HALLUCINOGENS

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HALLUCINOGENS

• Dr. Simran Kaur
• Simranjit.kaur_at_yahoo.co.uk

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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.

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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

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• 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

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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

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• Visual disturbances (i.e. flashes of light or
  kaleidoscope-like patterns)
• Hallucinations
• Feelings of enlightenment or spiritual awakening

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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

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Types

1. Psychomimetics
2. Psychedelics (mind-manifesting) drugs that
   enhance or amplify thought processes.
3. Dissociatives (a state of sensory deprivation)-
   drugs which reduce or block signals from the
   senses to the conscious mind.
4. Deliriants (anticholinergic hallucinogens)
   drugs that produce clouding of consciousness and
   amnesia.

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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

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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

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Anticholinergic hallucinogens

• Structurally similar to Acetylcholine and act by
  blocking muscarinic acetylcholine receptors
  (mAChRs)
• (Scopolamine structure on right above that of
  atropine)

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• Pharmacological effects
• Dry mouth
• Tachycardia
• Pupil dilation

• Excessive dosage
• Tremor
• Fatigue and ataxia
• Marked palpitations
• Restlessness and excitement
• Hallucinations

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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

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• Mescaline
• Psychostimulant action
• Via DAergic stimulation in mesolimbic system
• Psychedelic action
• Via serotoninergic action at postsynaptic 5HT2A
  receptors

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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).

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• 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.

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• Primary mechanism of action
• Stimulate DA release
• Enhance 5-HT release (cf amphetamine)
• Inhibition of 5-HT reuptake (cf amphetamine)

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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

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Source of picture NIDA website
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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).
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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)

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MDMA (from NIDA website)
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• 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

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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

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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 brains
  novelty sensor).

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• 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

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• Popularized by Timothy Leary in the 1960s
• Used the catchphrase Turn on, Tune in and Drop
  Out.

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Pharmacokinetics of LSD

• Onset 0.5 1 hour
• Peak plasma levels 3 hours
• Duration 6 8 hours

• LSD blotters

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Physiological effects

• Mainly sympathomimetic
• Pupil dilation
• Increase in heart rate and blood pressure
• Slight hyperthermia
• Nausea and vomiting

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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

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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

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• Tolerance to drug rapidly develops but is also
  rapidly lost ( 1 week)
• No physical dependence in human or animals

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• 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

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• DMT
• Reaches full effect within 10 60 seconds of
  inhalation and last for lt 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.

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• 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

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• 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.

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• 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

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• 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

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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

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PCP and Ketamine

• Non-competitive NMDA antagonists
• Induce toxic psychosis
• Repeated use induces chronic schizophrenic
  symptoms
• Psychosis
• Hallucinations
• Delusions
• Thought disorder
• Social withdrawal

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• 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.

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5. Salvinorin A

• The most potent naturally occurring
  non-nitrogenous drug (hallucinogen)
• Extracted from the plant Salvia divinorum
  (diviners sage, Mexican mint)
• Smoked (quick onset 1 min, short-duration 15
  min) or eaten to induce intense hallucinations

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• 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)

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REFERENCES

• MDMA
• Green (2003) Pharmacol Rev. 55 463-508
• Kalant (2001) CMAJ 165 917-928
• Serotonin and hallucinogens
• Aghajanian and Marek (1999) Neuropsychopharmacolog
  y. 21 (2 Suppl) 16S-23S
• Salvinorin A
• Chavkin et al. (2004) J. Pharmacol Exp. Ther.
  308 1197-1203