Hallucinogens

1. Hallucinogens • produce unusual perceptual and cognitive distortions, which some people find novel, stimulating, or even spiritually uplifting. • They produce these effects without producing a state of toxic delirium. • Many are synthesized by plants or are based on plant-derived compounds. • The different hallucinogens vary widely in potency, ranging from LSD as the most potent to mescaline as the least. • Psychedelic effects generally begin 30 to 90 minutes after ingestion. An LSD “trip” can last 6 to 12 hours. • A hallucinogenic trip may be experienced as mystical and spiritually enlightening (a “good trip”) or disturbing and frightening (a “bad trip”). • Whether the user has a good or a bad trip depends on the dose and individual and social factors. • May have been important in the development of spiritual and religious traditions and folklore in many societies

2. Terminology • Phantastica • Drugs that create a world of fantasy • Psychedelic • “Mind-viewing” • Implies a beneficial, visionary type of effect • Psychotomimetic • “Mimicking psychosis” • Produces hallucinations and altered reality, a state similar to psychosis • Entheogen • Substances that create spiritual or religious experiences • Entactogen • Substances that enhance feelings of empathy • Hallucinogens • A drug that produces profound alterations in perception, including unusual visual sensations and often changes in the perception of one’s own body • Animism • Objects attain certain characteristics because of spirits • If a plant contains a spirit, then eating the plant transfers this spirit to the person who consumes it

3. Table 15.1

4. Two Groups of Phantastica • Indole hallucinogens • Drugs that have the same basic indole structure of the neurotransmitter serotonin • Examples: LSD, psilocybin, DMT • Catechol hallucinogens • Drugs that have the same basic catechol structure of the neurotransmitters norepinephrine and dopamine • Examples: mescaline, MDMA (Ecstasy or molly)

5. LSD Lysergic acid diethylamide (LSD) is a synthetic compound based on fungal alkaloids.

6. LSD: Discovery • 1938: • Synthesized by Dr. Albert Hofmann of Sandoz Laboratories in Switzerland • First synthesized in 1938 from ergot, a parasitic fungus on rye. Ergot is very toxic. It produces powerful contractions of the uterus that can help trigger labor and reduce post-birth uterine hemorrhage. • 1943: • Dr. Hofmann took a large dose and described its hallucinogenic effects • Dose was 5–8 times the normal effective dose • Potency of the drug attracted attention • Comparable effects from mescaline would require 4,000 times the dose

7. LSD: Early Research • 1950s–1970s: a tremendous amount of LSD research • Attempting to develop a model of psychosis • Widely used as an adjunct to psychotherapy • 1970s: Funding institutes stopped supporting human research • Most research since 1975 has been conducted with animals in an effort to understand the mechanism at the neural level • Secret Army/CIA Research • Poorly done and violated many ethical codes • U.S. required to pay reparations to research subjects • The CIA even investigated LSD as a potential psychological weapon. • LSD use exploded with the hippie culture in the 1960s, but inevitably backlash occurred amid growing anecdotal accounts and scientific reports of LSD-related problems. • A 1965 law restricted research on LSD; recreational use was banned in 1967.

8. Timothy Leary Conducted research on LSD and psilocybin at Harvard Research was scientifically unsound and unethical Started a religion (League of Spiritual Discovery) with LSD as a sacrament Recreational use peaked in late 1960s Use declined due to anecdotal reports of problems associated with: “bad trips” prolonged psychotic reactions worries about possible chromosome damage self-injurious behavior “flashbacks” Recreational Use

9. LSD Pharmacology • One of the most potent psychoactive drugs • No known human overdose deaths • LD50 is about 400 times the behaviorally effective dose • LSD is usually taken orally • Absorbed rapidly through the gastrointestinal tract • Mechanism of action • Best evidence indicates that LSD acts by stimulating serotonin-2A receptors • Hallucinogens also have various physiological effects. • For LSD, these responses reflect activation of the sympathetic nervous system and include pupil dilation and small increases in heart rate, blood pressure, and body temperature. • Dizziness, nausea, and vomiting are more likely after consumption of peyote or mushrooms.

10. LSD Pharmacology • Metabolism • Metabolized by the liver • Half-life is about three hours • Tolerance develops rapidly • Within three to four days of daily doses • Recovery from tolerance is also rapid • Cross-tolerance occurs among LSD, mescaline, and psilocybin • Physical dependence to LSD or other hallucinogens has not been demonstrated • LSD binds with high affinity to at least eight different serotonergic receptor subtypes. • Their common receptor subtypes are 5-HT2A and 5-HT2C. This suggests that they may play a central role in producing hallucinations. • In humans, activation of 5-HT2A receptors seems to be the critical mechanism of action. • In one study, hallucinations were blocked by 5-HT2A receptor antagonists ketanserin and risperidone, but not by haloperidol, an antagonist at D2 but not 5-HT2A receptors. • Increased excitation of prefrontal cortical pyramidal neurons appears to be a critical feature.

11. Pharmacology of Hallucinogenic Drugs 1. Activation of 5-HT2A receptors enhances glutamate-excitation of pyramidal neurons in layer V of the prefrontal cortex. The glutamate is released from thalamocortical afferents, interfering with thalamic filtering of sensory information, and resulting in overload at the cortical level. 2. Pyramidal cells in cortical layer V are directly stimulated by activation of 5-HT2A receptors and secondarily stimulated by glutamate released from other pyramidal cells in the deep cortical layers that project to layer V. This activation disrupts the normal functioning of glutamatergic networks in the prefrontal cortex.

12. Psychological and Behavioral Effects • Modification of perception • Visual images: Users see shapes and patterns, usually with intense colors and brightness • Users report an altered sense of time, changes in the perception of their own bodies, and alterations of auditory input • Synesthesia (“mixing of senses”) • Example: sounds may appear as visual images • Enhanced emotionality • Images may be perceived as beautiful and awe-inspiring or as intensely sad or frightening

13. Time Course of Effects • Typically last six to nine hours • First 20 min: Autonomic responses occur • Next 30–40 min: Alterations in mood, perception, and sensation begin • Within 1 hour: Full intoxication occurs • Loss of self-awareness and loss of control of behavior may occur

14. Adverse Reactions • Impossible to determine true incidence of adverse reactions • For example, some bad reactions may be due to drug impurities • Flashbacks • DSM-5: Hallucinogen Persisting Perception Disorder • Recurrence of symptoms weeks or months after an individual has taken LSD • Relative rare in occurrence • Panic reactions • Relatively more common in occurrence

15. Mescaline (Peyote) Peyote Cactus Mescaline is found in several species of cactus, such as peyote (Lophophorwilliamsii). The crown of this small cactus is cut off and dried to form a mescal button or peyote button. Peyote buttons can be eaten raw or cooked, or the mescaline can be extracted and consumed as a powder. Peyote cactus is native to the US southwest and northern Mexico. Peyote has been used for thousands of years by Native Americans for religious and healing rituals. Aldous Huxley tried mescaline in 1953 and described his experienced in two books that helped spawn a rise in hallucinogenic drug use in the 1960s.

16. Psilocybin (Mushrooms) Mushrooms in several different genera produce alkaloids with hallucinogenic properties and are found in many places around the world. The dried mushrooms may be eaten raw or cooked or made into tea. The main compounds are psilocybin and related psilocin. After ingestion, psilocybin is converted to psilocin, the actual psychoactive agent. Hallucinogenic mushroom use also goes back thousands of years in several parts of the world. The Spanish suppressed mushroom eating in the conquered Aztecs but could not wipe it out completely. In 1955, Gordon Wasson participated in a mushroom-eating ritual in Oaxaca, Mexico, led by a Mazatec shaman. His experiences were described in a Life magazine article in 1957. Timothy Leary and Richard Alpert at Harvard experimented with psilocybin and LSD and helped to popularized these drugs.

17. Ketamine Ketamine was developed as a safer alternative to PCP, being less potent and shorter-acting. It is a valuable anesthetic for certain procedures, particularly in children, and is also used by veterinarians. It is currently marketed as a prescription medication under the trade names Ketalar, Ketaset, and Vetalar. Illicit ketamine usually comes from diversion or theft of medical or veterinary material and is sold on the street as “K,”“special K,” or “cat Valium.”

18. Table 15.3

19. Pharmacology of Ketamine Doses in the anesthetic range produce a dissociated state with many subjective effects reported. This state is called the “K-hole,” and can be either spiritually uplifting or terrifying. PCP and ketamine have been named dissociative anesthetics. PCP and ketamine are noncompetitive antagonists at NMDA receptors—ionotropic receptors for the excitatory neurotransmitter glutamate. The PCP/ketamine binding site is inside the receptor’s ion channel, separate from the site at which glutamate or NMDA binds. Use of ketamine has been growing because of the drug’s popularity within the dance scene. But abuse dates back many years, by people in the medical or veterinarian professions, and by some intellectuals who favored it as a mind-expanding drug in the tradition of LSD. Chronic use of ketamine or PCP can produce many negative effects, including: • Urological problems like bladder pain and incontinence • Deficits in memory and other cognitive functions • Gray- and white-matter abnormalities in chronic ketamine users

20. NMDA receptor properties Blockade of NMDA receptors in the cerebral cortex and hippocampus probably contributes to the cognitive deficits produced by PCP and ketamine. This may also increase presynaptic glutamate release (and thus excess glutamate transmission via non-NMDA receptors) within the cortex, a secondary result of NMDA receptor antagonism.

21. Pharmacology of Ketamine Among many changes recorded in neuron structure and function, repeated administration of high doses of ketamine caused apoptotic cell death in the developing brains of rats and monkeys. This is of some concern because ketamine is a recommended anesthetic agent for pediatric procedures. Other potential therapeutic uses for ketamine: • A single IV dose has been shown to produce rapid, though temporary, improvement in clinically depressed subjects. • It may be useful as a non-opioid analgesic agent for a variety of chronic pain conditions.

22. Amphetamine Derivatives • Large group of synthetic hallucinogens • Chemically related to amphetamines • Anecdotally, effects are similar to mescaline • But the chemical structure is close to the amphetamines • Examples • MDMA (“Ecstasy” or molly) • MDA • DOM

23. MDMA: “Ecstasy” or “molly” • Prior to 1985 • Some psychiatrists used it as a therapeutic aid • After 1985: Schedule I • Effects • Increased heart rate and blood pressure • Increased euphoria and sociability • Heightened sense of “closeness” with others • MDMA research raises concerns • In animals, selective destruction of serotonin neurons • Limited evidence of neurotoxic effects in humans

24. Ecstasy (MDMA) MDMA : 3-4 methylenedioxymethamphetamine • is related to • Mescaline • MDA • methamphetamine. • it prompts nerve cells to release a flood of serotonin. • bring about the increased awareness of • emotion • intimacy • self-confidence • The ensuing chemical low tide could explain the depression users describe when they are coming down. • damages serotonin cells • damages dopamine cells

25. Ecstasy (MDMA) Earlier animal studies had shown that repeated ecstasy use damages the serotonin brain cells, which help to regulate mood and behavior. This image shows that serotonin axons are destroyed in a squirrel monkey after a single dose of MDMA.

26. Control Users Ecstasy (MDMA) BRAIN CHANGES appear prominently in positron emission tomography (PET) scans of Ecstasy users as well as people who abstain. Drug users (right), though, have far less serotonin activity, as is indicated by the dark areas, compared to the controls (left). New studies show that this difference may contribute to permanent brain damage. Serotonin Activity

27. Ecstasy (MDMA) In the new work, Johns Hopkins University researchers working with squirrel monkeys and baboons found that two or three sequential doses of the drug—the amount typically taken by young adults at all-night "raves"—killed dopamine neurons, which are involved in controlling movement, emotional and cognitive responses and the ability to feel pleasure. Indeed, some 60 to 80 percent of the dopaminergic nerve endings in a region of the brain known as the striatum were destroyed after just one multi-dose regimen. Control MDMA Dopamine Neurons (yellow is more; green is less)

28. MDMA Induced Grey Matter Reduction (Daumann et al 2011) Compared to low exposure users Cingulate Cortex: • Medial Orbitofrontal • Dorsal Anterior

29. MDMA Induced Grey Matter Reduction (Daumann et al 2011) Compared to niave controls Cingulate Cortex: • Medial Orbitofrontal • Dorsal Anterior

30. MDMA Induced Cortical Thinning (Kish et al 2010) Cortical thinning in: • Parietal • Occipital • Temporal • Frontal • Cingulate

31. Serotonin Transporter Deficiency (Kish et al 2010) Visual Cortex Greatest 5HT Binding deficiency With MDMA Meth Users Control

32. Serotonin Transporter Binding (Kish et al 2010) Cortical Area Deficits No Subcortical Area Deficits

33. MDMA Induced Cortical Activity (Bauernfeind et al, 2011) Suggests loss Of 5-HT input to cortical and sub- cortical regions LGN Broadman Area 17/18

34. Proposed Mechanism of Action (Bauernfeind et al, 2011) Control 5-HT Neurotoxicity • Axotomy • Reduced 5-HT synthesis

35. Nigrostriatal DopaminergicAbnormalities in Ex-MDMA Users (Yen et al, 2011) Proposes damage to Dopamine transporter system Figure 1 Mean 18F-dopa uptake in the putamen of ex-ecstasy users, polydrug-using controls, and drug-naive controls. Error bars indicate SD. Significant comparison: *Ex-ecstasy users4drug-naive controls (p ¼ 0.021, corrected). • Users were abstinent for 3 yrs • Suggests long-term effect