Psychedelic/Hallucinogens- Chpt 12

• Primary effect is to produce perceptual changes & hallucinations

• Can influence several sensory systems, perception of time, space & events

DMT5-HTMescaline

Structure of hallucinogens• Most Hallucinogenic drugs have either a serotonin-like or a

catecholamine-like structure

• Serotonin-like are also known as indoleamine– LSD, psilocybin, psilocin, DMT and 5-MeO-DMT

• Catecholamine-like aka phenenthylamine – mescaline– has structural similarities to NE & amphetamine

Different Types of Psychedelics-based on their neurochemical characteristics

• Serotonergic– LSD– Psilocybin/Psilocin– DMT - Ayahuasca– Bufotenine

• Ololiuqui (oh-low-lee-oo-kee)• Catecholamine-like

– Mescaline– MDMA (ecstasy)

• MDA• MDE

– DOM– Myristin and Elemicin

• Cholinergic– Muscarine– Scopolamine

• Glutamatergic– PCP– Ketamine– Dextromethorphan

• Opioid– Salvinorin A

Pharmacology of Hallucinogenic Drugs

• Pyschedelic effects begin within 30-90 min (oral)

• LSD or mescaline trip lasts

for 6-12 hrs; Psilocybin dissipates sooner

• DMT effects user within seconds and dissipates in an hour or less

Depicts the typical dose range taken by recreational users (psilocybin is most potent and mescaline is the least)

Drug Route of Admin

Typical Dose Range

LSD Oral .05-.10 mg

Psilocybin Oral 10-20 mg

Mescaline Oral 200-500 mg

DMT Smoking 20-50 mg

Physiological Responses

• Activation of the sympathetic nervous system

• Pupil dilation, small increases in heart rate, body temp and blood pressure

• Dizziness, nausea, and vomiting

Psychological Effects• State of intoxication usually called a “trip”

• Trip can be divided into four stages:

• Other psychological effects include depersonalization, anxious or fearful state, disruption of logical thought.

• “Good trip” versus “Bad trip”: depends on dose, user’s personality, expectations, previous experiences, physical and social settings

1. Onset – 30 min to 1 hour visual effects begin

2. Plateau – next 2 hours sense of time slows, visual effects intensify

3. Peak – after about 3 hrs and lasts 2-3 hours

“in another world”, synesthesia

4. Come down – 2 hours May take up until next day to feel normal again

Neural mechanism

• Experimental animal studies– Lack of relevant human studies

• Location of critical receptors– Locus coeruleus (LC) – NE neurons

• Receives/integrates input from all major sensory systems• Sends information to cortex (sensory cortex)

• Activation of receptors– How does it produce sensory/cognitive distortions?

Experimental receptor study

• Vollenweider (1998)– Administration of antagonists

• Risperidone, Ketanserin (5-HT2A + D2 DA)– Decreased drug-induced visual illusions/hallucinations

• Haloperidol (Only D2 DA – Not 5-HT2A)– Completely failed to prevent hallucinogenic effects

• 5-HT2A is key mediator of hallucinogenic action– Tolerance acquired via down-regulation of

receptors– Very rapid tolerance – nearly complete in 4 days

Receptor Activation

• Serotonergic system involved in process– Perceptual and cognitive effects

• High affinity for 5-HT receptor subtypes (LSD)– 5-HT1A,B,D, 5-HT2A,C, 5-HT5A, 5-HT6, 5-HT7

• LSD compared to phenyl-ethylamine drugs– Only receptors in common

• 5-HT2A, 5-HT2C

Two mechanism theories

Administration of hallucinogenic drugs Aghajanian et al. (1999) Decrease spontaneous firing, enhanced excitation Drug intake LC more sensitive to sensory input

Generation of hallucinations Vollenweider et al. (2001) Disrupt frontal cortex/striatum/thalamus circuitry Drug intake interfere with sensory info ‘gating’

Information overload at cortical level

Hallucinogenic drug problems

Serious drug side effects ‘Bad trip’ – anxiety/panic

Interaction between drug, emotional state, environment Flashbacks

Re-experience perceptual symptom long after use Neural mechanism presently unknown

Psychotic breakdown Most severe adverse reaction Mental state – loss of contact with reality Typically occurs with psychiatric disorder

SerotonergicPsychdelics

Serotonergic Hallucinogens

• Lysergic acid diethylamide (LSD, Acid)• Psilocybin-Psilocybe mushrooms-Shrooms• Mescaline-Peyote cactus• Ergine-Morning glory• Harmaline-Ayahuasca,Yage’

LYSERGIC ACID DIETHYLAMIDE (LSD)

• Lysergic acid – Derived from ergot alkaloids• Ergot is a poisonous fungus that infects rye &

other grains & grasses• Albert Hoffman: 1938 - synthesized #25 in

series of new molecules doing ergot alkaloid chemistry

• 1943 - returned to #25 making new batch & absorbed some through skin

Aldous Huxley

Albert Hofmann-Discovered LSD

Timothy Leary and Ken Kesey

Doses of Acid

Effects of LSD etc...

• Sympathomimetic• Visual hallucinations

Visual Hallucinations

• Enhanced color perception• Flickering of the visual field• Perception of motion• Synesthesia• Form constants

Form Constants

• Lattice Pattern

Form Constants

• Lattice Pattern• Tunnel/Vortex

Form Constants

• Lattice Pattern• Tunnel/Vortex• Spiral Explosion

Visual Hallucinations

• Enhanced color perception• Flickering of the visual field• Perception of motion• Synesthesia• Form constants

Form Constants

• Lattice Pattern• Tunnel/Vortex• Spiral Explosion

Effects of LSD etc...

• Sympathomimetic• Visual hallucinations• Altered consciousness• Tolerance (but no dependence)

Adverse Effects: Myth & Reality

• Birth defects/chromosome damage– Myth!

• Acute Psychotic Reactions (Bad Trips)– Fairly Common

• Use 7 times and legally insane– Myth!

• Residual Psychosis– Rare; not certainly related to LSD

Adverse Effects: Myth & Reality

• Flashbacks– Fairly common among heavy users

• For some people, flashbacks are constant– Rare, but true: hallucinogen persisting perception

disorder

• Stored in spine?– Myth—Causes of flashbacks unclear

LSD in the USA

Came to U.S. in 1950s in two ways:

• Clinical usage: Supplied to psychologists and psychiatrists– encouraged their taking drug

• Military Usage: U.S. military and CIA as incapacitating agent and truth drug

• U.S. government gave LSD to unsuspecting individuals to study effects

LSD in the USA

• 1960s - popular use advocates– East Coast: Timothy Leary (clinical

psychologist at Harvard)– West Coast: Ken Kesey (noted author)

• graduate student in California got dose in psychology study

• shortly after this goes to work in psychiatry• year later, writes One Flew Over The Cuckoo's

Nest

LSD in the USA

• Spread through country with huge publicity until peak 1968 to 1972

• Schedule I in 1968

• Stuffy politicians didn’t know what to do because LSD was used by white, middle to upper class, college students

• Early 1990s - LSD came back

LSD & Neurotransmission

• Binds to 5-HT2A receptors – agonist effect

• Increases amount of sensory information getting to cortex through overriding filter mechanisms

• This is how the drug influences perception, especially for vision

Pharmacology of LSDPharmacological Effects • Effects heavily dependent

on dose taken– not just intensity of effects,

but type of effects• Low doses = mild

perceptual alterations– comparable to effects of

marijuana use, but greater clarity

 

Effects of LSDHigh Doses • progression through mental and

emotional experiences• 6-12 hrs duration• Each trip unique, highly

dependent upon setting and personal expectations

• Can alter subjects’ emotional feelings during trip by experimenter’s previous behavior– warm and supportive or

suspicious and nonsupportive

Effects of LSD

Effects of drug come on in about 30 min• first signs are autonomic activation• followed by overt behavioral signs - loosening of

emotional inhibitions– giddiness, laughter for no reason– mood euphoric and expansive, but labile mood

swings notable

• abnormal color sensations, luminescence• colors reported as more brilliant

Effects of LSD

• space and time disorders

• added depth with loss of perspective - up/down altered

• close in space influenced more than distant

• general slowing of time reported

LSD Hallucinationsgratings, latticework,

honeycomb, chessboard, tunnels, funnels, alleys, cones,

vessels, and spirals can be present with eyes open or

closedinvolve bright light in center

with figures moving in from periphery

forms appear to move in depth and take on color shades, red common

Sounds can take on visual forms music may take on enhanced

meaning or intensity

LSD & Bad Trips

• Psychological impact - traumatizing, imagery dark, insights appalling

• Usually occur in novice users, feel out of control• Generally negative set and setting are key

contributing factors• Can lead to suicide or prolonged psychotic

reaction• Can usually be talked down from a bad trip

LSD & Flashbacks

Spontaneous recurrence of trip after period of normalcy

• can occur after long periods of abstinence• more common after multiple high dose use• prolonged afterimages for days and weeks after

– tripping mechanism unknown

• can be brought on by other drugs or setting • most commonly reported in low light situations• not intrinsically dangerous and usually go away

Psilocybin/Psilocin• Magic Mushrooms,

Liberty Caps– Central America and

northwestern U.S.– Last about 6-10 hours – Need a lot to get same

effect as LSD– 5-HT2A agonist – Same basic effects as LSD– Mushrooms occasionally

toxic

Psilocybe Mushrooms-psilocybin

Psilocybe Mushrooms-psilocybin

Psilocybin, DMT, & 5-MeO-DMT

Psilocybin• “magic mushrooms” or “shrooms”

– Fungi that manufactured alkaloids with hallucinogenic properties

• Per os– Eaten raw, boiled in water to make tea, or cooked with

other foods to cover its bitter flavor• Major ingredients

– Psilocybin and related compound psilcon, the actual psychoactive agent psilocybin is converted to

Psilocybin, DMT, & 5-MeO-DMT (cont’d)DMT (dimethyltryptamine) Derived from plants in South America Devoid of psychoactivity when taken orally

Except with ayahauasca, “vine of the soul” Vines contribute to alkaloids called β-carbolines

Hypothesized to inhibit the enzyme monoamine oxidase which breaks down DMT

In solid powder form and smoked5-MeO-DMT (5-methoxy-dimethyltryptamine) “Foxy Methoxy” Oral active synthetic DMT analog

DMT

• Dimethyltriptamine– 5-HT2A agonist– Alkaloid– Often smoked– Main ingredient in Ayahuasca– Same effects as LSD

Bufotenine

• Dimethyl-serotonin– A product of abnormal

serotonin breakdown– Like LSD and others– Can occur in urine of

people with psychiatric disorders

• Psychosis• Paranoia• Depression

Ololiuqui

• Substance found in morning glory seeds• Similar to LSD• Significant nausea, vomiting and cramping

Tolerance/Dependence

• Not significant producers of tolerance or dependence

• No withdrawal either• People and animals do not self-administer• Problems related to the things people do while

under the influence– Accidents– Suicide– Aggression/violence– Toxic reactions

Catecholamine-likePsychedelics

Mescaline

• Active drug in peyote• Structurally similar to NE• However, most of the effect

is mediated by our friend, the 5-HT2A agonist action

• Legal for members of the Native American Church

Peyote cactus-mescaline

Religious Use of Hallucinogens

• Right to peyote ritual is protected for Native Americans

• Supreme Court is reviewing religious use of hoasca tea (DMT) now (November, 2005)

Peyote cactus-mescaline

Mescaline

• Peyote cactus– Mescal (peyote) button– Native to SW United States and N Mexico

• Administration– Chewed raw or cooked and eaten – Pure powder form

• High cost of synthesis and lacks a large market

Ecstasy

• MDMA (methylene-dioxy-methamphetamine)

• Synthesized in 1912

• Structurally related to amphetamines– Sympathomimetic – Weak in altering perceptual functions – But strong effects on emotions - empathogen – Used in combo with psychotherapy

Of interest: http://www.biopsychiatry.com/interview/index.html

MDMA

CH2 NHCH CH3

CH3O

O

Methylated Amphetamines

• Methylenedioxymethamphetamine (MDMA, Ecstasy, XTC)

• Methylenedioxyamphetamine (MDA)

Ecstasy (MDMA): Psychological Effects

• Increased alertness, arousal, insomnia--stimulant effects

• Euphoria, increased emotional warmth• Increased empathy and insight?• Hallucinogenic effects are largely absent

Ecstasy (MDMA): Physiological Effects

• Sympathomimetic• Bruxism & Trismus—teeth grinding & jaw

clenching (pacifiers)• Dehydration/Overhydration• Hyperthermia• Tachycardia• Collapse/Overdose death

Percent High School Seniors reporting MDMA use during their Senior year (Johnston, O'Malley,Bachman & Schulenberg, 2005)

96 98 00

Percent High School Seniors reporting MDMA use during their Senior year (Johnston, O'Malley,Bachman & Schulenberg, 2005)

96 98 00 02

Year

Per

cent

Usi

ng

2

4

6

8

04 06

Ecstasy and the brain

• MDMA increases release and blocks reuptake of serotonin

• MDMA also increases release of dopamine, and norepinephrine

• Long term/Permanent depletion of serotonin—damage to serotonin neurons in nonhumans

Ecstasy and the brain:Preclinical research

• Serotonin depletion, damage to serotonergic neurons reported in several species including rats and primates (see Morton, 2005 for a review)

• Effects were present in primate brain 7 years after MDMA exposure Hatzidimitrious et al., 1999)

• Mechanism of these effects?

Ecstasy and the brain:The Retraction

• Ricaurte et al. (2002) reported in Science that MDMA produced severe dopamine neurotoxicity in primates at doses in the range commonly encountered by human users.

• Ricaurte’s 2003 retraction and the fallout

Are doses used in preclinical research too high?

• Although neurotoxic doses in non-humans (5-20 mg/kg twice or more/day for several days) are generally higher than would be typical of human use, people often take several tablets at a time or throughout an night’s binge and a tablet may contain up to 300 mg: 4-5 mg/kg in an average person.

Clinical Research: Ecstasy in humans

• Topp et al. (1999) Australia study• Physical side effects

– Loss of energy (65%)– Muscular aches (60%)– Hot/cold flashes (48%)– Numbness (47%)– Profuse sweating (43%)– Tremors (42%)

Ecstasy in humans

• Topp et al. (1999) Australia study: Psychological side effects– Irritability (63%)– Sleep difficulty (56%)– Depression (56%)– Confusion (47%)– Anxiety (45%)– Paranoia (40%)

Clinical Research: Ecstasy in humans

• McCann et al. (1999)--MDMA users performance impaired in tasks of attention and STM--decreased serotonin in CSF

• Semple et al. (1999)--decreased serotonin transporter activity and cognitive impairment

• Holes in the brain?

Ecstasy in humans

– Morgan (2000) review: Heavy users more depression, sleep disorders, memory problems than controls

Ecstasy in humans

– Morgan (2000) Heavy users more depression, sleep disorders, memory problems than controls

– What is the proper control group?– Parrott et al. (2001) Heavy ecstasy users more

depression than non-users, but not more than other drug users.

Ecstasy in humans

– Morgan (2000) Heavy users more depression, sleep disorders, memory problems than controls

– What is the proper control group?– Parrot et al. (2001) Heavy ecstasy users more

depression than non-users, but not more than other drug users.

– Croft et al. (2001) Memory deficits in MDMA users, but also in group matched for THC use that used no MDMA

Ecstasy in humans

Thomasius et al. 2003 Psychopharmacology:Compared 30 current & 31 ex-MDMA users with 29

polydrug users (no MDMA) and 30 non-usersNo differences in psychopathology between MDMA

and PD groups (all showed more than NU) on Symptom Check List

Ecstasy in humans

Thomasius et al. 2003 Psychopharmacology:Compared 30 current & 31 ex-MDMA users with 29

polydrug users (no MDMA) and 30 non-usersNo differences in cognitive battery between MDMA

and PD groups

Ecstasy in humans

Thomasius et al. 2003 Psychopharmacology:Compared 30 current & 31 ex-MDMA users with 29

polydrug users (no MDMA) and 30 non-usersPET scans showed reduced serotonin transport

availability in some brain regions only in current MDMA users—suggests recovery after a period of abstinence (see also DeWin et al, 2004; McCann et al, 2005)

Why differing outcomes?

• Sampling issues and difficulties in matching controls

• Different behavioral & neurochemical measures• Problems with self-report (e.g., many different

drugs are sold as MDMA (dancesafe.org)

Ecstasy and the brain: What do we know?

• MDMA increases release and blocks reuptake of serotonin (increased release of DA and NE as well)

• Long term alterations of serotonin activity in nonhumans & humans--

Ecstasy and the brain: What do we need to know?

• What levels of use produce the serotonin effects and how long-term are they?

• Is there functional significance?

• Human data—Memory? Affect?

• Clinical trial for PTSD

Ecstasy and the brain: What do we need to know?

• Animal data—Does MDMA produce learning and memory deficits in rats: the UNCW project

• Student investigators: Laura Bullard, Miles Hulick, Brooke Poerstal, Becky Rayburn-Reeves, Andrea Robinson

History

• Patented by Merck in 1914• Advocated by some as adjunct to

psychotherapy (1970s-80s)• Picked up the name “ecstasy” & became

significant street drug (1980s)• Schedule I drug (1986)• Prototype “club drug” (1990s)

MDMA: Prototype Club Drug

PharmacodynamicsPharmacodynamics

Monoamine neurotransmission– increase synaptic DA and 5-HT– blocks 5-HT transporter– enters neuron and causes release of 5-HT

Ecstasy Effects

• Stimulant effects typically noted shortly after ingestion– increased heart rate– increased blood pressure– dry mouth– decreased appetite– increased alertness– elevated mood – jaw clenching

Ecstasy EffectsSubjective Effects

euphoria increased physical and emotional energy heightened sensual awarenesssubjective feeling of increased closeness or enhanced communication

Cognitive Effectsmemory loss

X Tox

• Malignant hyperthermia and dehydration• Idiopathic toxic response (not common but

nasty)– Renal failure– Rhabdomyolysis – disintegration of muscle tissue

• Street X is even more of a problem because it’s not always X or may have other drugs

X Tox

Potent neurotoxin• 1-2 times street dose• depletes forebrain 5-HT (not DA)• Kills the transporter receptor (SSRI)• Degeneration of 5-HT terminals

• Fine axons from dorsal raphe• Can get 30% loss with single injection• Up to 80% with repeated injections

Can induce psychiatric disturbance in vulnerable individuals. Treatment refractory depression

MDMA & MDA neurotoxicityMDMA & MDA neurotoxicity

9.9

Normal MDAPCA

5-HT immunoreactive fibers in rat parietal cortex

McCann et al.(1997)

Control

MDMA

Squirrelmonkeys 18 mo post-trtmt

Neocortex Hippocampus Caudate5-HT immuno-reactivity

What is PMA?

• Paramethoxy-amphetamine• "Death" "Mitsubishi Double Stack"

"Killer" "Red Mitsubishi"• Substitute for MDMA• Cheaper to make• Slower, longer effects• More hallucinogenic• Incidence of toxic side effects much higher than

MDMA (narrow safety margin)

Designer Psychedelics

• DOM, MDA, DMA, MDE, TMA, AMT, 5MeO-DIPT

• All structurally related to mescaline and methamphetamine; therefore MDMA.

• MDA is a metabolite of MDMA. May be responsible for much of the MDMA effect.

Myristin and Elemicin

• Found in nutmeg and mace• Structurally similar to mescaline• Significant nausea and vomiting• The sick usually limit use

GlutamatergicPsychedelics

Dissociative Anesthetics

Anesthetic Hallucinogens

• Phencyclidine (PCP, Angel dust, Lovely)

• Ketamine (Special K)

Anesthetic Hallucinogens

• Glutamate antagonists• Euphoria, numbness, loss of motor

coordination, blurred vision• Nystagmus• Distortions of body image, not visual

hallucinations• High rate of psychotic episodes some long-

term

PhencyclidinePCPPCPNMDA receptor antagonistNMDA receptor antagonist

Blocks the function of glutamateBlocks the function of glutamate

Used as an analgesic and anestheticUsed as an analgesic and anestheticCan be administered by any routeCan be administered by any routeOddly enough, animals self-administer Oddly enough, animals self-administer

(euphoria) (euphoria)Induces amnesia and true psychosisInduces amnesia and true psychosis

Hallucinations, paranoia, agitation, dissociation Hallucinations, paranoia, agitation, dissociation

Higher doses lead to stupor, coma Higher doses lead to stupor, coma seizures, death seizures, death

A perfect example of a Schedule I drugA perfect example of a Schedule I drug

Ketamine

• Special K• Very similar to PCP, not as

powerful• Liquid, but can be

powdered for snorting or smoking

• But just as dumb, stupid, useless and unsafe

• Another perfect example of a Schedule I drug

Subjective Effects of PCP/Ketamine

• Sensations of light coming through the body and/or colorful visions

• Complete loss of time sense• Bizarre distortions of body shape or size• Altered perception of body consistency• Sensations of floating or hovering in space• Feelings of leaving one’s body• Visions of spiritual or supernatural beings• Emotions ranging from euphoria to hositlity

Dalgarno & Shewan (1996)

Dextromethorphan

• Active ingredient in most OTC cough medicine• NMDA receptor blockade at high doses• Mostly teenage males abuse it• Like PCP and K at 20-30 X OTC dose• Coricidin –Bad news

CholinergicHallucinogens

Anticholinergic hallucinogens

• Atropine-from the Deadly nightshade, Datura, Jimson weed, and Mandrake

• Scopolamine-from Datura, Jimson weed, Mandrake and Henbane

Datura

Jimson weed

Muscarine/Muscimol

Found in mushrooms (Amanita Muscaria)

Muscimol is a GABAA agonist Trance-like, dreamy state

with dreamlike illusions Like Ambien

Muscarine is an Acetylcholine agonist (muscarinic receptors) Not psychotropic Peripheral effects: sweating,

limb twitching, seizure activity

Atropine & Scopolamine

Found in – Atropa belladonna, Datura Stramonium, Henbane

Acetylcholine receptor (muscarinic) antagonistsDissociatives that induces delirium , hallucinations, and amnesiaClassic anti-cholinergic symptoms

Hot as hellDry as a boneMad as a hatterBlind as a batRed as a beet

Used in the treatment of motion sickness & to dilate pupils during eye-exams.

Anticholinergic effects

• Dry mouth, blurred vision, loss of motor control

• Dream-like trance state• Little or no memory of experience

Opioid Hallucinogen - Salvinorin A

Comes from a plant in the mint family

Salvia Divinorum

Affinity for kappa opioid receptors

Agonist action

Like LSD and psilocybin

Fresh leaves are chewed and left in mouth

Dried leaves smokedNot effective if taken orally

Most potent, but not most powerful, of all naturally occurring hallucinogens

It’s still legal, but not likely for long

Salvia Divinorum• Plant used by the Mazatec people of Southern

Mexico: Diviner’s sage—leaves chewed or smoked• Active drug = salvinorum A (affects Kappa

receptors)--most potent natural hallucinogen (100 microgram ED50)

• Brief (30-60 min) intense trip: visual hallucinations, dissociative state, some bad trips, recent highly publicized suicide

• Marketed legally in US (in most states) as herbal dietary supplement—currently under DEA review