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P.3.039 Effects of LSD and music on brain activity
Clinical and translational
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A common functional polymorphism (Val66Met) in the brain-derived neurotrophic factor gene (BDNF) may play substantial role in these associations [1], but the findings are still not conclusive, potentially because the measurement of stress varies greatly across studies (e.g., childhood adversity vs. recent stressful events) [2] and the causality of any of the factors is unclear. Longitudinal study design would greatly contribute to the understanding of the role of the BDNF gene in development of psychiatric vulnerability. Therefore, the aim of this study was to longitudinally assess the association between BDNF Val66Met, depression-related personality traits and the occurrence of stressful events in a population representative sample. Method: The sample was based on both birth cohorts of the longitudinal Estonian Children Personality, Behaviour and Health Study (altogether n = 1238, valid genotype missing for 4) [3]. In the younger cohort, personality according to the five-factor model was measured at ages 9 (parental assessment), 15 and 18 (self-assessments), and in the older cohort at ages 15 (parental and self-assessments), 18 and 25 (all self-assessments). Stressful life events in childhood were reported at age 15 and recent personal SLE-s at age 25. BDNF Val66Met genotype distribution was 908 Val/Val, 306 Val/Met and 20 Met/Met subjects. Owing to a small number of Met/Met homozygotes, participants were classified into Val-allele homozygotes and Met-allele carriers. ANOVA and ANCOVA were used for statistical analysis. Table 1. Stressful life events (SLE-s) at age 25, expressed in mean z-scores (SEM). BDNF genotype
Female Val/Val Met-allele Male Val/Val Met-allele
Total sample
Younger cohort
Older cohort
−0.02(0.05) −0.11(0.08)
−0.10(0.08) 0.05(0.12)
0.05(0.07) −0.23(0.11)§
−0.04(0.06) 0.30(0.09)**
−0.08(0.09) 0.42(0.13)*
−0.01(0.08) 0.18(0.14)#
**p < 0.005 vs. all other groups; *p < 0.005 vs. Val/Val homozygotes; # p < 0.05 vs. Met-allele females; §p < 0.05 vs. Val/Val females.
Results: Analysis of both birth cohorts combined agewise at 15 and 18 years did not reveal genotype main effect on personality traits, except the lower conscientiousness in Met-allele carriers at age 15 [F(1,693) = 8.02, p < 0.005]. Significantly higher stress exposure by age 25 was observed in male Met-allele carriers across the sample [F(1,967) = 8.5, p < 0.005] and in Met-allele carriers in the younger cohort [F(1,967) = 7.5, p < 0.01] (Table 1). Interestingly, in the older cohort, female Met-allele carriers had experienced less SLE-s. No association with childhood stressful life events was detected in either cohort.
Adding personality traits as covariates revealed significant contributions of high neuroticism [age 18; F(3,755) = 5.44, p = 0.001] and low conscientiousness [age 15; F(3,579) = 3.03, p < 0.05] to stress exposure. Interestingly, these associations were also measurable with parental personality assessments from the first study wave, at ages 9 and 15 [neuroticism F(3,809) = 3.38, p < 0.05; conscientiousness F(3,809) = 3.90, p < 0.01]. Conclusion: These results suggest that the BDNF Val66Met genotype appears to influence the development of depression-related personality traits via multiple pathways, leading to changes in coping strategies, and hence differential exposure to stressful life events in adulthood. These associations seem to depend on gender and birth cohort, whereas the latter is probably serving as a proxy measure of environmental changes. Reference(s) [1] Aguilera, M., Arias, B., Wichers, M., BarrantesVidal, N., Moya, J., Villa, H., Van Os, J., Ib´an˜ ez, M.I., Ruip´erez, M.A., Ortet, G., 2009. Early adversity and 5-HTT/BDNF genes: new evidence of gene– environment interactions on depressive symptoms in a general population. Psychol Med 39, 1425–1432. [2] Hosang, G.M., Shiles, C., Tansey, K.E., McGuffin, P., Uher, R., 2014. Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med 12, 7. [3] Tomson, K., Meren¨akk, L., Loit, H.M., M¨aestu, J., Harro, J., 2011. The relationship between serotonin transporter gene promoter polymorphism and serum lipid levels at young age in a longitudinal populationrepresentative study. Prog Neuropsychopharmacol Biol Psychiatry 35, 1857–1862. P.3.039 Effects of LSD and music on brain activity M. Kaelen1 ° , L. Roseman1,2 , A. Lebedev3,4 , J. Kahan5 , A. Santos-Ribeiro1 , C. Orban1 , R. Lorenz2 , D. Nutt1 , R. Carhart-Harris1 . 1 Imperial College London, Centre for Neuropsychopharmacology, London, United Kingdom; 2 Imperial College London, The Computational, Cognitive and Clinical Neuroimaging Laboratory, London, United Kingdom; 3 Karolinska Institutet & Stockholm University, Aging Research Center, Stockholm, Sweden; 4 Stavanger University Hospital, Centre for Age-Related Medicine, Stavanger, Norway; 5 University College London, Institute of Neurology, London, United Kingdom Lysergic acid diethylamide (LSD) is a classic psychedelic drug that produces a profound altered state of con-
Clinical and translational sciousness, likely via serotonin 2A receptor activation. Results from recent pilot studies support the safety and efficacy of psychedelic compounds in the treatment of mood and addiction disorders [1,2]. Within this approach, attentive listening to a carefully designed music playlist is considered to be an important component [3,4] and predictor of long-term outcomes, including changes in personality trait “openness” [5]. The main purpose of the present study was to investigate the interactive effects of LSD and music on subjective experience and brain activity, using functional magnetic resonance imaging (fMRI) and measures of resting state functional connectivity (FC), effective connectivity (EC) and sample entropy (SE). Twenty healthy psychedelic-experienced participants (four female, mean age: 31.4±7.8) were scanned on two separate occasions, separated by at least 14 days. Participants received placebo (intravenous saline) on one occasion, and 75 micrograms of intravenous LSD on the other. Scanning was performed under eyes-closed resting state conditions and at peak drug effects. Two seven minute scans were performed under eyes-closed resting state conditions, with a seven minute eyes-closed passive music listening scan in between. Two different music tracks (balanced for emotional intensity and valence) were played in the two conditions in a counter-balanced fashion (i.e. half of the subjects listened to track A under LSD). A seed-based FC analysis was performed on the bilateral parahippocampus (PHC), an important hub-area in the brain that has previously been linked with: (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. This analysis informed the regions of interest for the subsequent stochastic dynamic causal modelling (sDCM) analysis, to assess music and drug induced changes in EC. sDCM utilized a network discovery method to identify changes in information flow between the PHC and visual cortex (VC) by drug, music, and an interaction between the two. Finally, a measure of SE was applied, that characterizes the complexity or predictability of an fMRI time-series. Using mixed-effects models, whole brain drug-and music-induced changes in SE were assessed, as well as their relation to acute druginduced changes in music-evoked emotion and long-term changes in personality traits. Results revealed increased PHC-VC FC and EC in the music × LSD condition. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. Finally, LSD had a strong and global effect on the SE, both in sensory and in hierarchically higher networks. These shifts predicted increases in the personality trait openness 2 weeks after LSD. Importantly, the predictive value of these entropy increases was greatest for the music-listening scans. These findings suggest a plausible mechanism by
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which LSD works in combination with music to enhance certain subjective experiences that may be useful in a therapeutic context. Reference(s) [1] Johnson M.W., Garcia-Romeu A., Cosimano M.P., Griffiths R.R., 2014. Pilot study of the 5-HT2A R agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28:983−92. [2] Grob, CS, Danforth, AL, and Chopra, GS (2011). Pilot study of psilocybin treatment for anxiety in patients with 478 advanced-stage cancer. Arch. Gen. Psychiatry 68, 71−78. [3] Kaelen, M., Barrett, F.S., Roseman, L., Lorenz, R., Family, N., Bolstridge, M., Curran, H.V., Feilding, A., Nutt, D.J., and Carhart-Harris, R.L., 2015. LSD enhances the emotional response to music. Psychopharmacology (Berl.). [4] Johnson M.W., Richards W., Griffiths R.R., 2008. Human hallucinogen research: guidelines for safety. J Psychopharmacol 22:603−20. [5] MacLean K.A., Johnson M.W., Griffiths R.R., 2011. Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol 25:1453−61.
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A common functional polymorphism (Val66Met) in the brain-derived neurotrophic factor gene (BDNF) may play substantial role in these associations [1], but the findings are still not conclusive, potentially because the measurement of stress varies greatly across studies (e.g., childhood adversity vs. recent stressful events) [2] and the causality of any of the factors is unclear. Longitudinal study design would greatly contribute to the understanding of the role of the BDNF gene in development of psychiatric vulnerability. Therefore, the aim of this study was to longitudinally assess the association between BDNF Val66Met, depression-related personality traits and the occurrence of stressful events in a population representative sample. Method: The sample was based on both birth cohorts of the longitudinal Estonian Children Personality, Behaviour and Health Study (altogether n = 1238, valid genotype missing for 4) [3]. In the younger cohort, personality according to the five-factor model was measured at ages 9 (parental assessment), 15 and 18 (self-assessments), and in the older cohort at ages 15 (parental and self-assessments), 18 and 25 (all self-assessments). Stressful life events in childhood were reported at age 15 and recent personal SLE-s at age 25. BDNF Val66Met genotype distribution was 908 Val/Val, 306 Val/Met and 20 Met/Met subjects. Owing to a small number of Met/Met homozygotes, participants were classified into Val-allele homozygotes and Met-allele carriers. ANOVA and ANCOVA were used for statistical analysis. Table 1. Stressful life events (SLE-s) at age 25, expressed in mean z-scores (SEM). BDNF genotype
Female Val/Val Met-allele Male Val/Val Met-allele
Total sample
Younger cohort
Older cohort
−0.02(0.05) −0.11(0.08)
−0.10(0.08) 0.05(0.12)
0.05(0.07) −0.23(0.11)§
−0.04(0.06) 0.30(0.09)**
−0.08(0.09) 0.42(0.13)*
−0.01(0.08) 0.18(0.14)#
**p < 0.005 vs. all other groups; *p < 0.005 vs. Val/Val homozygotes; # p < 0.05 vs. Met-allele females; §p < 0.05 vs. Val/Val females.
Results: Analysis of both birth cohorts combined agewise at 15 and 18 years did not reveal genotype main effect on personality traits, except the lower conscientiousness in Met-allele carriers at age 15 [F(1,693) = 8.02, p < 0.005]. Significantly higher stress exposure by age 25 was observed in male Met-allele carriers across the sample [F(1,967) = 8.5, p < 0.005] and in Met-allele carriers in the younger cohort [F(1,967) = 7.5, p < 0.01] (Table 1). Interestingly, in the older cohort, female Met-allele carriers had experienced less SLE-s. No association with childhood stressful life events was detected in either cohort.
Adding personality traits as covariates revealed significant contributions of high neuroticism [age 18; F(3,755) = 5.44, p = 0.001] and low conscientiousness [age 15; F(3,579) = 3.03, p < 0.05] to stress exposure. Interestingly, these associations were also measurable with parental personality assessments from the first study wave, at ages 9 and 15 [neuroticism F(3,809) = 3.38, p < 0.05; conscientiousness F(3,809) = 3.90, p < 0.01]. Conclusion: These results suggest that the BDNF Val66Met genotype appears to influence the development of depression-related personality traits via multiple pathways, leading to changes in coping strategies, and hence differential exposure to stressful life events in adulthood. These associations seem to depend on gender and birth cohort, whereas the latter is probably serving as a proxy measure of environmental changes. Reference(s) [1] Aguilera, M., Arias, B., Wichers, M., BarrantesVidal, N., Moya, J., Villa, H., Van Os, J., Ib´an˜ ez, M.I., Ruip´erez, M.A., Ortet, G., 2009. Early adversity and 5-HTT/BDNF genes: new evidence of gene– environment interactions on depressive symptoms in a general population. Psychol Med 39, 1425–1432. [2] Hosang, G.M., Shiles, C., Tansey, K.E., McGuffin, P., Uher, R., 2014. Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med 12, 7. [3] Tomson, K., Meren¨akk, L., Loit, H.M., M¨aestu, J., Harro, J., 2011. The relationship between serotonin transporter gene promoter polymorphism and serum lipid levels at young age in a longitudinal populationrepresentative study. Prog Neuropsychopharmacol Biol Psychiatry 35, 1857–1862. P.3.039 Effects of LSD and music on brain activity M. Kaelen1 ° , L. Roseman1,2 , A. Lebedev3,4 , J. Kahan5 , A. Santos-Ribeiro1 , C. Orban1 , R. Lorenz2 , D. Nutt1 , R. Carhart-Harris1 . 1 Imperial College London, Centre for Neuropsychopharmacology, London, United Kingdom; 2 Imperial College London, The Computational, Cognitive and Clinical Neuroimaging Laboratory, London, United Kingdom; 3 Karolinska Institutet & Stockholm University, Aging Research Center, Stockholm, Sweden; 4 Stavanger University Hospital, Centre for Age-Related Medicine, Stavanger, Norway; 5 University College London, Institute of Neurology, London, United Kingdom Lysergic acid diethylamide (LSD) is a classic psychedelic drug that produces a profound altered state of con-
Clinical and translational sciousness, likely via serotonin 2A receptor activation. Results from recent pilot studies support the safety and efficacy of psychedelic compounds in the treatment of mood and addiction disorders [1,2]. Within this approach, attentive listening to a carefully designed music playlist is considered to be an important component [3,4] and predictor of long-term outcomes, including changes in personality trait “openness” [5]. The main purpose of the present study was to investigate the interactive effects of LSD and music on subjective experience and brain activity, using functional magnetic resonance imaging (fMRI) and measures of resting state functional connectivity (FC), effective connectivity (EC) and sample entropy (SE). Twenty healthy psychedelic-experienced participants (four female, mean age: 31.4±7.8) were scanned on two separate occasions, separated by at least 14 days. Participants received placebo (intravenous saline) on one occasion, and 75 micrograms of intravenous LSD on the other. Scanning was performed under eyes-closed resting state conditions and at peak drug effects. Two seven minute scans were performed under eyes-closed resting state conditions, with a seven minute eyes-closed passive music listening scan in between. Two different music tracks (balanced for emotional intensity and valence) were played in the two conditions in a counter-balanced fashion (i.e. half of the subjects listened to track A under LSD). A seed-based FC analysis was performed on the bilateral parahippocampus (PHC), an important hub-area in the brain that has previously been linked with: (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. This analysis informed the regions of interest for the subsequent stochastic dynamic causal modelling (sDCM) analysis, to assess music and drug induced changes in EC. sDCM utilized a network discovery method to identify changes in information flow between the PHC and visual cortex (VC) by drug, music, and an interaction between the two. Finally, a measure of SE was applied, that characterizes the complexity or predictability of an fMRI time-series. Using mixed-effects models, whole brain drug-and music-induced changes in SE were assessed, as well as their relation to acute druginduced changes in music-evoked emotion and long-term changes in personality traits. Results revealed increased PHC-VC FC and EC in the music × LSD condition. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. Finally, LSD had a strong and global effect on the SE, both in sensory and in hierarchically higher networks. These shifts predicted increases in the personality trait openness 2 weeks after LSD. Importantly, the predictive value of these entropy increases was greatest for the music-listening scans. These findings suggest a plausible mechanism by
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which LSD works in combination with music to enhance certain subjective experiences that may be useful in a therapeutic context. Reference(s) [1] Johnson M.W., Garcia-Romeu A., Cosimano M.P., Griffiths R.R., 2014. Pilot study of the 5-HT2A R agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28:983−92. [2] Grob, CS, Danforth, AL, and Chopra, GS (2011). Pilot study of psilocybin treatment for anxiety in patients with 478 advanced-stage cancer. Arch. Gen. Psychiatry 68, 71−78. [3] Kaelen, M., Barrett, F.S., Roseman, L., Lorenz, R., Family, N., Bolstridge, M., Curran, H.V., Feilding, A., Nutt, D.J., and Carhart-Harris, R.L., 2015. LSD enhances the emotional response to music. Psychopharmacology (Berl.). [4] Johnson M.W., Richards W., Griffiths R.R., 2008. Human hallucinogen research: guidelines for safety. J Psychopharmacol 22:603−20. [5] MacLean K.A., Johnson M.W., Griffiths R.R., 2011. Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol 25:1453−61.