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, significant 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 five-factor model of personality101. Individuals who score highly in openness are considered to be imaginative, sensitive to art and beauty, creative, and have a rich and complex emotional life101. They are intellectually curious102, behaviorally flexible, and nondogmatic in their attitudes and values103,101. 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 administration104. In another study, openness increased in participants who had mystical experiences during their high-dose (30mg/70kg) psilocybin session, and remained significantly higher than baseline for more than one year after the session105. A recent PET study found limited association between 5-HT2A receptor availability and trait openness, warranting further study to evaluate 5-HT2A receptor-mediated mechanisms of change in personality traits after intake of psilocybin106. Together, these findings suggest that psychedelic experience may increase openness. However, increased openness has also been shown to predict response to classic hallucinogens107. 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 findings are consisted with previously identified 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 benefit of classic hallucinogens at post-acute time points. Studies of ritual users of ayahuasca reported modest benefits in cognitive control in ayahuasca users78,79. A recent report also demonstrated an increase in cognitive control following psilocybin administration to patients with MDD32. 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 thought76, improved mood, cognition, and creativity110, enhanced cognitive performance, and improved focus and productivity111. However, empirical evidence for such microdosing benefits is weak31 to non-existent112.
Hallucinogen users scored higher on measures of cognitive ability (e.g. WASI-II, WAIT-IIA) than controls. Specifically, 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, fluid 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 findings replicate previous findings 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 benefit of psychedelic use, specifically in the domains of intelligence and cognitive flexibility.
Previous use of illicit substances
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 mixed113, the gateway theory suggest people who reported having used less common drugs were likely to have reported that they had also used more common drugs114–116. Administered in a clinical setting, however, psychedelic drugs may help to reduce or eliminate problematic substance use6,77. Naturalistic, recreational psychedelic use in some cases may also lead to reduction or elimination of illicit substance use80,82,117 in addition to other psychological benefits23,117−122, though the rate of this occurrence is not clear. Recent anonymous survey studies found 343 individuals who reported reducing or stopping alcohol use81, 358 individuals who reported reducing or quitting smoking82, and 444 individuals who reported reductions in cannabis, opioid, and stimulant misuse80, 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, findings consistent with persisting benefits observed in controlled studies with psilocybin and smoking cessation15 and alcohol dependence16.
In the current study, lifetime use of cannabis, tobacco, alcohol, and tranquilizers was not significantly different between groups, but cocaine, stimulant (other than cocaine), narcotic, and inhalant use was significantly 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 finding 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).
White Matter Structure
Classic hallucinogens (5-HT2A 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 neuropsychological26 as well as neuropsychoplastogenic123 effects despite their different pharmacology. Previous studies described short term effect of various hallucinogens on brain network activity and connectivity41,43,50,71,72,124, 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 areas125,126 in support of object recognition processes. Thus, this pathway plays a major role in a large array of perceptual and cognitive functions125. The ILF demonstrates a strong leftward-lateralized connectivity pattern that suggests an additional role in the semantic system127. The left ILF was also shown to have a critical role in reading-related visual information processing125, with fractional anisotropy of the ILF correlating with reading comprehension128–131 and lexical/semantic task performance131–134. Thus, the current findings 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 users135. 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 performance125,136. Studies comparing healthy individuals and patients with brain damage suggest that a functional right ILF is crucial for efficient face recognition125,136,137. The ILF serves as a structural pathway between the amygdala and visual cortex, and is also involved in the integration of visual and emotional processes125.
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 findings. Acute9,10 and persisting52,68 reductions 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 capsule138,139. This is a pathway that involves a number of brain regions that are engaged during psychedelic drug effects. Specifically, the cortico-striato–thalamo-cortical (CSTC) gating hypothesis of psychedelic drug action140 proposes that psychedelic drug effects may result from disruption of thalamo-cortical and striatal-thalamic pathways involved in sensory processing56. Greater global connectivity of thalamic and sensory-somatomotor regions has been observed during acute effects of both LSD35 and psilocybin141, and LSD has been shown to alter effective thalamo-cortical thalamo-striatal connectivity46, consistent with psychedelic disruption of sensory and sensorimotor processes. The current finding 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 significance of altered thalamic structural connectivity in this context is not precisely clear.
The cingulum bundle is a distinctive fiber 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 pole142. 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 disease142. Imaging studies have implicated disruptions in the anterior cingulum in the pathophysiology of mood disorders143,144 and have found associations between lower structural integrity of white matter tracts of the left anterior cingulum and presence of unipolar depression or bipolar disorder143–145. As such, the anterior cingulum became a target for numerous treatments for depression including deep brain stimulation144, ECT143, and even anterior cingulotomy for refractory depression146,147, refractory obsessive compulsive disorder148,149 and chronic pain150,151. 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, fluency, verbal and symbolic tasks performance142,152. 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 depression3–5 and reduced risk of suicidality23,24,118,153 may be partly related to hallucinogen-evoked changes in the anterior cingulum. This finding is also consistent with previous findings 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 154,155. The FA plays an important role in motor control during speech production155. Imaging studies have shown that the left FA may play a role in speech initiation, verbal fluency, and stuttering155,156. Integrity of the right FA may be associated with certain executive functions, and specifically inhibitory control156,157. The current study found greater density structural connectivity in the hallucinogen using group in both left and right FA. These findings 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 significance 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 cortices158,159. This tract plays a critical role in several cognitive functions related to phonological and language processing 159,160. Imaging studies have found associations between lesions in the left arcuate fasciculus and impairment in speech production161, aphasia162 and depressive symptoms in patients with multiple sclerosis163. 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 studies78,79.
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) 164. Greater integrity of the right SLF is associated with better performance in non-verbal auditory165, attention164,165, and visual-spatial tasks164,166. White matter integrity in the SLF was also found to correlate positively with openness167,168. 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 findings 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 benefit, and that lower white matter density could represent a processing deficit, the current findings are consistent with previous findings 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 significance 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 hallucinogens67,169, 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 reflected 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 so118,170). However, our findings are consistent with previous studies suggesting that hallucinogens may confer cognitive benefit32,78,79,135,171 and increase openness21, 38–40,105,172,173. While we were interested in directly assessing the association between personality and cognitive ability scores and white matter integrity, some of these relationships were difficult 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 findings 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.