Lesson 22: Indolamine 'classic' Hallucinogens

Hallucination

• sensory perception without external stimulation → perceiving things outside the mind that are not outside the mind

• can happen for a variety of reasons:

  • hypnagogic hallucinations (ex. feeling like you’re falling right before falling asleep)

  • acute illness

  • chronic neuropathology (schizophrenia)

  • external injury

    • charles bonnet, phantom limb

  • drug effect

Charles bonnet syndrome

• Simple or complex visual hallucinations in people with impaired vision.

• 12% of people with age-related macular degeneration

• When V1 stops receiving sufficient input, it fills in the void by activating itself.

• Reported hallucinations include:

  • Simple patterns – lines, dots, other geometric shapes

  • Places – landscapes, such as mountains or waterfalls

  • People, animals, or insects

  • Imaginary creatures – dragons, unicorns, etc.

LSD

• Semisynthetic ergoline alkaloid

• 1938 – First synthesized by Albert Hofmann

  • Accidental ingestion led to discovery of hallucinogenic effects

• 1950s-1960s

  • Testing by governments to determine military / espionage uses

  • Diversion of LSD for recreational use

• Dr. Timothy Leary

  • Tries psilocybin and becomes fascinated with hallucinogens

  • Starts a quasi-religion with LSD as a ritual drug

  • Professor of Clinical Psychology, then a writer, then a fugitive, then a speaker.

• After the 1960s, the popularity of hallucinogens decreased.

• Recently, illicit hallucinogen use is rising in Canada.

• Since the 1960s, a renewed interest in hallucinogenic drugs for psychotherapeutic uses – “Psychedelic-assisted therapy”

Absorption

• routes of administration

  • Oral.

  • LSD ‘hits’ of drug taken in liquid form or dried on dissolving blotters/gummies/sugar cubes.

• effects are noticeable after 30-60 mins

Distribution

about 1% reaches the brain

Elimination

half life of 5 hrs; effects felt for 10-12 hrs

Neuropharmacology

• Indolamine hallucinogens tend to agonize 5-HT2A with high selective binding affinity vs other 5-HT, DA, and NE receptors.

  • Brain areas where indolamine hallucinogens act:

    • Locus coeruleus – Detection of novelty.

      • Activity here says “I am seeing things for the first time”

    • Cortex

      • Broad patterns of activation

      • All primary and secondary sensory regions

        • Activity here accounts for the perceptual phenomena of hallucinations

    • Raphe nuclei

      • Inhibits serotonin release to other regions

• An important consideration when designing / using drugs for hallucinogenic or non-hallucinogenic effects

  • Antipsychotics suppress psychosis-related hallucinations, and many have some selective antagonism of 5-HT2A.

  • Antidepressants also usually work on 5-HT receptors, but hallucinations are not desired

Primary effects

• Hallucinogenic effects

  • Simple hallucinations

    • Vivid visual patterns overlaid on the visual scene

    • Geometric shapes (spiral, lattice, cobweb, tunnel, etc.)

    • Vivid colours of all kinds

  • Complex hallucinations

    • People, animals, places, religious imagery

• Phantasticant effects

  • A sense that the experience being had is of great worldly significance or emotional importance.

  • May feel like the nature of the universe is being revealed to you.

    • Arguably responsible for the importance and use of some hallucinogens for traditional / ritual purposes.

    • Also arguably one of the main appeals of hallucinogenic drugs 

• Entactogenic / empathogenic effects

  • A sense that the experience is revealing previously-hidden memories or emotions

    • Intense feelings of empathy, love, emotional closeness toward other people.

    • In touch with yourself

Side effects

• ‘Bad trip’ – Anxiety, panic, terror. Hallucinations can be frightening!

• Decreased task motivation

• Impaired reaction time (hard to measure due to demotivating effects)

• Poorer performance on short-term memory tasks (hard to measure…)

• Poorer concentration and problem-solving tasks (hard to measure…)

• Changed creativity (art is ‘different’, maybe better maybe worse)

Can they be toxic?

mostly non toxic

• less lethal that asprin

Lasting effects

• Serotonin syndrome → most life threatening thing that can happen

  • Possible when hallucinogenic drugs mixed with MAOIs (ayahuasca, designer drugs; MAOI needed to enable absorption of DMT and other molecules through stomach)

• Hallucinogen Persisting Perception Disorder (HPPD)

  • DSM-V – drug induced disorder.

  • Perceptual effects that re-occur long after drug eliminated.

  • 60% of long-term hallucinogen users experience lasting effects

    • 24-40% experience HPPD ‘near constantly’.

    • Most do not feel severely distressed or impaired by them.

Self administration

• not in humans or animals unless pre trained

  • some animals find effects aversive

Tolerance

• Occurs rapidly (1-3 days in humans for full tolerance)

  • 5-HT receptors are down-regulated.

• Cross-tolerance occurs for most indolamine hallucinogens

• Sensitivity returns ~7 days after cessation.

Withdrawal

never used with enough frequency to develop