The Effect of Psychedelics on Individuals with a Personality Disorder: Results from two Prospective Cohort Studies

doi:10.21203/rs.3.rs-4203641/v1

Background: Personality disorders (PDs) are characterized by impairments in psychological functioning for which pharmacologic treatments have demonstrated limited efficacy. Psychedelics may offer a potential PD treatment, given support for their potential enduring positive effects on psychological functioning. However, little is known about the safety or therapeutic effects of psychedelics among individuals with a PD. Therefore, we examined the effects of psychedelic use on mental health among individuals with a PD.

Methods: Study 1 included three prospective observational studies where 21 individuals with a PD diagnosis completed mental health measures (depressive symptoms, anxiety, and suicidal ideation [SI]) before, 2 weeks (except SI), and 4 weeks after psychedelic use. Study 2 was a prospective observational study in which 55 individuals with a PD diagnosis completed mental health measures (anxiety, depressive symptoms, cognitive flexibility, expressive suppression, and cognitive reappraisal) before, 2-4 weeks, and 2-3 months after psychedelic use.

Results: In Study 1, elevations in SI were rare (6.67%) with no elevations to high risk of suicidal behavior post-psychedelic use. All participants with high baseline risk of suicidal behavior (6.67%) were at low-risk post-psychedelic use. SI reduced at 4 weeks (Hedges’ g=0.52). There were several cases of increased anxiety (Study 1: 13.6%-25.0%; Study 2: 16.3%-11.5%) and clinically significant worsening of depression symptoms (Study 1: 14.3%-14.2%; Study 2: 10.0%-8.0%). Across both studies, psychedelic use was associated with reductions in anxiety (Study 1: g=-.46–-.57; Study 2 g=-.52–-.89) and depression (Study 1 g=-.54–-0.59; Study 2 r_s= .52–.57) . In Study 2, there were transient increases in cognitive flexibility at 2-4 weeks (g=.26) and sustained increases in cognitive reappraisal up to 2-3 months (g=.36). Increases in cognitive reappraisal were associated with reductions in anxiety (r=.33) and depression (r_s=.37).

Conclusion: For individuals with PD, psychedelic use was associated with improvements in psychological functioning. There were no clinically significant elevations in SI and several cases of elevations in anxiety and depression severity. The studies are limited by a small sample size, self-reported data, and lack of differentiation between PDs. Further research should explore the safety and potential therapeutic effects of psychedelics among individuals with PD.

personality disorders

psychedelics

symptom exacerbation

mental health outcomes

Personality disorders (PDs) are characterized by impairments in intra- and interpersonal functioning that are pervasive over time and environments.(1) PDs are also associated with maladaptive mental health outcomes, such as depressive symptoms, anxiety, suicidal ideation, and impairments in emotion regulation and cognitive flexibility.(2–6) The point prevalence of PDs is approximately 6.1% among the general population.(7–9)

PDs often exhibit treatment-resistant trajectories, as psychotherapeutic interventions show modest effect sizes and poor remission rates.(7) Further, while medications such as antidepressants, mood stabilizers, and antipsychotics are commonly used as adjunctive treatment, none have been approved for use by regulatory agencies or have shown substantive clinical utility.(10,11)

Classic psychedelics include (but are not limited to) psilocybin, lysergic acid diethylamide (i.e., LSD), ayahuasca (a South American, psychoactive brew), N,N-dimethyltryptamine (DMT) (psychoactive component of ayahuasca), and mescaline (psychoactive compound found in several cactus species).(12) These compounds induce an acute non-ordinary state of consciousness via activation of the 5-HT2AR serotonin receptor subtype.(13) Psychedelic-assisted therapy (PAT) involves the administration of classic psychedelics in a therapeutic context.(14) PAT offers a novel and potentially promising approach to treat a myriad psychiatric disorders, many of which are known for substantial comorbidity with PDs, such as major depressive disorder (MDD), treatment-resistant depression(15–19), substance use disorders (e.g., alcohol use disorder)(20–22), eating disorders(23), and obsessive-compulsive disorder.(24–26) Research has also found that PAT may improve cognitive flexibility.(27) Randomized controlled trials (RCT), open label studies, and prospective observational research also suggest that administration/use of classic psychedelics may restructure maladaptive personality traits implicated in PDs, including impulsivity(28), introversion(28), antagonism(28–30), neuroticism(31,32), emotion dysregulation(28,33–35), depressivity, and anxiousness.(17–19,29,36–39)

While these findings suggest PAT may be efficacious PD-related dysfunction, data examining the effects of psychedelics in PDs are scarce.(40,41) Clinical investigators often exclude patients with PDs, such as paranoid personality disorder, borderline personality disorder (BPD), and antisocial personality disorder from trials.(17,36,42,43) Studies also often have exclusionary criteria that indirectly target PD patients, such as “psychiatric conditions judged to be incompatible with establishment of rapport or safe exposure to psilocybin.”(44) However, some clinical trials that have included individuals with a comorbid PD have noted improvement in depressive symptoms across the full sample.(45,46) Studies have reported reductions in suicidality among several individuals with BPD after psilocybin administration(46) and improvements in emotional regulation in those with BPD traits after ayahuasca use.(47) Early research on PAT described mixed results regarding treatment outcomes in individuals with PDs (for a review, see (40). Notably, a recent case report described significant reductions in depressed mood, emotional instability, and suicidal ideation following psychedelic treatment in a patient with mixed PD.(47,48) Recent research by Marrocu et al. also found transient improvements in psychological well-being 2-weeks following naturalistic psychedelic use among individuals with a PD diagnosis.(49) However, no recent prospective cohort studies have examined the effect of psychedelic use on affective symptoms (e.g., depressive symptoms or anxiety) or psychological mechanisms (e.g., emotion regulation, cognitive flexibility) for individuals with a PD diagnosis.

The lack of prospective studies on psychedelic effects among individuals with a PD constitutes a significant gap in current research. Considering the recent and rapid expansion of psychedelic therapy in practice, including policy change surrounding access, there is growing concern that patients with PDs may begin seeking treatment with psychedelics or use them outside of clinical care.(50,51) Further, harm reduction strategies are uninformed if the effects and potential risks of psychedelic use are not known in this patient population. Although psychedelics are generally safe with appropriate screening and support,(12) there are risks, including the potential for increased suicidality and decompensation in clinical(43,52) and non-clinical settings.(49,53–55) Of note, Marrocu et al. found evidence that, relative to individuals without a PD diagnosis, the presence of a PD diagnosis was associated with greater risk of worsened well-being following psychedelic use (only when controlling for baseline well-being and comorbid diagnoses).(49) However, this study did not examine whether there were exacerbations in suicidal ideation or depressive symptoms. Therefore, to better understand the safety concerns and potential therapeutic effects surrounding psychedelics in individuals with a PD, we used data from two prospective studies (Study 1: classic psychedelic use; Study 2: psilocybin use) to examine the effects of psychedelic use on mental health among individuals who reported having a PD diagnosis.

Procedures and Participants

Prospective data were collected between March 2017 and December 2019 from three anonymous cohort studies with similar designs focused on the effects of classic psychedelic use (56–58), which overlaps with data used by Marrocu et al.(49) The studies were administered via the online platform ‘Psychedelic Survey’ (www.psychedelicsurvey.com). The first two cohort studies recruited individuals using classic psychedelics in a naturalistic setting. The third cohort study recruited individuals who specifically planned to use a psychedelic in a ceremonial setting among others within a guided retreat. The studies received approval from Imperial College London’s Imperial College Research Ethics Committee (ICREC) and the Joint Research Compliance Office (JRCO).

Participants were recruited via online advertisements distributed on social media (ie. Facebook and Twitter), online forums (ie. Reddit), and email newsletters, and provided informed consent online. The participants were sent email reminders to fill out surveys based on when they planned to use a psychedelic at time points including 1 week prior to psychedelic use (baseline), 2-weeks and 4-weeks post psychedelic use. Inclusion criteria were individuals age >18 years, good comprehension of the English language, and intention to take a classic psychedelic (i.e. LSD, psilocybin/magic mushrooms/truffles, DMT, San Pedro, Ayahuasca) soon. In the present sub-analyses, we included all individuals who reported having a PD diagnosis and filled out surveys at baseline and at least one additional time point (2-weeks and/or 4-weeks).(49) Of the full sample of 2250 individuals, 21 individuals self-reported having a formal diagnosis of a PD and completed the necessary surveys.

Measures

Demographics

Demographic information such as age, gender, education level, and previous psychiatric diagnoses were collected at baseline.

Suicidal Ideation

The Suicidal Ideation Attributes Scale (SIDAS) is a 5-item self-report measure of the presence and severity of suicidal thoughts.(59) Responses are rated on a 10-point scale, with higher scores signifying higher levels of suicidal ideation. Individuals who score a 0 on the first question (“In the past month, how often have you had thoughts about suicide?”) receive a total score of 0. Suicide risk is stratified into 0 (no ideation), 1-20 (low ideation), and 21-50 (high ideation).(59) The SIDAS was measured at baseline and 4-weeks.

Depression Symptoms

The Quick Inventory of Depressive Symptoms (QIDS-SR-16) is a 16-item self-report measure of depression severity.(60) The responses are on a 4-point scale ranging from 0 to 3 and questions are based on the DSM-5 symptoms of depression. The QIDS-SR-16 was measured at baseline, 2-weeks, and 4-weeks.

Trait Anxiety

The shortened trait scale of the Spielberger State-Trait Anxiety Inventory-Trait (STAI-short) is a validated 6-item version of the original 20-item STAI to measure levels of trait anxiety.(61,62) Responses are rated on a 4-point scale from 1 (not at all) to 4 (very much). The STAI-short was measured at baseline, 2-weeks, and 4-weeks.

Analyses

Exacerbation in level of suicidal ideation relative to baseline were descriptively reported using categories of risk: 1-20 (low ideation), and 21-50 (high ideation). Exacerbations in depression symptoms relative to baseline were descriptively reported using the minimal clinically important difference of increase of > 28.5% for QIDS-SR-16.(60) Exacerbations in trait anxiety were descriptively reported using overall worsening as an increase in score relative to baseline and improvements as decrease relative to baseline.

Normality of distribution was assessed visually using a QQ plot and quantitatively using Shapiro-Wilk and Kolmogorov-Smirnov tests. To determine statistically significant changes for each trait variable, paired t-tests (for normally distributed data) and Wilcoxon tests (for non-normally distributed data) were performed to ascertain changes between baseline vs. 2-weeks and baseline vs. 4-weeks. ANOVA or Friedman’s test was not performed due to limited sample size and missing data at the time points following psychedelic use. Individuals who scored 0 on the SIDAS questionnaire at baseline, were not included in the change analyses. To determine effect sizes, Hedges’ g and r_s scores were calculated for each paired t-test and Wilcoxon test, respectively.

P values of < 0.05, two-tailed, were considered statistically significant. Data was analyzed using Microsoft Excel (Microsoft Corp., Redmond, Washington) and Prism (GraphPad, San Diego, California). FDR correction for multiple comparisons was employed using the Benjamini and Hochberg method(63) at the level of time, run separately for the paired t-tests (# of analyses = 5).

Descriptive Statistics

For participant demographics, see Table 1. For means, standard deviations, sample sizes at each time point, and tests of normality, see Table 2.

Table 1: Participant demographics for both Study 1 and Study 2.

		Study 1	Study 2
Total Sample		N=21	N=55
Gender	Male	11 (52.58%)	24 (43.64%)
	Female	9 (42.86%)	29 (52.73%)
	Other	1 (4.76%)	2 (3.64%)
Age M (SD)		28.38 (8.41)	35.16 (9.29)
Nationality	Other	10 (47.62%)	10 (18.18%)
	United States	4 (19.05%)	40 (72.73%)
	Netherlands	4 (19.05%)	2 (3.64%)
	Germany	1 (4.76%)	3 (5.45%)
	Saudi Arabia	1 (4.76%)
	United Kingdom	1 (4.76%)	2 (3.64%)
Type of Psychedelic Used	Psilocybin	11 (52.38%)	55 (100%)
	LSD / 1P-LSD	6 (28.57%)
	San Pedro	2 (9.52%)
	DMT	1 (4.76%)
	Ayahuasca	1 (4.76%)

Table 2: Means, standard deviations, number of participants, Shapiro-Wilk test, and Kolmogorov-Smirnov test for all measures included in Study 1 and Study 2.

*Variable*	*Time Point*	*Mean*	SD	n	*Shapiro-Wilk*	*Kolmogorov-Smirnov*
*Study 1*
Suicidal Ideation	Baseline	9.27	11.79	15	.75	.22
Suicidal Ideation	4-weeks	4.53	5.04	15	.85	.23*
Trait Anxiety	Baseline	15.67	4.63	40	.96*	.09*
	2-weeks	13.14	4.54	20	.97*	.12*
	4-weeks	14.25	4.42	15	.98*	.12*
Depression Symptoms	Baseline	8.90	5.65	40	.94*	.18*
	2-weeks	6.26	3.51	19	.97*	.14*
	4-weeks	6.64	4.96	14	.89*	.18*
*Study 2*
Trait Anxiety	Baseline	27.00	6.59	50	.97*	.08*
	2-4 weeks	23.44	6.74	50	.98*	.09*
	2-3 months	22.07	5.05	27	.95*	.14*
Depression Symptoms	Baseline	22.90	13.19	50	.97*	.09*
	2-4 weeks	11.24	12.36	49	.78	.24
	2-3 months	10.92	9.53	24	.91	.18
Cognitive Flexibility	Baseline	52.77	9.74	52	.98*	.07*
	2-4 weeks	55.35	9.65	52	.97*	.08*
	2-3 months	55.52	8.68	27	.97*	.08*
Expressive Suppression	Baseline	3.27	1.54	52	.95	.10*
	2-4 weeks	3.49	1.56	53	.94	.13
	2-3 months	3.85	1.38	28	.97*	.14*
Cognitive Reappraisal	Baseline	4.46	1.38	52	.96*	.12*
	2-4 weeks	4.91	1.25	53	.94	.14
	2-3 months	5.19	1.24	28	.94*	.13*

* denotes normality (p>.05)

Suicidal Ideation, Depressive Symptom, and Trait Anxiety Worsening

From baseline to 4 weeks, complete resolution of suicidal ideation was found in 20% (n = 3) of the sample, with a final SIDAS of 0. One individual (6.67%) had an increase in suicidal ideation. However, this individual remained within the low-risk category (maximum increase = 5) and did not elevate to the high-risk category. 0% of individuals increased from low or no risk to high-risk.

From baseline to 2 weeks, 78.6% (n = 11) of individuals demonstrated reductions in depression symptoms, with 64.3% (n = 9) of participants having clinically significant reductions. Three individuals (21.4%) had an increase in depression symptoms, with two individuals (14.3%) having clinically significant increases from baseline (maximum sum increase = 3). From baseline to 4 weeks, 71.4% (n = 10) of individuals demonstrated reductions in depression symptoms with 61.3% (n = 9) of participants having clinically significant reductions. One individual (7.1%) had no change and two individuals (14.2%) had a clinically significant increase in depression symptoms of 33.3% from baseline (maximum sum increase = 5).

From baseline to 2 weeks, trait anxiety reduced for 63.6% (n = 14) of participants. Five participants (22.7%) had no change in trait anxiety with 13.6% (n = 3) experiencing an increase (max sum increase = 2). From baseline to 4 weeks, trait anxiety reduced for 62.5% (n = 10) of participants. Two participants (12.5%) had no change in trait anxiety with 25% (n = 4) experiencing an increase (max sum increase = 2).

Primary Analyses

Suicidal Ideation

A non-parametric Wilcoxon matched-pairs signed rank test indicated that there was a significant reduction in suicidal ideation at 4-weeks (Md=5, n=15) compared to baseline (Md=9, n=15), z=0.63, p=.009, p-FDR=.015, with a large effect size r_s=0.86 (Figure 1a).

Depression Symptoms

Paired t-tests found significant decreases in depression at 2-weeks (6.26 ± 3.51) compared to baseline (8.95 ± 5.80), (t(18)=2.62, p=.018, p-FDR=.023, g=-0.54) and 4-weeks (6.64 ± 4.96) compared to baseline (10.00 ± 5.72), (t(13)=2.26, p=0.042, p-FDR=.042, g=-0.59) (Figure 1b).

Trait Anxiety

Paired t-tests indicated significant decreases in trait anxiety at 2-weeks (12.90 ± 2.83) compared to baseline (15.05± 4.27), (t(19)=3.37, p=.003, p-FDR=.015, g= -.57) and 4-weeks (13.53 ± 4.42) compared to baseline (15.73 ± 4.68), (t(14)=3.12, p=.008, p-FDR=.015, g= -.46) (Figure 1c).

Procedures and Participants

Prospective data were collected in a singular cohort study via Qualtrics between July 22, 2020 and July 14, 2022 (www.qualtrics.com).(64) This study was approved by an Institutional Review Board at the Johns Hopkins University School of Medicine. Participants were recruited through online advertisements on social media and through word of mouth. Individuals who planned to take single-dose of psilocybin outside of a research laboratory setting within the next 6 month were asked to fill out surveys at five different time points including 1-2 weeks before (baseline), 2-4 weeks after, and 2-3 months after psilocybin use. Email reminders were sent for each survey.

Inclusion criteria were being 18 years or older, good comprehension of English language, willingness to fill out surveys at stated time points, and intention to take psilocybin within the next 6 months. Of the full sample of 8,006 individuals, 457 participants self-reported having a formal diagnosis of a PD in their lifetime. Fifty-five individuals completed surveys at baseline and at least one additional time point of 2-4 weeks after or 2-3 months after psilocybin use.

Measures

Demographics

Demographic information such as age, gender, education level, and previous psychiatric diagnoses were collected at baseline.

Depression Symptoms

The Beck Depression Inventory (BDI-II) is a 21-item self-report measure of the severity of depression symptoms for the prior 2 weeks.(65,66) One of the questions includes suicide risk and was excluded from this questionnaire, due to the inability of clinicians to respond adequately to reported imminent risk.(64) Responses are rated on a 4-point scale from 0-3. The BDI-II was measured at baseline, 2-4 weeks, and 2-3 months.

Trait Anxiety

The trait scale of the validated shortened Spielberger State-Trait Anxiety Inventory (STAI) is a 10-item measure of trait anxiety.(67,68) Responses are rated on a 4-point scale from 1 (almost never) to 4 (almost always). The STAI was measured at baseline, 2-4 weeks, and 2-3 months.

Cognitive Flexibility

The Cognitive Flexibility scale (Cog Flex) is a 12-item self-report measure of the ability of an individual to adaptively modulate thinking and behavior in response to changing environmental demands.(27,64,65,69) Responses are rated on a 6-point scale ranging from 1 (strongly disagree) to 6 (strongly agree). The Cog Flex was measured at baseline, 2-4 weeks, and 2-3 months.

Emotion Regulation (Cognitive Reappraisal and Expressive Suppression)

The Emotion Regulation Questionnaire (ERQ) is a 10-item questionnaire that measures the ability of individuals to regulate their emotions and includes two scales: Cognitive Reappraisal (ERQ-Reappraisal) and Expressive Suppression (ERQ-Suppression).(70) Cognitive reappraisal measures the ability to re-interpret emotional events.(71,72) Expressive suppression is the tendency consciously interfere with an emotional response (e.g. facial expression) in efforts to regulate an emotional experience .(70,72,73) Responses are rated on a 7-point Likert-type scale ranging from 1 (strongly disagree) and 7 (strongly agree). The ERQ was measured at baseline, 2-4 weeks, and 2-3 months.

Analyses

Exacerbations in trait anxiety were descriptively reported using overall worsening as an increase in score relative to baseline and improvements as decrease relative to baseline. Exacerbations in depression symptoms relative to baseline were descriptively reported using the minimal clinically important difference of increase of >13.49% for the BDI-II.(65,66,74)

Normality of distribution was assessed visually using a QQ plot and quantitatively using Shapiro-Wilk and Kolmogorov-Smirnov tests. To determine statistically significant changes for each trait variable, paired t-tests (for normally distributed data) and Wilcoxon tests (for non-normally distributed data) were performed to ascertain changes between baseline vs. 2-4 weeks and baseline vs. 2-3 months. ANOVA or Friedman’s test was not performed due to limited sample size and missing data at the time points following psychedelic use. To determine effect sizes, Hedges’ g and r_s scores were calculated for each paired t-test and Wilcoxon test, respectively.

P values of < 0.05, two-tailed, were considered statistically significant. Data was analyzed using Microsoft Excel (Microsoft Corp., Redmond, Washington) and Prism (GraphPad, San Diego, California). FDR correction for multiple comparisons was employed using the Benjamini and Hochberg method(63) at the level of time, run separately for the paired t-tests (# of analyses = 8) and correlation analyses ((# of analyses = 4).

To determine whether changes in cognitive flexibility and cognitive reappraisal were associated with changes in depressive symptoms and trait anxiety (baseline minus 2-4 weeks), Pearson (for normally distributed data) and Spearman (for non-normally distributed data) correlation coefficients were calculated.

Descriptive Statistics

For participant demographics, see Table 1. For means, standard deviations, sample sizes at each time point, and tests of normality, see Table 2.

Depression Symptom and Trait Anxiety Worsening

From baseline to 2-4 weeks, depression symptoms reduced for 84.0% (n = 42) of participants, with 78.0%% (n = 39) of individuals experiencing a clinically significant reduction. From baseline to 2-3 months, depression symptoms reduced for 88.0% (n = 22) of participants, with 80.0% (n = 20) of individuals experiencing a clinically significant reduction. Eight percent of individuals (n = 4) had clinically significant increases in depression symptoms at 2-4 weeks, and 2 individuals (8.0%) had clinically significant increases in depression symptoms for 2-3 months. At 2-3 months, one individual (4.0%) had no change in depression symptoms.

From baseline to 2-4 weeks, trait anxiety reduced for 69.4% (n = 34) of participants. Eight participants (16.3%) had no change in trait anxiety with 16.3% (n = 8) experiencing an increase (max sum increase = 6). From baseline to 2-3 weeks, trait anxiety reduced for 80.7% (n =21) of participants. Two participants (7.7%) had no change in trait anxiety with 11.5% (n = 3) experiencing an increase (max sum increase = 6).

Primary Analyses

Trait Anxiety

Paired t-tests identified a significant decrease in trait anxiety at 2-4 weeks (23.33 ± 6.76) compared to baseline (26.88 ± 6.60), (t(48)=4.61, p<.001, p-FDR=.002, g= -.52) and 2-3 months (21.77 ± 4.90) compared to baseline (26.73 ± 5.92), (t(25)=4.50, p< .001, p-FDR=.002, g =-0.89) (Figure 2a).

Depression Symptoms

A Wilcoxon matched-pairs signed rank test identified a significant reduction in depression symptoms at 2-4-weeks (Md=7, n=49) compared to baseline (Md=23, n=49), z=.12, p<.001, p-FDR=.002, with a moderate effect size r_s=.52, and at 2-3 months (Md=9.5, n=24) compared to baseline (Md=23, n=24), z =.29, p<.001, p-FDR=.002, with a large effect size r_s =.71 (Figure 2b).

Cognitive Flexibility

Paired t-tests found a significant increase in cognitive flexibility at 2-4 weeks (55.35 ± 9.65) compared to baseline (52.77 ± 9.74), (t(51)=2.37, p=.021, p-FDR=.035, g=.26) but not at 2-3 months (55.52 ± 8.68) compared to baseline (53.26 ± 9.41), (t(26)=1.45, p=.158, p-FDR=.176, g=.24) (Figure 2c).

Cognitive Reappraisal

Wilcoxon matched-pairs signed rank test indicated a significant increase in cognitive reappraisal at 2-4-weeks (Md=4.91, n=52) compared to baseline (Md=4.46, n=52), z=-4.02, p<.001, p-FDR=.002 with a moderate effect size r_s=.74. A paired t-tests determined that there was a significant increase in cognitive reappraisal at 2-3 months (5.20 ± 1.26) compared to baseline (4.70 ± 1.40), (t(26)=2.07, p=.049, p-FDR=.07, g=.36) (Figure 2d).

Expressive Suppression

Wilcoxon matched-pairs signed rank tests indicated that there were not statistically significant changes in expressive suppression at 2-4-weeks (Md=3.25, n=52) compared to baseline (Md=3.00, n=52), z=-1.68, p=.123, p-FDR=.154, with a large effect size r_s=0.83, or at 2-3-months (Md=3.50, n=52) compared to baseline (Md=3.50, n=52), z=-2.61, p=.293, p-FDR=.293, with a large effect size r_s=.64 (Figure 2e).

Changes in Cognitive Flexibility vs. Changes in Depression Symptoms and Trait Anxiety

Changes in cognitive flexibility from baseline to 2-4 weeks were not significantly correlated with changes in depression symptoms (r_s=-0.17, p=.220, p-FDR=.293) or trait anxiety (r=0.11, p=.472, p-FDR=.472).

Changes in Cognitive Reappraisal vs. Changes in Depression Symptoms and Trait Anxiety

Increases in cognitive reappraisal from baseline to 2-4 weeks were correlated with reductions in both depression symptoms (r_s=-0.37, p=.007, p-FDR=.028) and trait anxiety (r=-0.33, p=.020, p-FDR=.04).

Modern clinical research suggests that PAT may be efficacious for the treatment of a wide range of psychiatric disorders.(15–22,24–27,75) However, little is known about how psychedelics affect individuals with a PD. This study sought to prospectively explore two main queries: 1. What are the potential mental health benefits of psychedelics for individuals with a PD?; and 2. What is the safety profile of psychedelics for individuals with a PD regarding suicide risk and worsening of depressive symptoms? We found significant improvements in multiple clinical outcomes for up to 4 weeks (Study 1) and 2-3 months (Study 2) following naturalistic psychedelic use. Of clinical importance, we also found reductions in, and no clinically significant elevations in suicide risk. Several instances of increased anxiety and clinically significant increases in depressive symptoms were observed, while the majority experienced reductions in anxiety and depression symptoms.

Understandably, concerns about increased suicidal ideation have led to the exclusion of individuals with a PD, especially particular PDs with higher suicide risk (e.g., BPD). Clinical studies and case reports from early psychedelic therapy trials have reported suicide-related adverse events.(53) For instance, a recent clinical trial (that included participants with a PD) reported no serious adverse events, but noted that two participants experienced a transient worsening of suicidality.(46) In the present study, while 6.67% of participants demonstrated increase in suicidal ideation, this worsening was not clinically significant given that no participant increased in risk category (i.e. from no risk to low risk or from low risk to high risk). Notably, our data showed that 20% of participants showed complete resolution of suicidal ideation. We also observed significant mean-level reductions in suicidal ideation 4 weeks after psychedelic use. This is consistent with previous studies indicating potential anti-suicidal effects of psychedelics in clinical (52) and non-clinical settings.(76) Given that suicidality is commonly seen in cluster B PD symptomatology (e.g., up to 10% of BPD patients die by suicide(77)), these findings provide preliminary support for the potential safety and efficacy of psychedelics for PD-related suicidal ideation. Given the nature of the study design, we urge caution regarding the interpretation of these findings. We also strongly suggest that further research pay close attention to potential exacerbation in suicidal ideation and be equipped to manage suicide risk when studying the effects of psychedelics in PD samples.

Across two separate studies, we found significant reductions in anxiety and depression among individuals with a self-reported PD. Importantly, significant reductions in these clinical symptoms were sustained up to 2-3 months. These findings are congruent with both clinical trials and non-clinical prospective studies that demonstrate antidepressant and anxiolytic effects of psychedelics (e.g., individuals with MDD).(18,19,36,37,43) At 4 weeks compared to baseline in Study 1, two participants (14.2%) had a clinically significant increase in depression, of 33.33%. One of the individuals showed a 26.7% reduction in depressive symptoms at 2 weeks following psychedelic use and then had increased 33.33% from baseline at 4 weeks. There was transient improvement, indicating potential efficacy for a limited time, with potential indication for repeated use/administration or the importance of providing psychotherapy during this window of sensitivity to avoid symptom worsening. For Study 2, at 2-3 months compared to baseline, 88.0% of individuals experienced reduction in symptoms and two of the participants (8.0%) had clinically significant increases in depression (of 3 points each). Trait anxiety demonstrated worsening for 4 of the participants (25%) in Study 1 and three participants (11.5%) in Study 2. However, the maximum increases were 2 and 6 points, for Study 1 and Study 2, respectively. While the majority of individuals experienced reductions in trait anxiety, these increases should not be ignored and may caution future clinicians from administering PAT for patients with PD. Further research should explore the clinical significance surrounding changes in trait anxiety and depression symptoms following psychedelic use, in reference to clinical presentation and treatment. Nonetheless, traits surrounding negative affectivity are pervasive over time in PD pathology.(1) Accordingly, the presently observed reductions in depression and anxiety following psychedelic use may bear clinical relevance to PD intervention.

Emotion regulation (including cognitive reappraisal and expressive suppression)(78) and cognitive flexibility(69) are often impaired in individuals with PDs and are key targets of therapeutic interventions.(79–81) Results of Study 2 suggest that naturalistic psilocybin use may durably enhance emotion regulation by improving cognitive reappraisal (but not expressive suppression), as improvements were found to be significant for up to 2–3-months after psychedelic use. These findings are consistent with the parent study and similar to previous observations that use of ayahuasca was associated with improvements in aspect of emotion regulation among individuals with BPD traits.(47) Notably, we found that improvements in cognitive reappraisal at 2-4 weeks post-psychedelic use were correlated with reductions in both depression symptoms and trait anxiety. This is consistent with research by Agin-Liebes et al. who found that higher levels of cognitive reappraisal during an ayahuasca ceremony were correlated with increased positive mood and psychological flexibility 3 months post-psychedelic use.(82) In Study 2, we found improvements in cognitive flexibility 2-4-weeks after psilocybin use. These increases in cognitive flexibility are congruent with prior prospective clinical(27) and observational research on psilocybin (including the larger sample from which the present findings were drawn).(27)^,(64) Of note, however, these reductions in cognitive flexibility were not significant at 2-3 months, suggesting possibly limited durability of such improvements following a single use of psilocybin. Additionally, we did not find a significant association between changes in cognitive flexibility and changes in trait anxiety or depression symptoms at 2-4 weeks, which is also consistent with a previous study of PAT in an MDD sample.(27) Overall, these findings suggest that psychedelics may enhance cognitive reappraisal and that these increases may drive improvements in psychological functioning following psychedelic use. Notably, the present findings are the first to establish improvements in emotion regulation and cognitive flexibility associated with psychedelics in a PD sample. Future research should further examine the durability of these effects and whether enhancements of cognitive reappraisal and cognitive flexibility are psychological mechanisms underlying clinical improvement.

Limitations and Future Directions

Our present study should be received with awareness of its important limitations. These studies used self-report data from naturalistic psychedelic use. The present findings may therefore be biased by regression to the mean, attrition, expectancy effects, and sampling bias. Moreover, particular psychedelics used were self-reported and self- administered, not in a controlled setting. Additionally, the parent studies did not specifically recruit individuals with a PD diagnosis, PD diagnoses were not specifically assessed (i.e., they were based on participants’ reports that they had received a PD diagnosis), and data related to specific PD diagnoses were not collected. While PDs are often studied in aggregate(2,40,83), future research would benefit from examining the effects of psychedelics delineated by specific PDs, including clinical assessment of outcomes and PD-specific measures of symptoms and functioning, such as the Personality Inventory for DSM-5 (i.e. negative affectivity, detachment, psychoticism, antagonism, and disinhibition).(84,85) Moreover, further investigation is indicated over a longer time period than our analysis allowed, especially given the generally chronic course of PD pathology. Additionally, research is also needed on the effects of repeated use of psychedelics to ascertain whether long-term changes in outcomes can be sustained following psychedelic use in individuals with a PD. Controlled clinical trials and larger observational studies will also be necessary to determine the potential for symptoms exacerbation (e.g., elevated suicide risk) and therapeutic efficacy associated with psychedelics among individuals with a PD.

In conclusion, following psychedelic use among individuals with a PD diagnosis, we did not observe cases of clinically significant worsening of suicidal ideation but did observe a limited number of cases of worsening anxiety and depressive symptoms. We also found that psychedelic use was associated with improvements in psychosocial functioning characterized by reductions in suicidal ideation, anxiety, and depression, as well as transient increases in cognitive flexibility and sustained increases in cognitive reappraisal. Notably, these reductions in depressive symptoms and anxiety were correlated with improvements in cognitive reappraisal, highlighting the potential importance of emotion regulation in understanding the effects of psychedelic use. These results provide preliminary evidence suggesting that psychedelics may provide therapeutic benefit in the treatment of PD pathology. They also highlight the importance of attending to potential symptom exacerbation among individuals with PDs. Given significant limitations of our study designs, we urge caution with interpreting the present findings, especially given the complexity and safety-related issues associated with PDs. Ultimately, controlled clinical trials will be necessary to determine the safety and potential efficacy of psychedelics for individuals with PD.

PD Personality Disorder

MDD Major Depressive Disorder

LSD Lysergic Acid Diethylamide

RCT Randomized Control Trial

BPD Borderline Personality Disorder

STAI The Spielberger State-Trait Anxiety Inventory

SIDAS The Suicidal Ideation Attributes Scale

QIDS-SR The Quick Inventory of Depressive Symptoms

WEMWBS The Warwick Edinburgh Mental Wellbeing Scale

BDI-II The Beck Depression Inventory-II

Cog Flex The Cognitive Flexibility Scale

ERQ The Emotional Regulation Questionnaire

ERQ Cog Emotional Regulation-Cognitive Reappraisal

ERQ Exp Emotional Regulation-Expressive Suppression

Ethics Approval and Consent to Participate

Studies involving human participants were both reviewed and approved by the Imperial College Research Ethics Committee (ICREC), Imperial College London Joint Research Compliance Office (JRCO), Imperial College London. The participants who participated in this study provided written informed consent to do so.

Consent for Publication

Not applicable.

Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests

ARG, BMC, AM, SN, and BJW have no disclosures. BAP and RJZ received funding from the NYU Langone Psychedelic Medicine Research Training program funded by MindMed. HK is a scientific advisor to Maya Health. DE is a paid advisor for Aya Biosciences, Clerkenwell Health, Lophora Aps and Mindstate Design Lab. RCH acts as an advisor to Entheos Lab, Mindstate, Maya Health, Osmind, Beckley Psytech, TRYP Therapeutics, Journey Collab, Journey Space, and Usona Institute. DER has received compensation as an independent contractor from Fluence. RJZ received funding from the Canadian Institutes of Health Research (Grant Number: 202110MFE-472921-HTB-272687). None of the aforementioned organizations were involved in the design, execution, interpretation, or communication of findings from the present study.

Acknowledgements

Not applicable.

Author Contributions

RJZ, ARG, and BMC contributed to study design and conception. RJZ, ARG, and BMP analyzed data and interpreted the results. ARG and BMC are responsible for the first draft of the manuscript. All authors contributed to editing the manuscript and reviewed the manuscript in its final form.

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No competing interests reported.

The Effect of Psychedelics on Individuals with a Personality Disorder: Results from two Prospective Cohort Studies

Status:

Version 1

Abstract

Figures

Introduction

Methods (Study 1)

Results (Study 1)

Methods (Study 2)

Results (Study 2)

Discussion

Conclusion

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Additional Declarations

Status:

Version 1