Drugsandthe Brain Part7 Psychedelics
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Drugsandthe Brain Part7 Psychedelics

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Drugsandthe Brain Part7 Psychedelics Drugsandthe Brain Part7 Psychedelics Presentation Transcript

  • Drugs & the Brain Part 7 Psychedelics
  • What are Psychedelics?
    • A broad range of drugs that effect core consciousness & sensory perception
    • Include: LSD, mescaline, psilocybin, peyote, ayahuasca
    • Effects include:
      • Synesthesia – senses are transmuted so touch may be experienced as sound, etc.
      • Altered sense of time & space
      • Loss of ego boundaries - oneness
  • The Effects of Psychedelics
    • “ Half an hour after swallowing the drug I became aware of a slow dance of golden lights. A little later there were sumptuous red surfaces swelling and expanding from bright nodes of energy that vibrated with a continuously changing pattern, patterned light.”
    • Aldous Huxley, Doors of Perception
    • describing the effects of mescaline
  • Mescaline
    • Active ingredient in the peyote cactus
    • Used for centuries by Mexican Indians
    • Methoxyamphetamines
      • synthesized in the 1960’s
      • the amphetamine derivative of mescaline
      • increased potency
  • Dow Derivatives
    • Chemical companies, especially Dow, tried to enhance the potency of mescaline:
    • Methoxyamphetamine – additioanl methyl group on side chain
    • TMA – trimethoxyamphetamine – added a methyl group to the side chain
    • DOM (STP) – dimethoxy methylamphetamine - changed location of methoxy groups & added a methyl group
    • DOET - dimethoxy ethylamphetamine – the ethyl derivative of DOM
    • MDMA (ecstasy) – methylene dioxy-N-methylamphetamine
  • Magic Mushrooms
    • The oldest class of mind-altering plants: Psilocybe mexicana
    • Active ingredients, psilocybin & psilocin isolated in 1958, by Albert Hoffman, the creator of LSD
    • Structurally very similar to LSD
    • Also similar to serotonin
  • Serotonin & Psilocin serotonin psilocin Psilocin is the hydrolysed form of psilocybin, with the change shown in blue. It closely resembles serotonin. The indole rings are shown in red.
  • Structure of Hallucinogens: Psilocybin & Mescaline psilocybin mescaline Many hallucinogens are variations of biological substances called indole-amines. These contain an indole ring structure (highlighted in red), which is simply a 6-membered benzene ring fused to a 5-membered ring containing nitrogen.
  • Ergot & the Genesis of LSD
    • Ergot is an extract of the fungus Claviceps purpurea , which grows on grain, especially rye
    • Ergot is toxic:
      • can cause gangrene of the limbs & convulsions
      • Can also cause hallucination & bizarre behavior
    • Some speculate the Salem witch trials derived from ergot induced hallucinations
    • Used in the middle ages to induce uterine contractions
    • Hydrogenated form marketed as Hydergine
      • widely used to improve mental function in the elderly
      • action similar to caffeine
  • Chemical Basis of Ergot
    • Ergotamine
      • First active compound isolated from ergot in 1918
      • Constricts blood vessels
      • Used to treat migraine
    • Ergonovine
      • an active ingredient in ergot that induces uterine contractions
    • Ergotoxine – a mixture of 3 chemicals in ergot that were toxic to animals
    • 1930 – researchers at Rockefeller Institute isolated the common core of all ergot compounds: lysergic acid
  • LSD
    • The best known & first synthetic psychedelic
    • Albert Hoffman, working for Sandoz Pharmaceuticals, made many ergot derivatives
    • Prepared lysergic acid with different amines
    • The 25 th of these was lysergic acid diethylamide: LSD-25
    • Considered a failure after animal testing
    • 1943 – acting on a hunch Hoffman again synthesized this compound
  • The First Trip
    • “ Last Friday, April 16, 1943, I was forced to interrupt my work in the laboratory in the middle of the afternoon and proceed home, being affected by a remarkable restlessness being combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state with eyes closed I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away.”
  • Confirmation
    • Hoffman believed his experience was due to handling LSD-25
    • Tested this by ingesting .25 mg.
      • A massive dose
      • A very “bad trip” –lasted about 14 hours
    • Sandoz confirmed LSD’s action
    • Tried to find a medicinal use – unsuccessful
    • Popularization by Timothy Leary in 1960s led to reports of adverse effects, schizophrenic breaks, psychoses, suicides
  • Psychedelics Mimic Neurotransmitters
    • All psychedelics resemble serotonin, norepinephrine and/or dopamine
    • 2 of the 4 rings in LSD are identical to serotonin (indole rings)
    • Serotonin side chain is also identical to LSD
    • Psilocin, psilocybin, & dimethyltryptamine (DMT) are also close chemical relatives of serotonin
    • Mescaline is closer to norepinephrine & dopamine
  • Structure of LSD
    • The structure of lysergic acid diethylamide.
    • The diethylamide group is shown in red.
    • The indole ring is in blue.
  • Mode of Action
    • Despite similarity to neurotransmitters, exact mode of action is unknown
    • One line of evidence suggests that LSD exerts its effects by blocking serotonin receptors
    • Other investigators believe that is not the basis of the psychedelic action
    • Mescaline, an effective psychedelic, is not a serotonin antagonist
  • Site of Action in the Brain
    • Researchers looked at the direct action of psychedelics on the brain using microelectrodes
    • Recorded activities of serotonin containing neurons
    • All serotonin projections in the brain originate from the raphe nucleus in the brainstem
      • Sends dense projections to the limbic system
  • Serotonin Neurons & LSD
    • Investigators injected rats with LSD and recorded the activity of serotonin neurons in the raphe nucleus
    • Caused serotonin cells to stop firing
    • Required only very low doses of LSD
    • Other cells were unaffected
    • Psilocin, psilocybin & DMT had the same effect
    • Mescaline did not
    • Lisuride, an LSD derivative with no psychedelic effects, worked just like LSD
  • Norepinephrine Neurons & LSD
    • Recent studies looked at norepinephrine neurons in the locus coeruleus (recall from amphetamines)
    • The locus coeruleus integrates all sensory input
    • Direct stimulation of the locus coeruleus in rats seems to produce a state of panic
    • Hyper-responsive to environmental stimuli
    • Rats have same response when given LSD
    • Hypersensitivity to sensory input also occurs in humans under the influence of psychedelic drugs
    • Suggests psychedelics may act on the locus coeruleus
  • Effect on the Locus Coeruleus
    • Any sensory stimulation – sight, sound, touch, etc. – increases firing rate of locus coeruleus neurons in rats
    • This increase is accelerated by LSD or mescaline
    • Non-psychedelic drugs and LSD analogs that do not produce psychedelic effects do not have this effect
    • LSD does not cause neurons to fire spontaneously without stimulation
    • So effect on sensory stimulation must be indirect
    • Drugs must interact with other neurons that then activate the locus coeruleus
  • Multiple Systems May Be Involved
    • Psychedelic drugs exert an effect on serotonin receptor subtype S2
    • At these receptors, psychedelic drugs mimic serotonin
      • Relative binding to S2 receptors correlates with psychedelic activity of drugs
    • Neurons with S2 receptors that connect to the locus coeruleus may account for how these drugs indirectly activate the locus coeruleus
    • The exact role of these different systems still unclear