repairing dysfunctional neural circuits commonly observed in individuals with BPD and comorbid TRD [13].

Emerging studies support ketamine’s potential in alleviating depressive symptoms, suicidal ideation, and anxiety in BPD populations. In one open-label study, repeated intravenous infusions of ketamine (35–52.5mg/70kg) over two weeks significantly reduced depressive symptom severity and improved both positive and negative symptom domains in individuals with and without BPD. In participants with moderate to extreme baseline suicidal ideation, the reduction in suicide scores was more than twice the magnitude observed in the overall sample, suggesting a particularly robust effect in those at higher risk. 

Case reports provide further insights. One case described a 27-year-old woman with BPD and TRD who received esketamine nasal spray over two years. She experienced a 70% reduction in depression and anxiety, and an 80% improvement in behavioural symptoms [14]. In another case, a patient treated with low-dose sublingual ketamine (25mg daily) over 10 months showed sustained remission from BPD symptoms, including emotional dysregulation, fear of abandonment, and impulsivity, ultimately no longer meeting diagnostic criteria for BPD [13].

Ketamine and esketamine are generally well tolerated. Dissociative effects during infusion are usually transient and mild. However, some reports have highlighted risks in certain BPD patients, including heightened impulsivity, disinhibition, or worsened suicidal ideation, particularly in the absence of concurrent psychotherapeutic support [14].

MDMA and BPD

MDMA-assisted therapy (MDMA-AT) combines the administration of MDMA with structured psychotherapy sessions. Over the past decade, this approach has shown promise in treating complex mental health conditions, particularly PTSD, which shares significant overlap with BPD. In 2017, MDMA was granted “breakthrough therapy” designation by the FDA following compelling results in trials involving individuals with severe, treatment-resistant PTSD, including military veterans [10].

To date, no completed or active clinical trials have directly investigated MDMA-AT for BPD. Patients with BPD have often been excluded from MDMA trials due to concerns about high-risk behaviours and emotional instability. However, the shared symptomatology between PTSD and BPD, including emotional dysregulation, dissociation, and relational difficulties, has led to growing interest in extending this therapy to BPD populations. 

MDMA-AT typically includes preparatory psychotherapy sessions to discuss safety, set intentions, and establish coping strategies. This is followed by 8-hour dosing sessions conducted with two therapists in a supportive, controlled environment designed to encourage introspection and emotional processing.

During treatment, patients usually receive two to three doses of MDMA (ranging from 80 to 180mg) across two or three experimental sessions over a 12-week period. Preparatory and integration sessions bracket each dosing session to reinforce therapeutic insights and promote long-term benefits [10]. 

Although direct evidence for BPD is currently lacking, outcomes from MDMA-AT for PTSD are striking. In Phase III trials, 67% to 71.2% of participants in the MDMA group no longer met diagnostic criteria for PTSD following treatment, compared to only 32% in the placebo-with-therapy group. These improvements were durable, with many participants maintaining benefits 12 months post-treatment [15-17]. The magnitude and persistence of these effects in a trauma-based disorder have fuelled speculation that MDMA-AT could also benefit individuals with BPD.

Currently, early-stage research is beginning to explore this possibility. A Phase II study evaluating MDMA-AT for comorbid PTSD and BPD is underway in the United States (NCT06683014), alongside another registered trial in Australia (ACTRN12624000871549)

Psilocybin and BPD

Psilocybin, a classic psychedelic compound, is under extensive investigation for its therapeutic potential across a range of mental health conditions. It primarily acts as an agonist at the 5-HT2A receptor, inducing perceptual alterations, enhanced emotional openness, and introspective experiences; features considered central to its therapeutic action. 

Growing evidence supports the efficacy of psilocybin-assisted therapy in treating MDD and TRD. Clinical trials have demonstrated reductions in depressive symptoms, as well as improvements in anxiety and psychological well-being following administration in controlled settings.

Interest in psilocybin as a treatment for PTSD is increasing, with several Phase III clinical trials currently underway. Although results have not yet been published, preliminary hypotheses suggest psilocybin may offer similar benefits to those seen with MDMA-assisted therapy, particularly in terms of emotional processing and trauma resolution [12].

Given the symptom overlap between PTSD and BPD, including emotional dysregulation, affective instability, and interpersonal difficulties, psilocybin may also hold therapeutic potential for BPD. Its ability to modulate emotional reactivity and foster new psychological insights makes it a candidate for future research in this area, though no dedicated trials have been conducted to date.

Ayahuasca and BPD

Ayahuasca is a traditional plant-based brew originating from the Amazon basin, historically used in ceremonial and spiritual contexts. It is typically consumed as a tea and contains two key components: beta-carboline alkaloids (such as harmine and tetrahydroharmine), which act as monoamine oxidase inhibitors (MAOIs), and DMT, the primary psychoactive compound.

The psychotropic effects of ayahuasca, including perceptual changes, emotional intensification, introspection, and memory recall, are primarily mediated through DMT’s action as an agonist at 5-HT2A and 5-HT1A receptors and its modulation of the intracellular sigma-1 receptor (S1R). These mechanisms contribute to alterations in brain connectivity, enhanced cognitive flexibility, and increased neuroplasticity, which are believed to underlie its potential therapeutic effects.

Although no formal clinical trials have yet evaluated ayahuasca for BPD, some exploratory research has begun to investigate its impact on emotional regulation, one of the core challenges in BPD. In a 2019 study by Domínguez-Clavé and colleagues, healthy volunteers with subclinical BPD traits participated in ayahuasca ceremonies. Results suggested improvements in emotional regulation and reduced emotional interference, pointing to possible benefits for individuals with BPD-related symptomatology.

However, these findings must be interpreted cautiously. The exploratory study did not include participants formally diagnosed with BPD, and sample sizes were small. Further research is needed involving clinically diagnosed populations, larger cohorts, controlled comparisons, and placebo conditions to better evaluate the potential role of ayahuasca as a complementary therapy in BPD.

Psychedelic Industry and Future Research

Emerging research suggests that psychedelic-assisted therapies may address core symptoms of BPD, including emotional dysregulation, trauma reactivity, and interpersonal instability. These effects are thought to be mediated through enhanced neuroplasticity and improved emotional processing. Recent theoretical frameworks propose conceptualising BPD as a trauma-induced personality stress disorder, broadening the rationale for the application of psychedelic interventions.

Companies Working on BPD

While scientific interest in psychedelic therapies is growing, clinical exploration specific to BPD remains in its infancy. Many studies have excluded individuals with BPD due to concerns about emotional instability, suicidality, and the potential for unpredictable responses. As a result, BPD is underrepresented in psychedelic research despite its high burden and unmet clinical needs.

Compass is a leading biotechnology company developing COMP360, a proprietary synthetic formulation of psilocybin, for TRD. It has conducted the largest psilocybin trials to date, across sites in North America and Europe. However, patients with a formal diagnosis of BPD have historically been excluded from these trials. This exclusion reflects a common risk-mitigation strategy in pharmaceutical development to reduce population heterogeneity and avoid adverse events such as emotional destabilisation or suicidality, which could confound outcomes. In its Phase III programme, COMP360 showed a clinically meaningful reduction of -3.6 points on the MADRS scale at six weeks compared to placebo [16-20].

MindMed, another clinical-stage psychedelic company, is advancing MM-120, its proprietary LSD formulation, for generalised anxiety disorder (GAD). In a Phase IIb trial, a single dose of MM-120 produced rapid and sustained reductions in anxiety symptoms over 12 weeks. Although BPD is not currently a target for MindMed, these findings may inform future research on anxiety-related disorders with overlapping features [21, 22].

Upcoming Research on BPD

Despite promising theoretical rationale, clinical trials specifically investigating psychedelic-assisted therapies in BPD remain limited. Safety, ethical concerns, and diagnostic complexity continue to pose barriers. However, new studies are beginning to address this gap. The University of Chicago is conducting a Phase I open-label study evaluating the safety and efficacy of psilocybin in adults with co-occurring major depressive disorder (MDD) and BPD. It represents one of the first formal attempts to explore psilocybin therapy in individuals with BPD symptoms.

Another trial investigates whether intravenous ketamine can reduce suicidality in individuals with BPD, while also assessing effects on mood, pain, social cognition, neuroplasticity, and core BPD symptoms. While ketamine has shown promise in MDD and suicidality, its application in BPD remains largely unexplored. Given the lack of approved pharmacological treatments for BPD, this trial could provide important insights.

External references for BPD 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. Leichsenring, F., Heim, N., Leweke, F., Spitzer, C., Steinert, C., & Kernberg, O. F. (2023). Borderline Personality Disorder: A Review. JAMA, 329(8), 670–679. https://jamanetwork.com/journals/jama/article-abstract/2801843 

2. Dahlenburg, S. C., Bartsch, D. R., & Gilson, K. J. (2024). Global prevalence of borderline personality disorder and self-reported symptoms of adults in prison: A systematic review and meta-analysis. International Journal of Law and Psychiatry, 97, 102032. https://www.sciencedirect.com/science/article/pii/S0160252724000815 

3. Amad, A., Ramoz, N., Thomas, P., Jardri, R., & Gorwood, P. (2014). Genetics of borderline personality disorder: systematic review and proposal of an integrative model. Neuroscience and biobehavioral reviews, 40, 6–19. https://linkinghub.elsevier.com/retrieve/pii/S0149-7634(14)00006-2 

4. NHS, Causes-Borderline Personality Disorders. https://www.nhs.uk/mental-health/conditions/borderline-personality-disorder/causes/ 

5. Stepp, S. D., Lazarus, S. A., & Byrd, A. L. (2016). A systematic review of risk factors prospectively associated with borderline personality disorder: Taking stock and moving forward. Personality Disorders, 7(4), 316–323. https://pmc.ncbi.nlm.nih.gov/articles/PMC5055059/ 

6. Bozzatello, P., Rocca, P., Baldassarri, L., Bosia, M., & Bellino, S. (2021). The Role of Trauma in Early Onset Borderline Personality Disorder: A Biopsychosocial Perspective. Frontiers in Psychiatry, 12, 721361. https://pmc.ncbi.nlm.nih.gov/articles/PMC8495240/ 

7. Keepers, G. A., Fochtmann, L. J., Anzia, J. M., Benjamin, S., Lyness, J. M., Mojtabai, R., … Medicus, J. (2024). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Borderline Personality Disorder. American Journal of Psychiatry, 181(11), 1024–1028. https://psychiatryonline.org/doi/10.1176/appi.ajp.24181010

8. Personality disorders: borderline and antisocial. https://www.nice.org.uk/guidance/qs88 

9. Borderline personality disorder: recognition and management. https://www.nice.org.uk/guidance/cg78 

10. Inouye, A. M., Wolfgang, A. S., & Philhower, L. T. (2023). MDMA-assisted therapy for borderline personality disorder. Journal of Psychedelic Studies, 7(3), 227-237. https://akjournals.com/view/journals/2054/7/3/article-p227.xml 

11. Zeifman, R. J., & Wagner, A. C. (2020). Exploring the case for research on incorporating psychedelics within interventions for borderline personality disorder. Journal of Contextual Behavioral Science, 15, 1-11. https://www.sciencedirect.com/science/article/abs/pii/S2212144719301024 

12. Martire, G., et al., (2024). Theorizing that Psychedelic Assisted Therapy May Play a Role in the Treatment of Trauma-Induced Personality Disorders. Journal of Addiction Psychiatry, 8(2), 161–165. https://pmc.ncbi.nlm.nih.gov/articles/PMC11616086/ 

13. Liester, M., Wilkenson, R., Patterson, B., & Liang, B. (2024). Very Low-Dose Sublingual Ketamine for Borderline Personality Disorder and Treatment-Resistant Depression. Cureus, 16(4), e57654. https://pubmed.ncbi.nlm.nih.gov/38707115/ 

14. Nandan, N. K., Soni, P. K., Parsaik, A., & Hashmi, A. (2022). “Esketamine” in Borderline Personality Disorder: A Look Beyond Suicidality. Cureus, 14(4), e24632. https://pubmed.ncbi.nlm.nih.gov/35664413/  

15. Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology 25(4), 439–452. https://pmc.ncbi.nlm.nih.gov/articles/PMC3122379/ 

16. COMP360 Psilocybin Therapy Study Results by Compass Pathways. https://compasspathways.com/our-work/comp360-psilocybin-treatment-in-trd/ 

17. The safety and efficacy of COMP360 psilocybin therapy in treatment-resistant depression – Compass Pathway. https://compasspathways.com/wp-content/uploads/2022/06/Compass_Posters.pdf 

18. Compass Pathways Successfully Achieves Primary Endpoint in First Phase 3 Trial Evaluating COMP360 Psilocybin for Treatment-Resistant Depression. https://ir.compasspathways.com/News–Events-/news/news-details/2025/Compass-Pathways-Successfully-Achieves-Primary-Endpoint-in-First-Phase-3-Trial-Evaluating-COMP360-Psilocybin-for-Treatment-Resistant-Depression/default.aspx 

19. Compass Pathways’ Psilocybin Clears First Phase 3 Hurdle – Psychedelic Alpha. https://psychedelicalpha.com/news/compass-pathways-psilocybin-clears-first-phase-3-hurdle 

20. Kirlić, N., Lennard-Jones, M., Atli, M., Malievskaia, E., Modlin, N. L., Peck, S. K., … Koelpin, D. (2025). Compass Psychological Support Model for COMP360 Psilocybin Treatment of Serious Mental Health Conditions. American Journal of Psychiatry, 182(1), 126–132. https://www.psychiatryonline.org/doi/10.1176/appi.ajp.20230884 

21. MindMed Receives FDA Breakthrough Therapy Designation and Announces Positive 12-Week Durability Data From Phase 2B Study of MM120 for Generalized Anxiety Disorder. https://ir.mindmed.co/news-events/press-releases/detail/137/mindmed-receives-fda-breakthrough-therapy-designation-and-announces-positive-12-week-durability-data-from-phase-2b-study-of-mm120-for-generalized-anxiety-disorder 

22. MindMed Announces Positive Topline Results from Phase 2b Trial of MM-120 in Generalized Anxiety Disorder. https://ir.mindmed.co/news-events/press-releases/detail/131/mindmed-announces-positive-topline-results-from-phase-2b-trial-of-mm-120-in-generalized-anxiety-disorder