Download - Psychedelic/Hallucinogens- Chpt 12
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
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
Visual Hallucinations
• Enhanced color perception• Flickering of the visual field• Perception of motion• Synesthesia• Form constants
Visual Hallucinations
• Enhanced color perception• Flickering of the visual field• Perception of motion• Synesthesia• Form constants
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
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
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
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)
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)
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
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
Anticholinergic hallucinogens
• Atropine-from the Deadly nightshade, Datura, Jimson weed, and Mandrake
• Scopolamine-from Datura, Jimson weed, Mandrake and Henbane
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