Download Week 8

HALLUCINOGENS
Dr. Simran Kaur
[email protected]
What?
Substances which induce alterations in
perception, cognitive function and feeling,
producing gross impairment of memory.
 Cause people to see images, hear sounds
and feel sensations which appear real but
do not exist.

Where?




Most come from plants (plant alkaloids)
Others are synthetic
Traditionally used in shamanic rituals by Native
American tribes
Resemble
ACh
 Catecholamines (NE and DA)
 Serotonin




Have been used for
thousands of years
Used in religious
ceremonies by cultures
from the tropics to the
arctic
Used to induce states of
detachment and produce
‘visions’ providing
mystical insight
Common effects:

Alterations in time and space perception




Minutes can be as slow as hours
Reliving old events
Changes in self-awareness
Increased sensitivity to textures, shapes, tastes and
sounds



Person feels as if they are floating or being pulled by gravity
Brighter colours, sharper sounds
Colours can be heard or sounds seen



Visual disturbances (i.e. flashes of light or
kaleidoscope-like patterns)
Hallucinations
Feelings of enlightenment or spiritual awakening
Physiological side-effects:








Rapid heart rate
Increased blood pressure
Nausea and appetite loss
Chills or flushing
Shaking
Paranoia
Confusion
Abnormal rapid
breathing




Acute panic (‘a bad trip’)
Muscle spasms and loss
of coordination
Convulsions and
unconsciousness
Aggressive, hostile and
violent behaviour
Types
1.
2.
3.
4.
Psychomimetics
Psychedelics (mind-manifesting) – drugs that
enhance or amplify thought processes.
Dissociatives (a state of sensory deprivation)drugs which reduce or block signals from the senses to
the ‘conscious mind’.
Deliriants (anticholinergic hallucinogens) –
drugs that produce clouding of consciousness and
amnesia.
Classification
1. Anticholinergic
3. Serotonin-like
Scopolamine (Hyoscine)
Mandrake
Hyoscyamine
Atropine
Lysergic acid diethylamide (LSD)
Dimethy-tryptamine (DMT)
Psilocybin
2. Catecholamine-like
Mescaline
MDA (methylene-dioxyamphetamine)
MDMA (methylene-dioxymethamphetamine – Ecstasy)
Myristicin, Elemicin
4. Glutamatergic NMDA
Receptor Antagonists
Phencyclidine (PCP)
Ketamine
5. Opioid Kappa receptor
agonist
Salvinorin A
1. Anticholinergic hallucinogens
Scopolamine (hyoscine)
 Tropane alkaloid drug
obtained from plants of
the Solanaceae family
Atropa belladonna
(Nightshade)
Datura stramonium (Thorn
apple)
Atropine
 Found in several
members of the
Solanaceae family. Most
common sources are
Atropa belladonna, Datura
innoxia, D. metel and D.
stramomium
Anticholinergic hallucinogens
Structurally similar to
Acetylcholine and act by
blocking muscarinic
acetylcholine receptors
(mAChRs)
(Scopolamine structure on right
above that of atropine)

Pharmacological effects
 Dry mouth
 Tachycardia
 Pupil dilation
Excessive dosage
 Tremor
 Fatigue and ataxia
 Marked palpitations
 Restlessness and
excitement
 Hallucinations
2. Catecholamine-like hallucinogens
Also called phenthylamine
hallucinogens (partial stimulants,
partial hallucinogens)
a. Mescaline (3, 4, 5trimethoxyphenethylamine)
Strucurally similar to
catecholamine neurotransmitters
NA (NE) and DA but with a
methoxy OCH3 group attached
to the phenolic ring
Mescaline
Norepinephrine
Mescaline:
Psychostimulant action
 Via DAergic stimulation in mesolimbic system
Psychedelic action
 Via serotoninergic action at postsynaptic 5HT2A
receptors
Mescaline: Source




From peyote cactus (SW USA and
North Mexico)
Hallucinogenic dose is about 0.3 –
0.5 g
Effects last 10 – 12 hours
Notable effects on visual system


Hallucinations of bright lights,
geometric designs, people and
animals
Not only drug of abuse but also
sacramental drug

Permitted for religious use in 23
US states
(Literary ref: Aldous Huxley's The Doors
of Perception, where Huxley writes of
his experimentation with mescaline in
Mexico).




b. Amphetamine
derivatives
i. MDMA (3, 4methylenedioxymethampheta
mine)
ii. MDA (3, 4methylenedioxyamphetamine
) (a metabolite of MDMA)
iii. MDE (3, 4methyllenedioxy-Nethylamphetamine)



All are synthetic derivatives
of amphetamines
Also effects on emotional
responses (i.e. nonhallucinogenic, non-stimulant
effects)
Entactogens: substances
which enhance the ability to
introspect and deal with
disturbing or sorrowful
feelings.
Primary mechanism of
action
 Stimulate DA release
 Enhance 5-HT release (cf
amphetamine)
 Inhibition of 5-HT
reuptake (cf amphetamine)
Psychological effects






Memory impairments and deficits in decisionmaking
Loss of self-control
Panic attacks on withdrawal
Recurrent paranoia, depersonalization
Depression
Animal studies indicate serotoninergic
neurotoxicity
Source of picture: NIDA website
From NIDA website: sections taken from the neocortex of monkeys that were given Ecstasy
twice a day for 4 days (control monkeys were given saline).
Peripheral effects





Increased heart rate and blood pressure
Hyperthermia
Dehydration (sweating and salivation) – can be
fatal for dancers
Tremor
Trismus and bruxism (tightening of jaw muscle
and grinding of teeth)
MDMA (from NIDA website)
c. Myristicin and Elemicin
 Source:



From Nutmeg and mace.
Structurally similar to
mescaline
Onset of effects, within 2-5
hours and last up to 24-72
hours
5-15 g  confusion,
euphoria, hallucinations,
nausea and vomiting, tremors
Myristicin
3. Serotonin-like psychedelics
Also called Indoleamine Hallucinogens
A. Lysergic Acid Diethylamide (LSD)
HISTORY:
 Albert Hofmann, Sandoz Pharmaceutical Company
 1930s – to synthesize new cardiovascular and respiratory
stimulants (Analeptics) from ergot alkaloids
 1938 – Lysergic acid diethylamide synthesized
 1943 – re-examine product and accidental ingestion 
hallucinogenic properties of the drug
 1947 – launched as Delysid for psychotherapy
 1970s – product banned and abandoned
LSD



A clear or white odourless water-soluble material
Synthesized from lysergic acid, which is derived
from a rye fungus.
Strongest effects in cerebral cortex and locus
ceruleus (area of the brain which receives
sensory signals and has been called the brain’s
‘novelty sensor’).



Most potent hallucinogen
Therapeutic dose: 50 mg –
300 mg [14,000 mg (lethal
dose x 280)]
Available as




Microdots (tablets)
Window panes: LSD in gelatin
Blotter acid: liquid added to
paper
Sugar cubes: LSD in sugarlumps

Popularized by Timothy
Leary in the 1960s

Used the catchphrase
‘Turn on, Tune in and
Drop Out’.
Pharmacokinetics of LSD



Onset: 0.5 – 1 hour
Peak plasma levels: 3
hours
Duration: 6 – 8 hours
LSD blotters
Physiological effects
Mainly sympathomimetic
 Pupil dilation
 Increase in heart rate and blood pressure
 Slight hyperthermia
 Nausea and vomiting
Psychological effects






Alterations in perception, thinking, emotion and
self-image
Distortion of time
Synaesthesia
Hallucinations of lights, shapes, distorted images
Mood swings
May experience loss of boundaries, fear of
fragmentation
Long-lasting effects:

Permanent reduction of information processing
by neocortex
Sensory overload
 Difficulty in coping and controlling emotional
reactions


Recurrence of psychological effects
Flashbacks – brief, benign, pleasant
 Hallucinogen persisting perception disorder (HPPD)
– long-term and distressing



Tolerance to drug rapidly develops but is also
rapidly lost (~ 1 week)
No physical dependence in human or animals
B. DMT (Dimethyltryptamine)
 Partial agonist at 5-HT2A
and 5-HT2C receptors
 Metabolized rapidly by MAO
 Source:
 Found in several South
American plants e.g. Mimosa
hostilis
DMT:
 Reaches full effect within 10 – 60 seconds of
inhalation and last for < 30 minutes but effect is
intense and similar to LSD effect.
 The Ayahuasca brews’ effect begin 20 – 60
minutes after ingestion and lasts about 3 – 4
hours.
Ayahuasca Brew:
 Medicinal tea brewed from N, Ndimethyltryptamine (DMT) and harmala
alkaloid-containing plants.
 The main harmala alkaloid components in
Ayahuasca are:
Harmine, harmaline and tetrahydroharmine (THH)
 Believed to possess highly active reversible MAO-A
inhibiting properties
 DMT present is slowly degraded by MAO-A

C. Bufotenine (dimethylserotonin)
 Source:
 Originally isolated from
secretions of Bufo alvarius
toad skin
 Can also be isolated from
beans of the Anadenanthera
colubrina, Anadenanthera
peregrina trees.


Similar effect to LSD and DMT
Has also been found in urine in a proportion of:
Violent offenders (those with paranoid personality
traits have even higher urinary levels)
 People with autism
 Schizophrenic patients

D. Psilocybin (4 – phosphoryl
DMT)
 Active metabolite: Psilocin
(4-hydroxy-DMT)
 Source:
 Present in many mushroom
species



Psilocybe cubensis and
Psilocybe semilanceata (Liberty
Caps)
Similar effects to LSD and
DMT
Intoxication regarded as
inducing a schizophrenia-like
psychosis
4. Phencyclidine (PCP) and Ketamine



Developed as i.v.
anaesthetics but also
discovered to be
psychodelic
PCP withdrawn from
clinical use due to sideeffects
Ketamine used mainly in
veterinary anaesthesia
(occasional human
usage)
Phencyclidine
Ketamine
PCP and Ketamine



Non-competitive NMDA antagonists
Induce toxic psychosis
Repeated use induces chronic schizophrenic
symptoms:
Psychosis
 Hallucinations
 Delusions
 Thought disorder
 Social withdrawal


In the Acute phase
Induce intense analgesia and amnesia
 But subjects may appear to be awake though
unresponsive


PCP and Ketamine – only hallucinogens which
induce addiction.
5. Salvinorin A



The most potent naturally
occurring non-nitrogenous
drug (hallucinogen)
Extracted from the plant
Salvia divinorum (diviner’s
sage, Mexican mint)
Smoked (quick onset ~ 1
min, short-duration ~15 min)
or eaten to induce intense
hallucinations

Radioligand binding assays involving 50 human
cloned GPCRs, ion channels and transporters
reviewed that
The first described selective kappa opioid receptor
agonist hallucinogen
 Does not activate 5-HT2A receptors (main molecular
target responsible for classical hallucinogens)
(Ref: Bryan et al., (2002) Salvinorin A: A potent naturally
occurring non-nitrogenous kappa opioid selective agonist. Proc.
Natl. Acad. Sci. 99: 11934-11939)

REFERENCES
MDMA
 Green (2003) Pharmacol Rev. 55: 463-508
 Kalant (2001) CMAJ 165: 917-928
Serotonin and hallucinogens
 Aghajanian and Marek (1999)
Neuropsychopharmacology. 21 (2 Suppl): 16S-23S
Salvinorin A
 Chavkin et al. (2004) J. Pharmacol Exp. Ther. 308:
1197-1203