Psilocybin slows binocular rivalry switching through serotonin modulation. modulation. Current contact information
O. Carter1,2, J. Pettigrew1, F. Hasler2, G. Wallis3, & F. Vollenweider2.
(
Previous findings Psychosis – People with Bipolar disorder show slower than normal binocular rivalry switching (Pettigrew & Miller, 1998).
Harvard University, Cambridge MA Email:
[email protected]
Cortical activity)
Subjective effects
5-HT2A
5-HT1A&2A Receptors - Activation of 55-HT2A receptor by psilocybin increases cortical activity. Activation of 55-HT1A reduces the release of serotonin from the Raphe into the cortex.
Adjective Mood Rating Scale (AMRS)
Psilocybin – The hallucinogen psilocybin slows down binocular rivalry switching switching in Ketanserin - A selective antagonist at the 55-HT2A receptor. Can be used to block psilocybin’ psilocybin’s 55-HT2A mediated effects.
5-HT1A
(
5-HT release)
Methods Project Aims
Plasma conc ng / mL mL]] Psilocybin [[ng
Binocular Rivalry
• Determine whether ketanserin can block psilocybin’s effect on binocular rivalry or if the subjective psychosislike effects can be dissociated from the binocular rivalry switching rate.
10
Ketanserin/ Placebo
Psilocybin/ Placebo
RIGHT EYE`
LEFT EYE
0 0
60
120
Binocular Rivalry
180
300
240
360
420
Time (sec)
- vertical & horizontal gratings (1.5˚ (1.5˚ patch) - 11 blocks (4x60sec) over 9 hours
Results
Binocular rivalry
Psilo
* † * †
originate in the Raphe nucleus in the brainstem. From here, the rostral neurons project into limbic & cortical areas (preferentially into frontal regions). 5-HT is an endogenous neurotransmitter involved in arousal (sleep/wake cycles), mood, appetite, temperature regulation, cognition & is also implicated in clinical psychosis.
CEREBELLAR CORTEX
RAPHE NUCLEUS (rostral & dorsal)
Psilocybin Is found in hallucinogenic psilocybe mushrooms. Psilocin, the active metabolite of psilocybin, is an agonist at 5– 5–HT1A/2A receptors & has a similar chemical structure to serotonin. H H
H3 C
N
CH3 N
Seconds
Serotonin (5(5-HT) - Serotonergic neurons
135
180
* = p < 0.05 † = p < 0.05
Psilo + Ket
1.0 Ket (50mg)
Psilocybin Slows down rivalry
Psilo (215µg/kg)
0 PrePre-test
- 45
30
60 90
240
300
360
Psilo
* = p < 0.05
Proportion of mixed percept 20 *
*
Psilo + Ket
No difference **Ketanserin ** has no effect
420
† = p < 0.05
†
10
-45
Indole
Psilocybe mushrooms Psilocin
5 member, Nitrogen containing, ring joined to a benzene ring
H
Serotonin (5(5-HT)
0 “ManiaMania-like” like” symptoms
0
Visionary Reduced Anxious Auditory Vigilance Ego Restructuralization Alterations Dissolution
-2 ‡
Ketanserin blocked all of the psilocybin’s Psychosis-like effects, but NOT the attention/arousal effects
- Psilocybin produced a variety of subjective changes in conscious conscious state. - Ketanserin blocked most effects, except those relevant to attention attention & arousal (i.e. the “positive” positive” but not the “negative” negative” psychosispsychosis-like symptoms).
slows down the rate of rivalry switching & the duration of the transition phase. • Pre-treatment with the 5-HT2A antagonist Ketanserin
• These findings link binocular rivalry switching rate to subjective measures of attention and arousal
• Suggest the involvement of serotonin & the 5-HT1A receptor in this association.
Psilo (215µg/kg)
30
60
90
135
180
240
300
360
420
Time post psilocybin (min)
H
20
5
N N
*
• This result raises the possibility that rivalry may have diagnostic implications for conditions characterised by attentional deficits such as autism and ADHD.
15
PrePre-test
Psilocybin
*
*
40
blocked the “positive” psychosis-like symptoms (hallucinations) but not psilocybin’s effect on binocular rivalry or the “negative” psychosis- like symptoms (attention & arousal).
2.0
0
HO
*
3.0
Ket (50mg)
OH
* †
4.0
% Time Grid / Mixed
Introduction
HIPPOCAMPUS
Psilocybin Psilo + Ket Ketan Ketanserin Placebo
Mean Phase Duration 5.0
AMYGDALA
*
2
†
*
* = p < 0.05
Summary
the relative contribution of the serotonin (5-HT) 1A and 2A receptors in any observed effects on rivalry rate and conscious state.
CORTEX
4
*
* *
• Hallucinogenic doses of the 5-HT1A/2A agonist psilocybin
• To use this pharmacological manipulation to tease out
THALAMUS
‡
6
5D5D-ASC selfself-rating scale (Dittrich 1998). 80
Psychometric Rating
5
-90
8
v pla *† == psilo psilo + ket v pla ‡ = psilo + ket v pla & psilo
-4
10 Healthy human subjects - 4 conditions: placebo; psilocybin (215 µg/kg); ketanserin (50mg/kg); psilocybin + ketanserin.
• To investigate the proposed link between switching rate and symptoms of psychosis (eg bipolar disorder & schizophrenia).
change from pretest
Ketanserin – Is a drug that has been found to block psilocybin’ psilocybin’s subjective psychosispsychosis-like symptoms (Vollenweider (Vollenweider et al., 1998).
p < 0.05
A C cti on v a ce tio nt n ra & ti o n G Le en th era ar l g ex y tr o ve rs se io he lf-c n ig on ht fi e n de e d nc e m & o em od s e ot ns i on iti a l vi ty D A ep n re xie ss t y iv & en es D re am s in es s
parallel with increases in drug induced psychosispsychosis-like symptoms (Carter et al., 2005).
Placebo Psilocybin Psilo + Ket Ketan Ketanserin
% Total possible score
University of Zu Zurich, Switzerland
University of Queensland
VISION SCIENCES LABORATORY
1 Vision touch and Hearing Research Centre, School of Biomedical Sciences, Sciences, University of Queensland, Australia 2 Heffter Research Centre, Department of Clinical Research, Psychiatric University Hospital Zurich, Switzerland Switzerland 3 Perception and Motor Systems Lab, School of Human Movement Studies, Studies, University of Queensland, Australia.
- Psilocybin reduced the rate of binocular rivalry switching and increased the proportion of the mixed/ transitional state (the transition duration). -This effect was not blocked by the drug ketanserin.
References Carter, O. L, Pettigrew, J. D., Hasler, Hasler, F. & Wallis, G. M., Liu, G. B., Hell, D., & Vollenweider, Vollenweider, F. X. (2005) Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 55-HT2A and 55-HT1A agonist psilocybin. Neuropsychopharmacology 30: 11541154-1162 Dittrich, Dittrich, A. (1998) The standardized psychometric assessment of altered states of consciousness (ASCs (ASCs)) in humans. Pharmacopsychiatry, Pharmacopsychiatry, 31 Suppl 2, 8080-84. Pettigrew JD, Miller SM (1998). A 'sticky' interhemispheric switch in bipolar disorder? Proc R Soc Lond B Biol Sci 265: 265: 21412141-8. Vollenweider FX, VollenweiderVollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998). Psilocybin induces schizophreniaschizophrenia-like psychosis in humans via a serotonin3897-902 serotonin-2 agonist action. Neuroreport 9: 3897-
