In a matched-sample study of 53 hallucinogen users and 53 controls, hallucinogen use was associated with higher openness to experience, better cognitive performance, greater lifetime illicit drug use and increased white matter structural connectivity in tracts linked to cognition, emotion and creativity. These macroscale brain differences and personality shifts provide clues to potential neural mechanisms underlying reported therapeutic effects of hallucinogens.
Recent research has demonstrated potential therapeutic effects of hallucinogens, but little is known regarding enduring effects of hallucinogens on human brain structure. Preclinical findings suggest micro-scale structural neuroplastic changes after hallucinogen administration. The current study sought to investigate the association between hallucinogen use, macroscale brain structure, personality, cognitive ability, and illicit drug use in a naturalistic sample. Data from 53 subjects reporting ever having used hallucinogens and 53 approximately hallucinogen-naïve matched controls were drawn from the Nathan Kline Institute-Rockland Sample database. Participants had completed diffusion tensor imaging, psychological, behavioral, and psychiatric assessments. Groups were compared on measures of personality, cognitive ability, history of illicit drug use, and the density of white matter tracts determined from probabilistic tractography. Hallucinogen users reported greater lifetime use of illicit drugs than controls and scored higher on measures of openness to new experiences and cognitive ability. Hallucinogen users also had greater density of structural connectivity in white matter tracts that are thought to support cognition, emotion, and creativity. These findings are consistent with reports that hallucinogen use may lead to shifts in personality as well as multiple cognitive domains. These novel findings provide clues to potential neural mechanisms underlying therapeutic effects of hallucinogens.
Papers cited by this study that are also in Blossom
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
Data were drawn from the Nathan Kline Institute-Rockland Sample, which is a publicly available dataset containing a wide array of physiological and psychological assessments, genetic information, and advanced neuroimaging outcomes in a lifespan sample (ages 6-85 years old). As part of a larger battery of measures, each participant completed measurements of drug use history, including the Comprehensive Addiction Severity Index for Adolescents (CASI-A) and the National Institute on Drug Abuse questionnaire (NIDA). Participants also completed psychiatric diagnostic questionnaires including Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and Structured Clinical Interview for DSM-IV-TR Axis I Disorders -Non-Patient Edition (SCID-I/NP). All experiments were performed in accordance with relevant guidelines and regulations. Among 831 participants with Diffusion Tensor Imaging (DTI) data, 81 answered positively to the CASI-A question "Have you ever used a hallucinogen?" or the NIDA questionnaire item assessing lifetime hallucinogen use (the item speci es "LSD, acid, mushrooms, PCP, ketamine, ecstasy etc."). These participants were approximately matched in age and sex to 81 control participants who had consistently indicated in both the NIDA and the CASI-A questionnaires that they had NOT used a hallucinogen in their lifetime. A subset of individuals were then identi ed within this sample who were approximately matched for psychiatric diagnoses (including no psychiatric diagnosis) at the time of assessment, for a total of 53 hallucinogen users and 53 controls who were balanced on age, sex, and psychiatric diagnosis (see Supplementary Tablefor a list of all NKI subject IDs included in the analysis). Analyses of Questionnaire and Psychiatric Assessment Data Measures of personality, cognitive ability, and drug use history were compared between groups, given the potential enduring effects of hallucinogens on these domains. The NEO Five Factor Inventory (NEO-FFI-3) was used to assess the personality traits of Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism 83 . Assessments of cognitive abilities included the Wechsler Abbreviated Scale of Intelligence (WASI-II) designed to assess speci c and overall cognitive capabilities 84 , the Wechsler Individual Achievement Test second edition abbreviated (WIAT-IIA), and the Cognitive Failures Questionnaire (CFQ) assessing failures in perception, memory, and motor function in the completion of everyday tasks in the past 6 months 86 . Drug abuse questionnaires included the CASI-A and NIDA, assessing lifetime use of cannabis, cocaine, amphetamine-type stimulants, inhalants, sedatives, hallucinogens, opioids, alcohol, tobacco, and other miscellaneous drugs. Unfortunately, too few respondents provided information regarding the frequency of use of most drugs of abuse, and thus a characterization of samples outside of lifetime use of these substances was not possible. Normality of the distributions of continuous data was assessed using Shapiro-Wilk test for normality. Two sample T-Tests were used for normally distributed data, and the nonparametric Mann Whitney U test was used for non-normally distributed data, to test for between-group differences in continuous outcome measures. Chi-square tests were used to assess group differences in categorical variables. Statistical analyses of questionnaire and psychiatric assessment data were performed using IBM SPSS statistics 22.0 software. DTI Acquisition, Preprocessing, and Analysis DTI data were acquired in 137 directions, with 2mm isotropic voxel size, a b-value of 1500 s/mm², A > > P encoding direction, and multi-band acceleration factor of 4 using a Siemens Tim Trio 3T MRI. Image preprocessing and analysis was conducted using functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL). Steps included skull stripping using the brain extraction tool (BET) 89 , followed by eddy current and motion correctionand DTIFIT for local tting of diffusion tensors, resulting in a fractional anisotropy (FA) image for each subject. Voxelwise FA statistics were then generated using Tract-Based Spatial Statistics (TBSS). TBSS performs nonlinear registration of FA images to a standard space by projecting all subjects' FA data onto a mean FA skeleton. A voxel-wise, two sample T-Test was then calculated to test whether FA differed between hallucinogen users and controls. For statistical inference, including correction for multiple comparisons across space, maximal statistic permutation testing with threshold-free cluster enhancement (TFCE) was conductedusing RANDOMISE. The number of permutations to be performed was set at 5,000 for signi cant group differences at a level of p < 0.05 (FWE).
Preliminary steps to tractography were performed by rst using Bayesian Estimation of Diffusion Parameters Obtained using Sampling Techniques (BEDPOSTX). BEDPOSTX uses Markov Chain Monte Carlo sampling to build null distributions on diffusion parameters and models crossing bers within each voxel of the brain. Linear registration using FMRIB's Linear Image Registration (FLIRT) was applied. Diffusion space was registered to native structural space using high-resolution T1-weighted image of the same subject and then registered to standard space (MNI152 brain standard). Tractography was then performed on each subject using a cross-species tractography toolbox (XTRACT) with graphics processing unit (GPU) acceleration. XTRACT performs probabilistic tractography using a library of validated tractography protocols for 42 white matter tracts (19 bilateral and 4 commissural in each hemisphere, see supplementary Table) 100 . Out of the 42 tracts, 2 tracts (Left and Right corticospinal tract) were removed due to insu cient number of subjects with full brain data coverage for these areas. Tract volume (mm 3 ) and the mean, median, and standard deviation of tract probability, length, fractional anisotropy, and mean diffusivity was extracted for each subject and for each of the 40 tracts that were analyzed 100 . A Shapiro-Wilk test for normal distribution demonstrated a non-normal distribution for tractbased statistics. Therefore, a nonparametric Mann-Whitney U test was used to assess group differences in summary statistics for each tract.
Separate voxel-wise general linear models (GLM) were estimated in FSL to compare white matter density between groups for each of 40 white matter tracts. GLM analyses for each tract were masked using the corresponding region of interest from XTRACT tract atlases generated from the human connectome project (HCP) data 100 . To control for potential effects of age, sex, and history of drug use on tractography-related outcome measures, statistical tests for Two-Group Difference Adjusted for Covariates were performed. All models were adjusted for age, sex, and previous drug use history of the subjects, and continuous variables were mean-centered. We then tted a multiple covariates model to adjust for lifetime use of cocaine, stimulants, narcotics, and inhalants (as these were the drugs that showed signi cant differences between groups in lifetime prevalence of use). For statistical inference, including correction for multiple comparisons across space, maximal statistic permutation testing with TFCE was conducted using RANDOMISE. The number of permutations to be performed was set at 5,000 for signi cant group differences at a level of p < 0.05 (FWE). Association of white matter density with questionnaire assessments Separate GLMs were estimated for each white matter tract that showed a signi cant difference in density between groups, to evaluate the association between differences in white matter density and differences in questionnaire assessment data between groups. Questionnaire scores that were signi cantly different between groups were included in the analysis. The regression also controlled for age, sex, and history of drug use. Continuous variables were mean-centered. For statistical inference, including correction for multiple comparisons across space, maximal statistic permutation testing with TFCE was conducted using RANDOMISE. The number of permutations to be performed was set at 5,000 for signi cant group differences at a level of p < 0.05 (FWE).
The demographic characteristics of both groups are detailed in Table. The majority of hallucinogen users and controls were females (60% and 58.5% respectively). Subjects represented a broad range of ages, from 17 to 77 years old. A small number of affective and other disorders were found in both control and hallucinogen users group s, but there were no signi cant differences between groups in the incidence of any diagnostic category (Table).
Age of rst use of hallucinogens averaged 20.44 years (SD = 3.8 years, Fig.). 71.15% of hallucinogen users reported never using hallucinogens on a "regular basis" (de ned as at least once per month; Fig.). 68.18% of hallucinogen users reported 0-1 years of regular use (Fig.). No subjects used a hallucinogen in the month prior to their participation. 82% did not use hallucinogens in the year prior to their participation (Fig.). In their peak pattern of use in the year prior to their participant, 15.91% (7 participants) of the 44 participant who answered this question used hallucinogens one to ten times and 2.27% (1 participant) used hallucinogens once per week, whereas the remainder indicated no hallucinogen use in the year prior to participation (Fig.).
CASI-A and NIDA questionnaire responses showed a signi cant difference between hallucinogen users and controls in the lifetime use of stimulants (p = 0.023), cocaine (p = 0.000), narcotics (p = 0.004), and inhalants (p = 0.012) in addition to hallucinogens (p = 0.000). There were no signi cant differences in use of tobacco (p = 0.278), marijuana (p = 0.153), alcohol (p = 0.079), and tranquilizers (p = 0.22) use (see Table).
Higher scores on the personality trait of openness to experience were observed in the hallucinogen users (M = 60, SD = 9) compared to controls (M = 56, SD = 9; t = 2.321, p = 0.014). No signi cant differences were observed in any other Big Five personality traits (see Supplementary Table).
For scores on the WASI-II questionnaire, hallucinogen users (M = 61) had signi cantly higher total score (comprised from vocabulary, block design, similarities and matrix reasoning) than controls (M = 46; Mann-Whitney U = 1033, p = 0.012). A signi cant difference was found in verbal comprehension index scores in hallucinogens users (M = 61.1) compared to controls (M = 45.9; Mann-Whitney U = 1014.5, p = 0.008) as well as higher vocabulary (Mann-Whitney U = 981.5, p = 0.008) and similarities (Mann-Whitney U = 1079, p = 0.031) subset scores. Hallucinogen users also had signi cantly greater perceptual reasoning index scores (M = 60.25) compared to controls (M = 45.6; Mann-Whitney U = 1062.5, p = 0.024) as well as higher block design subset scores (M = 61.3) compared to controls (M = 45.7; Mann-Whitney U = 1014, p = 0.009). Hallucinogen users scored higher than controls on the following WIAT-IIA subscales: spelling (Mann-Whitney U = 1017, p = 0.021), numerical operations (Mann-Whitney U = 910, p = 0.009), and the composite standard score (Mann-Whitney U = 8897, p = 0.006). No signi cant group differences were observed in any of the Cognitive Failures Questionnaire (CFQ) scales, which assessed failures in perception, memory, and motor function in the completion of everyday tasks in the past 6 months found. Descriptive statistics for all cognitive assessment scores are presented in Supplementary Table.
Fractional Anisotropy-Based Measures Signi cantly greater volume (mm 3 ) was observed in the hallucinogen users group (M = 57.98) than in controls (M = 46.135) (p = 0.044, Mann-Whitney-U = 1021) and larger mean tract probability was observed in the control group (M = 57.87) than in hallucinogen users group (M = 46.02; p = 0.044, Mann-Whitney-U = 1021) within the right inferior longitudinal fasciculus (ILF). Larger mean tract probability in the hallucinogen users group (M = 60.37) than in control group (M = 46.63; p = 0.021, Mann-Whitney-U = 1040.5) was also detected within the right superior thalamic radiation (STR). See supplementary tablefor statistics for all tracts.
While our subjects are grouped by their history of hallucinogen use, there are also signi cant betweengroup differences in lifetime use of cocaine, stimulants, narcotics, and inhalants. Therefore, each of the 40 probabilistic white matter tract analyses was adjusted for the presence or absence of lifetime use of each of these four drugs, in addition to sex and age. After performing multi-covariate regression to correct for multiple drug use, we found greater density of white-matter tracts in the hallucinogen users group than in controls (Fig.) in the left superior thalamic radiation (STR; p = 0.031), left arcuate fasciculus (AF; p = 0.026), left perigenual cingulum (CBP; p = 0.009), left (p < 0.001) and right (p = 0.035) frontal aslant (FA), right superior longitudinal fasciculus (SLF; p = 0.004), and left inferior longitudinal fasciculus (ILF; p = 0.017). Signi cantly less white matter tract density was observed in the hallucinogen users group compared to controls in the right inferior longitudinal fasciculus (ILF; p < 0.001) (Fig.). A secondary analysis was performed after excluding two subjects who reported an atypical pattern of classic hallucinogen use ("once a month", "binge use", or peak use of "once a week") and their most closely matched controls (N = 4 removed). Six out of the 8 signi cant tracts remained signi cant: ve tracts with greater density of structural connectivity in the hallucinogen users group, consisting of left STR (p = 0.018), left ILF (p < 0.001), left FA (p = 0.022), left AF (p = 0.008), right SLF (p < 0.001), and one tract with less density of structural connectivity in the hallucinogen users group, consisting of the right ILF (p = 0.003). Two tracts did not remain signi cant: left CBP and right FA. For the full list of the tracts and associated statistics, see Supplementary Table.
WIAT-IIA word reading score was predictive of signi cantly greater density of structural connectivity in the left CBP (p = 0.019). WIAT-IIA domains of numerical score (p = 0.024), composite standard score (p = 0.0009), composite sum of subset standard scores including scores of word reading, numerical, and spelling subset scores (p < 0.001), and WASI-II vocabulary score (p = 0.049) were predictive of signi cant greater density structural connectivity in the left ILF. WASI-II domains of vocabulary (p = 0.047), verbal composite (p = 0.037) and full scale score (p = 0.038) were predictive of signi cant greater density structural connectivity in the right SLF.
The objective of this study was to determine if there was any association between lifetime hallucinogen use and personality, cognitive ability and brain structure in a natural sample of the population. Consistent with previous literature on the associations between hallucinogen use, personality, and cognition, signi cant differences were observed in trait openness and cognitive abilities between subjects who reported ever having used a hallucinogen and a control group that reported never having used hallucinogens. Hallucinogen users also reported greater lifetime use of illicit drugs. Finally, greater density of white matter tracts was observed in a number of white matter tracts implicated in the support of cognition, emotion, and creativity.
Openness to experience is one of the major dimensions of the ve-factor model of personality. Individuals who score highly in openness are considered to be imaginative, sensitive to art and beauty, creative, and have a rich and complex emotional life 101 . They are intellectually curious 102 , behaviorally exible, and nondogmatic in their attitudes and values. Individuals who score low in openness may be more likely to appreciate and rely on experiences and situations they have encountered before, since they are seen as safe. Hallucinogen users in the current sample scored higher in personality trait of openness than controls. This is consistent with previous controlled laboratory experiments that demonstrated an increase in openness after classic hallucinogen administration. A moderate dose of LSD (75 µg intravenously) was shown to increase optimism and trait openness two weeks after administration. In another study, openness increased in participants who had mystical experiences during their high-dose (30mg/70kg) psilocybin session, and remained signi cantly higher than baseline for more than one year after the session. A recent PET study found limited association between 5-HT 2A receptor availability and trait openness, warranting further study to evaluate 5-HT 2A receptor-mediated mechanisms of change in personality traits after intake of psilocybin 106 . Together, these ndings suggest that psychedelic experience may increase openness. However, increased openness has also been shown to predict response to classic hallucinogens 107 . It is possible that those with higher openness scores to begin with are simply more likely to take hallucinogens than those with lower openness scores. Either way, our current ndings are consisted with previously identi ed associations between greater openness and exposure to hallucinogens.
While administration of psychoactive doses of classic hallucinogens can acutely impair cognition 26-30, 108,109 , some evidence indicates either no effect or a modest cognitive bene t of classic hallucinogens at post-acute time points. Studies of ritual users of ayahuasca reported modest bene ts in cognitive control in ayahuasca users. A recent report also demonstrated an increase in cognitive control following psilocybin administration to patients with MDD. Anecdotal reports on microdosing with psychedelic substances (psilocybin and LSD) suggest acute and post-acute cognitive enhancement (problem-solving and understanding), improved memory and clarity of thought 76 , improved mood, cognition, and creativity 110 , enhanced cognitive performance, and improved focus and productivity 111 . However, empirical evidence for such microdosing bene ts is weakto non-existent 112 . Hallucinogen users scored higher on measures of cognitive ability (e.g. WASI-II, WAIT-IIA) than controls. Speci cally, on measures of word knowledge, verbal concept formation, crystallized intelligence, language development, abstract reasoning, associative and categorical thinking, and verbal expression. Hallucinogen users also scored higher on measures of analysis and synthesis of visual stimuli, nonverbal concept formation, uid intelligence, visual perception and organization, and visual-motor coordination. Of course, in the current sample, causality of psychedelic use cannot be conclusively inferred. It may be that those who score higher on these tests are more likely to try hallucinogen drugs than those who score lower on these tests. However, these ndings replicate previous ndings of higher scores on cognitive tests in hallucinogen using groups compared to non-hallucinogen-using controls, and are consistent with a potential long-term cognitive bene t of psychedelic use, speci cally in the domains of intelligence and cognitive exibility.
The hallucinogen-using group in the current study reported greater lifetime use of illicit drugs than the control group. This is consistent with previous studies that have shown a progressive relationship between various forms of polydrug use. Though evidence is certainly mixed 113 , the gateway theory suggest people who reported having used less common drugs were likely to have reported that they had also used more common drugs. Administered in a clinical setting, however, psychedelic drugs may help to reduce or eliminate problematic substance use. Naturalistic, recreational psychedelic use in some cases may also lead to reduction or elimination of illicit substance usein addition to other psychological bene ts, though the rate of this occurrence is not clear. Recent anonymous survey studies found 343 individuals who reported reducing or stopping alcohol use 81 , 358 individuals who reported reducing or quitting smoking 82 , and 444 individuals who reported reductions in cannabis, opioid, and stimulant misuse 80 , after taking a psychedelic drug in a non-clinical setting. Most of the respondents in these surveys reported lasting reductions in their substance use over 1 year after using a hallucinogen, ndings consistent with persisting bene ts observed in controlled studies with psilocybin and smoking cessationand alcohol dependence. In the current study, lifetime use of cannabis, tobacco, alcohol, and tranquilizers was not signi cantly different between groups, but cocaine, stimulant (other than cocaine), narcotic, and inhalant use was signi cantly higher in the hallucinogen users group. However, it is unclear whether this illicit drug use preceded, followed after, or was concurrent with hallucinogen use. Although comprehensive information regarding the extent of illicit drug use is not available in the current sample, 7.4% of subjects in the hallucinogen user group and 5.6% of subjects in the control group reported a current diagnosis of substance use disorder related to alcohol or cannabis at the time of the assessments. Since groups were cross-sectional and roughly matched for psychiatric diagnoses, this precludes any nding regarding the effects of hallucinogen use on substance use disorder diagnosis, prevalence, duration, or severity (or the prevalence or severity of other psychiatric disorders, such as mood disorders).
Classic hallucinogens (5-HT 2A receptor agonists) such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT) and dissociative hallucinogens (NMDA receptor antagonists) such as dextromethorphan (DXM) and ketamine may share neuropsychological 26 as well as neuropsychoplastogenic 123 effects despite their different pharmacology. Previous studies described short term effect of various hallucinogens on brain network activity and connectivity, however, to our knowledge, no previous study has investigated long-term changes in white matter structure after hallucinogen use. The current study reports greater density of structural connectivity among hallucinogen users when analyzing seeds and tracts for the left superior thalamic radiation, left perigenual cingulum, left arcuate fasciculus, left and right frontal aslant, right superior longitudinal fasciculus and the left inferior longitudinal fasciculus. Lower density of structural connectivity was observed in the hallucinogen users group in the right inferior longitudinal fasciculus. The inferior longitudinal fasciculus (ILF) is a long-range white matter pathway that supports the ventral visual stream (the "what" pathway, as opposed to the "where" pathway), connecting the occipital and temporal-occipital areas of the brain to anterior temporal areasin support of object recognition processes. Thus, this pathway plays a major role in a large array of perceptual and cognitive functions. The ILF demonstrates a strong leftward-lateralized connectivity pattern that suggests an additional role in the semantic system 127 . The left ILF was also shown to have a critical role in readingrelated visual information processing, with fractional anisotropy of the ILF correlating with reading comprehensionand lexical/semantic task performance. Thus, the current ndings of greater structural connectivity in the left ILF are consistent with higher perceptual reasoning scores in the current hallucinogen users group, and better performance on verbal memory tests in previous studies of hallucinogen users 135 . This is further supported by positive associations between WIAT-IIA and WASI-II scores and density of structural connectivity of the left ILF. Previous DTI studies demonstrated a double dissociation between the functions of the right ILF and those of the fornix with respect to visual processing; white matter integrity in the ILF (though not in the fornix) was strongly associated with face processing performance, while white matter integrity in the fornix (though not in the ILF) were found to be associated with scene processing performance. Studies comparing healthy individuals and patients with brain damage suggest that a functional right ILF is crucial for e cient face recognition. The ILF serves as a structural pathway between the amygdala and visual cortex, and is also involved in the integration of visual and emotional processes 125 . Lower mean tract probability and density of structural connectivity in the right ILF in hallucinogen users compared to controls in the current sample is therefore quite intriguing in the context of other recent ndings. Acute 9,10 and persistingreductions in amygdala response to negative facial emotional expressions have been demonstrated, and may be associated with an enduring reduction in negative affect and antidepressant, anti-anxiety, and pro-positive-affective responses to psychedelic drug administration. It may be that observed, persisting reductions in amygdala reactivity and negative affect are a function of reduced white matter density or integrity in the right ILF. The Superior Thalamic Radiation (STR) connects the ventral nuclear group of the thalamus with the precentral and the somatosensory area of the postcentral gyrus through the superior thalamic peduncle and the posterior limb of the internal capsule. This is a pathway that involves a number of brain regions that are engaged during psychedelic drug effects. Speci cally, the cortico-striato-thalamocortical (CSTC) gating hypothesis of psychedelic drug action 140 proposes that psychedelic drug effects may result from disruption of thalamo-cortical and striatal-thalamic pathways involved in sensory processing. Greater global connectivity of thalamic and sensory-somatomotor regions has been observed during acute effects of both LSDand psilocybin 141 , and LSD has been shown to alter effective thalamo-cortical thalamo-striatal connectivity, consistent with psychedelic disruption of sensory and sensorimotor processes. The current nding of greater mean tract probability and density of structural connectivity in the left STR is consistent with a crucial role of the thalamus in hallucinogen effects, and consistent with hallucinogen exposure leading to long-term alteration of circuits that are altered acutely, though the functional signi cance of altered thalamic structural connectivity in this context is not precisely clear. The cingulum bundle is a distinctive ber tract in the brain, forming a near-complete ring from the orbital frontal cortices, along the dorsal surface of the corpus callosum, then down through the temporal lobe towards the temporal pole. Clinical studies reveal cingulum abnormalities in various conditions, including schizophrenia, depression, posttraumatic stress disorder, obsessive compulsive disorder, autism spectrum disorder, mild cognitive impairment, and Alzheimer's disease. Imaging studies have implicated disruptions in the anterior cingulum in the pathophysiology of mood disordersand have found associations between lower structural integrity of white matter tracts of the left anterior cingulum and presence of unipolar depression or bipolar disorder. As such, the anterior cingulum became a target for numerous treatments for depression including deep brain stimulation 144 , ECT 143 , and even anterior cingulotomy for refractory depression, refractory obsessive compulsive disorderand chronic pain. Imaging studies also found association between structural integrity of white matter tracts of the left anterior cingulum and wide range of cognitive functions, including attention, executive functions, memory performance, uency, verbal and symbolic tasks performance. When examining density of structural connectivity in the perigenual cingulum, the current analysis yielded greater density of structural connectivity in the hallucinogen users group. This suggests that a possible neurobiological mechanism underlying the therapeutic effects of hallucinogens in the treatment of depressionand reduced risk of suicidalitymay be partly related to hallucinogen-evoked changes in the anterior cingulum. This nding is also consistent with previous ndings of higher scores on cognitive function tasks in hallucinogen using groups. The frontal aslant (FA) is a white matter pathway that connects the inferior frontal gyrus with the supplementary motor area (SMA) and the pre-SMA. The FA plays an important role in motor control during speech production. Imaging studies have shown that the left FA may play a role in speech initiation, verbal uency, and stuttering. Integrity of the right FA may be associated with certain executive functions, and speci cally inhibitory control. The current study found greater density structural connectivity in the hallucinogen using group in both left and right FA. These ndings are generally consistent with overall higher performance on tests of cognitive abilities in hallucinogen using groups in the current study as well as previous studies, though the precise functional signi cance of altered bilateral FA structural connectivity in this context is not precisely clear. The arcuate fasciculus (AF) is a white matter pathway that connects temporal, frontal and parietal cortices. This tract plays a critical role in several cognitive functions related to phonological and language processing. Imaging studies have found associations between lesions in the left arcuate fasciculus and impairment in speech production 161 , aphasia 162 and depressive symptoms in patients with multiple sclerosis. Greater AF white matter density observed in the hallucinogen users in the current study is consistent with higher verbal comprehension scores in hallucinogens users in the current dataset and higher performance in lexically-focused tasks in previous studies 78,. The right superior longitudinal fasciculus (SLF) is a long white matter pathway that extends from the anterior region of the cortex (e.g. prefrontal cortex) to the posterior region (e.g. parietal cortex). Greater integrity of the right SLF is associated with better performance in non-verbal auditory 165 , attention, and visual-spatial tasks. White matter integrity in the SLF was also found to correlate positively with openness. Findings of greater white matter density in the right SLF in the hallucinogen users group are consistent with higher perceptual reasoning scores demonstrated in the hallucinogen users group compared to the control group. Overall, the current ndings provide evidence for a potential white matter structural consequence of exposure to hallucinogens. White matter density is generally greater in hallucinogen users, compared to controls, in canonical tracts that are associated with perception, cognition, and affect. If we can generally assume that greater white matter density within a tract confers a processing bene t, and that lower white matter density could represent a processing de cit, the current ndings are consistent with previous ndings suggesting improved cognitive function and reduced negative affect among hallucinogen users. Though it is not possible from the present data to conclusively ascribe causal functional signi cance to between-group differences in white matter structure, it is notable that differences in white matter density in the current sample are localized to regions that are associated with functional alterations reported during the acute effects of hallucinogens. Given proposed psychoplastogenic effects of hallucinogens, it may be that circuits or pathways that are acutely altered during hallucinogen drug action are open to undergoing some lasting structural change that can be observed with diffusion imaging methods.
Subjects were drawn from NKI-RS database of natural general population sample. Subjects were selected according to their report of ever (or never) having used hallucinogens. Since the study population re ected a natural sample, some of the subjects had psychiatric diagnoses and previous drug use. We attempted to mitigate these effects by balancing the groups in criteria of age, sex, and psychiatric diagnoses, and this led to groups that were also balanced for previous use of alcohol, tobacco, and cannabis, as well as scores on measures of depression, anxiety and trauma. Given the cross-sectional nature of this dataset, we cannot conclusively determine whether hallucinogen users scored higher due to their use of hallucinogens, or whether individuals with higher cognitive scores and openness to new experiences are more likely to use hallucinogens. Given that we explicitly matched groups on psychiatric diagnosis, and the majority of individuals in both groups did not have a diagnosis, we are unable to make any statements regarding the effects of lifetime use of a hallucinogen on psychopathology (though others have done so). However, our ndings are consistent with previous studies suggesting that hallucinogens may confer cognitive bene tand increase openness. While we were interested in directly assessing the association between personality and cognitive ability scores and white matter integrity, some of these relationships were di cult to interpret. The observed relationship between word reading scores and differences in CBP white matter density and WASI-II scores and right SLF white matter density escape immediate interpretation. Replication of these ndings in a longitudinal study and more direct assessment of cognitive abilities with carefully-controlled behavioral tasks in a prospectively sampled and controlled study population may address some of these limitations.
The current report compared a group of individuals who have used hallucinogens in their lifetime to a control sample who report never having used hallucinogens. Individuals who used hallucinogens performed better on a wide array of cognitive ability assessments that are broadly associated with intelligence, consistent with previous ndings in the literature suggesting cognitive bene t conferred to regular users of peyote 171 and ayahuasca. Hallucinogen users also scored higher on the personality trait of openness to new experiences, which is believed to re ect higher creativity, intellectual curiosity, and cognitive exibility. This is consistent with previous ndings of increased openness after controlled hallucinogen administration. Differences were observed in the density of white matter tracts that may support ndings of higher cognitive performance and increased openness, providing a potential neural mechanism underlying persisting psychological bene ts that have been described in both healthy and clinical populations.
Funding and Disclosures: Dr. Aharon-Almagor was supported by the Beer-Yaakov/Hopkins postdoctoral fellowship in psychiatry. Dr. Barrett
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