Drugs & the BrainPart 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 25th 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