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HALLUCINOGENS. Dr. Simran Kaur Simranjit.kaur@yahoo.co.uk. 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?.

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hallucinogens

HALLUCINOGENS

Dr. Simran Kaur

Simranjit.kaur@yahoo.co.uk

slide2
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
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
slide4
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
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
slide6
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

Physiological side-effects:
types
Types
  • 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

Scopolamine (Hyoscine)

Mandrake

Hyoscyamine

Atropine

2. Catecholamine-like

Mescaline

MDA (methylene-dioxy-amphetamine)

MDMA (methylene-dioxy-methamphetamine – Ecstasy)

Myristicin, Elemicin

3. Serotonin-like

Lysergic acid diethylamide (LSD)

Dimethy-tryptamine (DMT)

Psilocybin

4. Glutamatergic NMDA Receptor Antagonists

Phencyclidine (PCP)

Ketamine

5. Opioid Kappa receptor agonist

Salvinorin A

Classification
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

1. Anticholinergic hallucinogens
anticholinergic hallucinogens
Structurally similar to Acetylcholine and act by blocking muscarinic acetylcholine receptors (mAChRs)

(Scopolamine structure on right above that of atropine)

Anticholinergic hallucinogens
slide12
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, 5-trimethoxyphenethylamine)

Strucurally similar to catecholamine neurotransmitters NA (NE) and DA but with a methoxy OCH3 group attached to the phenolic ring

Mescaline

Norepinephrine

2. Catecholamine-like hallucinogens
slide14
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).

Mescaline: Source
slide16
b. Amphetamine derivatives

i. MDMA (3, 4-methylenedioxymethamphetamine)

ii. MDA (3, 4-methylenedioxyamphetamine) (a metabolite of MDMA)

iii. MDE (3, 4-methyllenedioxy-N-ethylamphetamine)

All are synthetic derivatives of amphetamines

Also effects on emotional responses (i.e. non-hallucinogenic, non-stimulant effects)

Entactogens: substances which enhance the ability to introspect and deal with disturbing or sorrowful feelings.

slide17
Primary mechanism of action

Stimulate DA release

Enhance 5-HT release (cf amphetamine)

Inhibition of 5-HT reuptake (cf amphetamine)

psychological effects
Psychological effects
  • Memory impairments and deficits in decision-making
  • Loss of self-control
  • Panic attacks on withdrawal
  • Recurrent paranoia, depersonalization
  • Depression
  • Animal studies indicate serotoninergic neurotoxicity
slide20

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
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)
slide23
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
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
slide25
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’).
slide26
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 sugar-lumps

slide27
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

Pharmacokinetics of LSD
physiological effects
Physiological effects

Mainly sympathomimetic

  • Pupil dilation
  • Increase in heart rate and blood pressure
  • Slight hyperthermia
  • Nausea and vomiting
psychological effects1
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
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
slide32
Tolerance to drug rapidly develops but is also rapidly lost (~ 1 week)
  • No physical dependence in human or animals
slide33
B. DMT (Dimethyl-tryptamine)

Partial agonist at 5-HT2A and 5-HT2C receptors

Metabolized rapidly by MAO

Source:

Found in several South American plants e.g. Mimosa hostilis

slide34
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.
slide35
Ayahuasca Brew:
  • Medicinal tea brewed from N, N-dimethyltryptamine (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
slide36
C. Bufotenine (dimethyl-serotonin)

Source:

Originally isolated from secretions of Bufo alvarius toad skin

Can also be isolated from beans of the Anadenanthera colubrina, Anadenanthera peregrina trees.

slide37
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
slide38
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 side-effects

Ketamine used mainly in veterinary anaesthesia (occasional human usage)

Phencyclidine

Ketamine

4. Phencyclidine (PCP) and Ketamine
pcp and ketamine
PCP and Ketamine
  • Non-competitive NMDA antagonists
  • Induce toxic psychosis
  • Repeated use induces chronic schizophrenic symptoms:
    • Psychosis
    • Hallucinations
    • Delusions
    • Thought disorder
    • Social withdrawal
slide41
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

5. Salvinorin A
slide43
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
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