Hallucinogens & PerceptionHallucinogens & PerceptionThis tutorial provides an introduction to This tutorial provides an introduction to

basic concepts of neuropharmacology and basic concepts of neuropharmacology and

a more detailed discussion of the influence a more detailed discussion of the influence

of hallucinogens on perception.of hallucinogens on perception.

For more tutorials on visual perception visitFor more tutorials on visual perception visit

viper2go on the Viper website www.viperlib.comviper2go on the Viper website www.viperlib.com

Olivia Carter (2007)

H3CO NH2

H3CO

H3CO

Pharmacology ofPharmacology of Perception Perception

Structure in the BrainStructure in the Brain

~ 100 billion neurons in the brain~ 100 billion neurons in the brain

~ 0.15 quadrillion synapses in ~ 0.15 quadrillion synapses in the cortexthe cortex

Brain & spinal cord Neuron Dendritic spines

Signalling in the Brain: NeuronSignalling in the Brain: Neuron

Signal goes from the Signal goes from the cell body down the axoncell body down the axon

Neuron fires (action potential) – All or none….Neuron fires (action potential) – All or none…. - single units of activity - single units of activity

Signals receivedSignals received

++

+

+

-

-

-

-

+

+ +

+

Axon terminal

At rest the neuron has a negative At rest the neuron has a negative charge, an action potential is charge, an action potential is triggered when the charge becomes triggered when the charge becomes sufficiently positivesufficiently positive

Signalling in the Brain: SynapseSignalling in the Brain: Synapse

Neurons influence each other through Neurons influence each other through chemical signals (neurotransmitters)chemical signals (neurotransmitters)

11 SynthesisSynthesis

22 Release from synaptic vesiclesRelease from synaptic vesicles

33 Binds to receptors Binds to receptors

44 +/-+/- influence on post synaptic cellinfluence on post synaptic cell

55 Broken down by enzymes Broken down by enzymes

66 reuptake of transmitter reuptake of transmitter

77 formation & storage in formation & storage in vesicles vesicles

Cycle of NeurotransmittersCycle of Neurotransmitters

22

33

44 (+ or -)

55

66

7711

11

22

33

44

55

66

77

Drug ActionDrug Action

Drugs can effect Drugs can effect all stagesall stages

22

33

44 (+ or -)

55

66

7711

Action at the receptorAction at the receptor

1) drugs generally act by mimicking (agonists) or 1) drugs generally act by mimicking (agonists) or blocking (antagonists) natural neurotransmittersblocking (antagonists) natural neurotransmitters

2) Specific to receptor subtypes2) Specific to receptor subtypes

AgonistAgonistNaturalNatural

CompoundCompound AntagonistAntagonist

(+ or -) (+ or -)Signal

Receptor specificityReceptor specificityEach neurotransmitter can only act on specific receptors (lock and key)Each neurotransmitter can only act on specific receptors (lock and key)

In reality receptors are not simple “open-shut” gates… They have In reality receptors are not simple “open-shut” gates… They have complex structures and it is often a small change in their shape that will complex structures and it is often a small change in their shape that will “open” a channel, or cause it to “do its thing”. “open” a channel, or cause it to “do its thing”.

SummarySummary

-Neurons communicate through neurotransmitter release at synapses

-The action of neurotransmitters can be altered at many stages in many different ways.

- Receptors either act as ion channels (gates) or the cause down stream effects within the neuron through a “second messenger”

- - Recent history:Recent history: Albert Hofmann discovered LSD in 1943 Albert Hofmann discovered LSD in 1943 & isolated/synthesised psilocybin (“magic mushrooms”) in & isolated/synthesised psilocybin (“magic mushrooms”) in 1958.1958.

- Mechanism:Mechanism: The exact action of these drugs is not The exact action of these drugs is not known. However that the majority of hallucinogens (LSD, known. However that the majority of hallucinogens (LSD, Psilocybin, Mescaline etc) activate thePsilocybin, Mescaline etc) activate the Serotonin 5-HTSerotonin 5-HT2A2A

receptor. receptor.

PsilcybePsilcybe mushrooms mushrooms (“Magic” mushrooms)

Lophophora willimasii Lophophora willimasii (peyote cactus)

Basic facts about hallucinogensBasic facts about hallucinogens

- - Effects:Effects: rarely cause full hallucinations but commonly rarely cause full hallucinations but commonly induce striking perceptual distortions, mystical experiences & induce striking perceptual distortions, mystical experiences & altered sense of selfaltered sense of self

Hallucinogens have striking effects on perception! These drawings, by an artist under the influence of LSD, illustrate the perceptual changes experienced over the time course of the drug effects.

Prior to LSD 1h 25min 2h 30min

2h 45min 5h 45min 8h

Hallucinogens also cause illusions of motions. Objects and patterns Hallucinogens also cause illusions of motions. Objects and patterns are often seen to move, without actually changing location – similar are often seen to move, without actually changing location – similar to the sense of motion that occurs when your eyes move over this to the sense of motion that occurs when your eyes move over this pattern (pattern (Note Note that different mechanisms are likely to be responsible that different mechanisms are likely to be responsible for this illusion and the action of hallucinogens). for this illusion and the action of hallucinogens).

OH

N

H

NCH3

H3C

PsilocinPsilocin

PsilcybePsilcybe mushrooms mushrooms (“Magic” mushrooms)

Psilocybin in magic mushrooms is broken down into psilocin when it is digested. Psilocin is believed to be the structure that makes you hallucinate.

Psilocybin (psilocin)Psilocybin (psilocin)

OH

N

H

NCH3

H3C

PsilocinPsilocin

HO

N

H

NH

H

Serotonin (5-HT)Serotonin (5-HT)

N

H

NCH3

NC

OH5C2

H5C2

LSDLSD

N

H

NCH3

H3C

DMTDMT

They all share a 5 member ring containing They all share a 5 member ring containing Nitrogen joined to a benzene ringNitrogen joined to a benzene ring

Hallucinogens often have structure Hallucinogens often have structure similar to similar to serotoninserotonin… here are a … here are a

selection of Indoleamine selection of Indoleamine hallucinogenshallucinogens

Many receptor subtypes:Many receptor subtypes: 5-HT1 (A, B, D, E & F)5-HT1 (A, B, D, E & F)

5-HT2 5-HT2 (A, B, & C)(A, B, & C) 5-HT35-HT3 5-HT45-HT4 5-HT5 (A & B) 5-HT5 (A & B) 5-HT6? 5-HT6? 5-HT7?5-HT7?

THALAMUSTHALAMUS

RAPHE NUCLEUSRAPHE NUCLEUS(rostral & dorsal)(rostral & dorsal)

AMYGDALAAMYGDALA

HIPPOCAMPUSHIPPOCAMPUS

CORTEXCORTEX

NUCLEUS ACCUMBENSNUCLEUS ACCUMBENS

CEREBELLAR CEREBELLAR CORTEXCORTEX

5-HT is associated with Mood, Sleep, Appetite, 5-HT is associated with Mood, Sleep, Appetite, Clinical Psychosis & Clinical Psychosis & Hallucinogens!!Hallucinogens!!

AllAll 5-HT in the brain comes 5-HT in the brain comes from the raphe nucleus in from the raphe nucleus in the brainstem, from there it the brainstem, from there it is sent all over the brainis sent all over the brain

HO

N

H

NH

H

Serotonin (5-HT)Serotonin (5-HT)

5-hydroxytryptamene5-hydroxytryptamene

5-HT5-HT2A2A receptors are found in a number of specific brain regions receptors are found in a number of specific brain regions

(particularly along cortical-thalamic pathways). However, new research (particularly along cortical-thalamic pathways). However, new research

suggests 5-HTsuggests 5-HT2A2A receptors in the prefrontal cortex are particularly receptors in the prefrontal cortex are particularly

relevant in hallucinogen effects.relevant in hallucinogen effects.

Location of 5-HTLocation of 5-HT2A2A receptors receptors

Location of 5-HTLocation of 5-HT2A2A Receptors Receptors

5-HT5-HT2A2A receptors are found predominantly on the dendrites of layer V receptors are found predominantly on the dendrites of layer V

pyramidal cells. pyramidal cells.

Corticothalamic loopsCorticothalamic loops

ThalamusThalamus

Co

rtex

Co

rtex

5-HT5-HT2A2A activation disrupts corticothalamic loops, exactly how this happens activation disrupts corticothalamic loops, exactly how this happens

is a matter of debate. It was thought that the effect was at the “input” to is a matter of debate. It was thought that the effect was at the “input” to

the cortex from the thalamus. Now it appears hallucinogens primarily the cortex from the thalamus. Now it appears hallucinogens primarily

effects “effects “outputoutput” from layer V to thalamus. ” from layer V to thalamus.

Corticothalamic loops & consciousnessCorticothalamic loops & consciousness

Corticothalamic loops are an integral part of many theories Corticothalamic loops are an integral part of many theories

of consciousness… for example, of consciousness… for example,

-Tononi:Tononi: BMC Neuroscience (2004) 5:42 BMC Neuroscience (2004) 5:42

““The fact that consciousness as we know it is generated by the The fact that consciousness as we know it is generated by the thalamocortical system fits well with the information integration thalamocortical system fits well with the information integration theory.”theory.”

- Dehaene:Dehaene: PlosBiology (2005) 3: 0911-27 PlosBiology (2005) 3: 0911-27

““we provided a framework of a formal architecture of we provided a framework of a formal architecture of thalamocortical areas… which plays a key role in .. “access to thalamocortical areas… which plays a key role in .. “access to consciousness.”consciousness.”

Note:Note: most of the recent research was done using most of the recent research was done using slices of mouse prefrontal cortex.slices of mouse prefrontal cortex.

5-HT5-HT2A2A receptors are also found in other places including: receptors are also found in other places including:

- Claustrum Claustrum (the function of this area is unknown but Crick & Koch believe (the function of this area is unknown but Crick & Koch believe it is likely to be relevant to consciousness – it is likely to be relevant to consciousness – Crick & Koch (2005) Crick & Koch (2005) Phil. Trans. R. Phil. Trans. R.

Soc. BSoc. B 360360 1271-1279 1271-1279))

- Ventral StriatumVentral Striatum

- HippocampusHippocampus

- AmygdalaAmygdala

Not so simple!Not so simple!

Serotonin and PerceptionSerotonin and Perception-- Hallucinogen experiments ---- Hallucinogen experiments --

Hallucinogens as a research toolHallucinogens as a research tool

- Model psychosis:Model psychosis: The majority of current research uses The majority of current research uses hallucinogens to induce transient psychosis-like episodes hallucinogens to induce transient psychosis-like episodes in normal people, to better understand pharmacology of in normal people, to better understand pharmacology of clinical psychosis and to improve drug development. clinical psychosis and to improve drug development.

- - Perceptual pharmacology:Perceptual pharmacology: Hallucinogens effect sensory Hallucinogens effect sensory perception, emotions and can induce spiritual perception, emotions and can induce spiritual experiences.experiences.

- Consciousness:Consciousness: To date, no research has been done in To date, no research has been done in this area. Hallucinogens and anaesthetics seem to this area. Hallucinogens and anaesthetics seem to influence opposite ends of the consciousness spectrum influence opposite ends of the consciousness spectrum and seem to act on systems in the brain often discussed and seem to act on systems in the brain often discussed in models of consciousness. in models of consciousness.

1 example of a Motion perception experiment using psilocybin.

• 2 alternative forced choice: leftward rightward motion 2 alternative forced choice: leftward rightward motion

• Presentation time 300msecPresentation time 300msec

• 3 x 30 trials 3 x 30 trials

Trial 1Trial 1 Trial 30Trial 30

oror

1st task: Contrast Sensitivity for moving gratings1st task: Contrast Sensitivity for moving gratings

22ndnd Task: Coherent Motion Task: Coherent MotionTrial 1Trial 1 Trial 40Trial 40

or or

• 2 alternative forced choice: leftward rightward motion 2 alternative forced choice: leftward rightward motion

• Presentation time 300msecPresentation time 300msec

• 3x 40 trials3x 40 trials

1 example of a Motion perception experiment using psilocybin.

Contrast Contrast sensitivitysensitivity(local motion)(local motion)

Coherent motion(global motion)

V1

Frontal Lobe

Temporal LobeCerebellum

MT/V5

Parietal Lobe

Processing of global, but not local, motion direction is deficient in schizophreniaProcessing of global, but not local, motion direction is deficient in schizophrenia- Chen Y, Nakayama K, Levy D, Matthysse S and Holzman P. (2003) - Chen Y, Nakayama K, Levy D, Matthysse S and Holzman P. (2003) Schizophr Res Schizophr Res 6161:215-227.:215-227.

3) Clinical3) Clinical

2) Anatomical/functional dissociation2) Anatomical/functional dissociation

1) Subjective reports 1) Subjective reports People report increased sensitivity to People report increased sensitivity to

brightness, contrast and motion.brightness, contrast and motion.

Why these motion tasks?Why these motion tasks?

Cells in V1 Cells in V1 are sensitive are sensitive

to Local to Local motionmotion

MT seems to MT seems to be be

necessary necessary for coherent for coherent

motion motion detectiondetection

Psilocybin

Placebo

Co

ntr

ast

Sen

siti

vity

Co

ntr

ast

Sen

siti

vity

Pre-test Pre-test Peak ~ 120min Peak ~ 120min 2 2

10 10

20 20

30 30

2 2 Peak ~ 120min Peak ~ 120min

Co

her

ence

Sen

siti

vity

Co

her

ence

Sen

siti

vity

Pre-test Pre-test

10 10

20 20

30 30

*

ResultsResults

Local motion Local motion detection is detection is unaffectedunaffected

Coherent motion Coherent motion detection is detection is

impairedimpaired

- High level but not low level motion processing was - High level but not low level motion processing was impaired.impaired.

- In line with Schizophrenia findings.- In line with Schizophrenia findings.- Successful transfer of information from retina, LGN to V1- Successful transfer of information from retina, LGN to V1

- These results suggest that hallucinogens do not effect - These results suggest that hallucinogens do not effect sensitivity to individual motion signals, but instead disrupt sensitivity to individual motion signals, but instead disrupt the brains ability to integrate the individual motion signals the brains ability to integrate the individual motion signals in order to generate a percept of a single motion direction. in order to generate a percept of a single motion direction.

Future QuestionsFuture Questions

- If hallucinogens do not change sensitivity to the incoming - If hallucinogens do not change sensitivity to the incoming sensory information, where does the feeling of increased sensory information, where does the feeling of increased sensitivity to contrast, motion & colour come from? sensitivity to contrast, motion & colour come from?

SummarySummary

Take Home MessageTake Home Message

1)1) Pharmacology is relevant!Pharmacology is relevant! Activity of neurons is crucial, but it is the pattern of activity that Activity of neurons is crucial, but it is the pattern of activity that

determines our moment to moment state depends on determines our moment to moment state depends on neurotransmitters. neurotransmitters.

2) There is remarkable specificity in the action of 2) There is remarkable specificity in the action of hallucinogens.hallucinogens. Many drugs exist that activate many receptors but there is Many drugs exist that activate many receptors but there is something special about those that activate the 5-HTsomething special about those that activate the 5-HT2A2A receptor. receptor.

3) Pharmacology is great research tool.3) Pharmacology is great research tool. Drugs that alter perception provide a fantastic opportunity to Drugs that alter perception provide a fantastic opportunity to manipulate network properties of the brain in a systematic way. manipulate network properties of the brain in a systematic way.

Huxley, A. (1954) The doors of perception (available to download from the web at Huxley, A. (1954) The doors of perception (available to download from the web at http://www.druglibrary.org/schaffer/lsd/doors.htm) ) - * a fantastic description of the phenomenology- * a fantastic description of the phenomenologyCarter OL, Pettigrew JD, Burr DC, Alais D, Hasler F, Vollenweider FX (2004) Psilocybin impairs high-level but Carter OL, Pettigrew JD, Burr DC, Alais D, Hasler F, Vollenweider FX (2004) Psilocybin impairs high-level but not low-level motion perception. not low-level motion perception. Neuroreport Neuroreport 15: 1947-195115: 1947-1951 - *A detailed report of the motion - *A detailed report of the motion experiment experiment described in described in the previous slidesthe previous slidesNichols DE (2004) Hallucinogens. Nichols DE (2004) Hallucinogens. Pharmacol TherPharmacol Ther 101: 131-81 101: 131-81 -*A very detailed review-*A very detailed review

------------------- (more references) ----------------------------------------- (more references) ----------------------

Beique JC, Imad M, Mladenovic L, Gingrich JA, Andrade R (2007) Mechanism of the 5-hydroxytryptamine 2A Beique JC, Imad M, Mladenovic L, Gingrich JA, Andrade R (2007) Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad SciProc Natl Acad Sci U S A U S A 104: 9870-5104: 9870-5Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX (2005a) Using psilocybin to investigate the Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX (2005a) Using psilocybin to investigate the relationship between attention, working memory and the Serotonin1A&2A receptors. relationship between attention, working memory and the Serotonin1A&2A receptors. J Cog NeuroscienceJ Cog Neuroscience 17: 1497-17: 1497-15081508Carter OL, Pettigrew JD, Hasler F, et al (2005b) Modulating the rate and rhythmicity of perceptual rivalry alternations Carter OL, Pettigrew JD, Hasler F, et al (2005b) Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin. with the mixed 5-HT2A and 5-HT1A agonist psilocybin. NeuropsychopharmacologyNeuropsychopharmacology 30: 1154-62 30: 1154-62Gonzalez-Maeso J, Weisstaub NV, et al (2007) Hallucinogens Recruit Specific Cortical 5-HT(2A) Receptor-Gonzalez-Maeso J, Weisstaub NV, et al (2007) Hallucinogens Recruit Specific Cortical 5-HT(2A) Receptor- Mediated Mediated Signaling Pathways to Affect Behavior.Signaling Pathways to Affect Behavior. Neuron Neuron 53: 439-5253: 439-52Gouzoulis-Mayfrank E, Hermle L, Thelen B, Sass H (1998) History, rationale and potential of human experimental Gouzoulis-Mayfrank E, Hermle L, Thelen B, Sass H (1998) History, rationale and potential of human experimental hallucinogenic drug research in psychiatry. hallucinogenic drug research in psychiatry. Pharmacopsychiatry 31 SupplPharmacopsychiatry 31 Suppl 2: 63-8 2: 63-8Lambe EK, Aghajanian GK (2007) Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and Lambe EK, Aghajanian GK (2007) Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation. D1/D5 dopamine receptor activation. Neuroscience Neuroscience 145: 900-10145: 900-10DE Presti & DE Nichols. Biochemistry and neuropharmacology of psilocybin mushrooms. In DE Presti & DE Nichols. Biochemistry and neuropharmacology of psilocybin mushrooms. In Teonanacatl:Sacred Teonanacatl:Sacred Mushrooms of VisionsMushrooms of Visions (edited by R Metzner). Green Earth Foundation (2004). (edited by R Metzner). Green Earth Foundation (2004). Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drug-induced Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drug-induced psychoses. psychoses. Brain Res BullBrain Res Bull 56: 495-507 56: 495-507Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998) Psilocybin induces Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroreportNeuroreport 9: 3897-9029: 3897-902Weisstaub NV, Zhou M, Lira A, et al (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors Weisstaub NV, Zhou M, Lira A, et al (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. in mice. Science Science 313: 536-40313: 536-40

ReferencesReferences