Hallucinogens/ Psychedelics

Mescaline

found in tops of peyote cacti. Dried, powder, chewed, or cooked and eaten. Inspired Aldous Huxley’s “Doors of Perception” which influenced psychedelic use in 1960s

Psilocybin

come from a few mushroom species (conocybe, copelandia, pnaeolus, psilocybe, and stropharia)—dried, eaten raw, boiled to tea or cooked in food. 1-5g to have psychedelic effects.

Psilocin

the active agent in psylocybin, which it is converted into enzymatically after ingestion

DMT

most used tryptamine—smoked or snorted for an intense 30 min trip. When taken orally, completely metabolized by MAO in liver so no effect

“Foxy” or AMT

synthetic versions of DMT—can be taken orally in pill form or crushed and snorted

Other tryptamines

-5-MeO-DMT

-Bufotenine

Ayahausca

a strong herbal tea with DMT and B-carbolines from the Banisteriopsis vine—the B-carbolines inhibit MAO and prevent metabolism of DMT in the liver, allowing it to have it’s psychedelic effects. Used by Amazonian tribes in religious ceremonies and now only legal in US for specific syncretistic Catholic/traditional religious ceremonies

LSD

lysergic acid diethylamide—synthetic compound with similar chemical structure to fungal alkaloids. Banned for recreational use in 1967, but many still use illicitly and buy as droppers or tabs to swallow. Much research done on both therapeutic applications and by CIA and US Gov on utilizing as a psychochemical weapon (1940s-70s)

NBOMes

new hallucinogens—most notable one is 25I-NBOMe which is used on blotter paper or in powdered form, placed under tongue or chewed on gum. Subject to first-pass metabolism if taken orally. Very potent, easy to overdose and toxicity can be fatal

Salvanorin A

compound of the salvia mint plant native to Mexico—leaves chewed, dried and crushed. Administered sublingually or smoked. Effects only last 15 minutes but have a unique hallucinogenic profile including:

-out of body experiences of being a foreign object

-visiting the past/childhood

-motion or pulling/twisting sensations

-depersonalized or separate form self

-in several places at once

Legal status of Salvia

not on DEA controlled substances, but is illegal to own or sell in most states

Ibogaine

from a west African shrub “tabernanthe iboga”—typically dried bark or roots are chewed or ground into powder. Primarily a stimulant producing high energy, appetite reduction and euphoria, but at high doses is a hallucinogen. Was marketed in Europe as an antidepressant “Lamberene”, and also researched as a treatment for drug addiction.

Legal status of Ibogaine

Schedule I controlled by DEA, and not FDA approved. Toxicity can cause death

Route of administration and potency

Stages of LSD trip

1) Onset—30-60 mins after ingestion, colors brighten and strange patterns or objects appear

2) Plateau—next 2 hrs, slowed sense of time and more intense visuals

3) Peak—next 2-3 hrs, feeling of otherworldliness, stream of bizzare distorted images and synsethesia

4) Come-down—2 more hours, effects dissipate

Psychological aspect of “trips”

can swing from anxiety to euphoria to illogical thought to depersonalization— a “good” trip produces a mystical or enlightening experience, a “bad” trip a frightening or disturbing one

Psychometrics to evaluate trips

1) Altered States of Consciousness rating scale (ASC)

2) Strassman’s Hallucinogen Rating scale

Indeolamines

psychedelics that have a serotonin-like structure—includes:

-LSD

-Psilocybin/ psolicin

-DMT

-5-MEO- DMT

-Ibogaine

-synthetic Tryptamines

Phenethylamines

psychedelics that have a catecholamine-like structure (especially resembling NE, and amphetamine). Includes:

-NBOMes

-Mescaline

Salvanorin A structure

unique compared to other psychedelic compounds—not indoleamine or phenethylamine

Key serotonergic receptor subtype for hallucinogens

5-HT2a receptors—specifically, those that have complexed with glutamate receptor mGluR2, which changes it’s second messenger pathway signaling to produce psychedelic effects

Reason for LSD long trip

when LSD binds to a receptor, part of receptor protein forms a “lid” clamping it in place and allowing for extended duration of action

Salvanorin A’s chemical action

binds to k-opioid receptors in the thalamus, temporal and parietal cortices, and claustrum

Ibogaine’s chemical action

it and it’s active metabolite noribogaine both act as:

-partial agonists at k-opioid receptors and m-opioid receptors

-NMDA antagonists

-5-HT and DA reuptake inhibitors

Psychedelic neural circuit

Activation 5-HT2a and mGluR2 disrupts this circuit:

Cortices—> striatum—>thalamus—> cortices

which is necessary for thalamic gating of sensory/cognitive input running from subcortical to cortical areas

fMRI and EEG discoveries

REDUCED activity within the DMN

INCREASED connectivity among sensory cortical areas, between sensory cortical areas and thalamus, and between thalamus and ventral striatum and posterior cingulate cortex (PCC)

REDUCED connectivity between association areas and thalamus

Possible therapeutic use

psychedelics are being investigated for treatment of:

-treatment-resistant depression

-anxiety disorders

-OCD

-PTSD

-SUDs

-Cancer

Microdosing

administering small doses of hallucinogens frequently—unclear if there is any benefit

Psychoplastogen

a drug that results in increased neuroplasticity and dendritic and synaptic growth, e.g., hallucinogens

Adverse reactions

psychosis, agitation, kidney damage, seizures, hypertension, tachycardia, fever, muscle breakdown—at toxic doses, NBOMes are the worst and can even lead to death

Other hallucinogen use disorder

for those that continue using despite no addictive qualities and without regard for negative life effects—disincludes PCP

Hallucinogen Persisting Perception Disorder (HPPD)

in DSM V—effects of a trip last for an extended time afterwards and will not go away—producing great distress

PCP

phencyclidine—originally synthesized as anesthetic. Has analgesic properties, but instead of sedation it produces a trance-like state with complete dissociation, muscle rigidity or flexibility, and vacant face. Adverse reactions were disorientation, hallucinations, agitation and even violence. Gained some street popularity as “angel dust” or “hog” but not much

Ketamine

invented as safer alternative to PCP—still used as anesthetic and surpassed PCP as street drug. Taken by IV (for medical), intramuscular, oral, smoked, or snorted. Less potent and shorter acting with less adverse effects

Characteristics of “dissociative anesthesia”

as shown with PCP and Ketamine, produces symptoms very similar to those of schizophrenia

PCP & ketamine action

uncompetitive antagonists of NMDA— block ion flow and remain trapped in channel even when it closes. Results in increased GLU release which relates to positive psychotic symptoms

PCP & Ketamine effects on DA

increases firing in the dorsal striatum, NAcc, and PFC—constitutes the reinforcing component

Adverse effects of chronic Ketamine use

-persisting psychosis

-memory/ cognitive deficits

-delusions

-gray and white matter abnormalities

Therapeutic uses of Ketamine

treats MDD (alongside SSRI), analgesic, possibly addiction and PTSD