HALLUCINOGENS

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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?
   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              Acute panic (‘a bad trip’)
   Increased blood pressure      Muscle spasms and loss
   Nausea and appetite loss       of coordination
   Chills or flushing            Convulsions and
   Shaking                        unconsciousness
   Paranoia                      Aggressive, hostile and
                                   violent behaviour
   Confusion
   Abnormal rapid
    breathing
                         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.
                     Classification
1. Anticholinergic                3. Serotonin-like
Scopolamine (Hyoscine)            Lysergic acid diethylamide (LSD)
Mandrake                          Dimethy-tryptamine (DMT)
Hyoscyamine                       Psilocybin
Atropine                          4. Glutamatergic NMDA
2. Catecholamine-like                Receptor Antagonists
Mescaline                         Phencyclidine (PCP)
MDA (methylene-dioxy-             Ketamine
     amphetamine)                 5. Opioid Kappa receptor
MDMA (methylene-dioxy-               agonist
     methamphetamine – Ecstasy)
                                  Salvinorin A
Myristicin, Elemicin
      1. Anticholinergic hallucinogens

Scopolamine (hyoscine)      Atropine
 Tropane alkaloid drug      Found in several
  obtained from plants of     members of the
  the Solanaceae family       Solanaceae family. Most
Atropa belladonna             common sources are
  (Nightshade)                Atropa belladonna, Datura
Datura stramonium (Thorn      innoxia, D. metel and D.
  apple)                      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   Excessive dosage
 Dry mouth                Tremor

 Tachycardia              Fatigue and ataxia

 Pupil dilation           Marked palpitations

                           Restlessness and
                            excitement
                           Hallucinations
    2. Catecholamine-like hallucinogens

Also called phenthylamine              Mescaline
hallucinogens (partial stimulants,
partial hallucinogens)
a. Mescaline (3, 4, 5-
trimethoxyphenethylamine)
Strucurally similar to
catecholamine neurotransmitters      Norepinephrine
NA (NE) and DA but with a
methoxy OCH3 group attached
to the phenolic ring
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                         (Literary ref: Aldous Huxley's The Doors of
        Permitted for religious use in 23       Perception, where Huxley writes of his
         US states                               experimentation with mescaline in
                                                 Mexico).
   b. Amphetamine                 All are synthetic derivatives
    derivatives                     of amphetamines
   i. MDMA (3, 4-                 Also effects on emotional
    methylenedioxymethampheta       responses (i.e. non-
    mine)                           hallucinogenic, non-stimulant
   ii. MDA (3, 4-                  effects)
    methylenedioxyamphetamine      Entactogens: substances
    ) (a metabolite of MDMA)        which enhance the ability to
   iii. MDE (3, 4-                 introspect and deal with
    methyllenedioxy-N-              disturbing or sorrowful
    ethylamphetamine)               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 decision-
    making
   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         Myristicin
 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
         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 sugar-
        lumps
   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     LSD blotters
   Peak plasma levels: 3
    hours
   Duration: 6 – 8 hours
            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 (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
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, 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
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.
   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.           Phencyclidine
    anaesthetics but also
    discovered to be
    psychodelic
   PCP withdrawn from
    clinical use due to side-
    effects                     Ketamine
   Ketamine used mainly in
    veterinary anaesthesia
    (occasional human
    usage)
                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

				
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posted:3/19/2012
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