Hallucinogenic Drugs Drugs that create unusual perceptual and cognitive distortions

1. Hallucinogenic Drugs • Drugs that create unusual perceptual and cognitive distortions • Many different names • Psychotomimetic (psychosis mimicking) • not used these days • Drugs no longer considered a model for psychosis • Psychedelic (mind opening) • Sometimes the term used by those that use the drug class • Hallucinogenic (hallucination producing) • Modern pharmacological literature uses this term

2. Mescaline • Obtained from the peyote cactus plant • Dried crown of the plant is know as a mescal button, or peyote button. • Buttons can be chewed raw or cooked and then eaten • It is also possible to extract the mescaline from the plant and create a relatively pure powder

3. Archeological evidence suggests that natives of Southwestern United States and Northern Mexico Have used for thousands of years • Native Americans used peyote for religious and healing rituals • Aldous Huxley (Brave New World) • Used mescaline and advocated use of hallucinogens • Some consider his writings about the experiences of hallucinogens to have spawned the rise of their popularity in the 1960s • “The Doors of Perception” • “Heaven and Hell” • Mescaline is not as readily available in present times as other hallucinogens

4. Psilocybin, DMT, and 5-MeO-DMT • “Shrooms” or “Magic Mushrooms” • Numerous species of mushrooms have hallucinogenic properties • Psilocybe mushrooms  • Depending on the species, users take about 1-5 g of dried mushrooms to obtain desired effects • Can be consumed raw, boiled in water to make tea, or cooked with other foods • Tends to be bitter alone

5. The major ingredient of mushrooms are psilocybin and the related compound psilocin • Psilocin is the actual psychoactive agent • Psilocybin is converted by enzymatic action to psilocin after ingestion • Use of hallucinogenic mushrooms probably goes as far back as peyote use • Algerian painting dated to at least 3500 B.C. • Shaman? • Notice mushrooms sprouting from entire body and held in hands

6. The Spaniards tried to suppress the use of mushrooms when they conquered the Aztecs in the early 1500s • They were not completely successful • The existence of hallucinogenic mushrooms was largely ignored until the 1950s and 60s • Timothy Leary lecturer at Harvard ate magic mushrooms while visiting Mexico in 1959 • Formed the Harvard Psychedelic Drug Research Program • Purpose was “to teach individuals how to self-administer psychoactive drugs in order to free their psyches without reliance upon doctors or institutions” • Gave psilocybin to students and faculty • Also experimented with LSD • Dismissed from Harvard in 1963 • Became leader in psychedelic movement

7. DMT and 5-MeO-DMT • DMT and 5-MeO-DMT are substances found in several plants indigenous to South America • Native tribes make hallucinogenic snuffs from these plants • DMT in this country is usually sold in powdered form and taken by smoking • Synthetic analogs have been gaining popularity • Α-methyltryptramine (AMT) • 5-methoxy-diisopropyltryptamine • Foxy Methoxy or Foxy

8. LSD • LSD is a synthetic compound • Its structure is based on a family of fungal alkaloids • Alkaloids are chemical compounds containing nitrogen that have psychopharmacological effects • often found in plants and fungi

9. LSD first synthesized in 1938 • Albert Hofmann • Worked for a pharmaceutical company in Switzerland (Sandoz) • Studying ergot • a substance produced by a parasitic fungus that can infest rye and wheat • Ergot is extremely toxic to humans • A core structure of the alkaloids contained in ergot is lysergic acid • Hofmann combined lysergic acid with other compounds in an attempt to generate drugs to stimulate the circulatory system

10. LSD-25 (LSD) • The 25th compound synthesized was d-lysergic acid diethylamide • LSD-25 • Hoffman accidentally ingested some and had strange sensations • Later he took a small amount on purpose • Had powerful effects • Sandoz marketed the drug in 1947 • Delysid • To help neurotic patients uncover repressed thoughts and feelings

11. In the 50s and 60s there were a lot of studies published on the effects of LSD • The fact that LSD altered serotonergic activity led many researchers to consider this a powerful tool to understand human mental activity and behavior • Some considered the drug psychotomimetic • Perhaps could be a model for a schizophrenia • Replaced now by PCP and Ketamine • Some considered LSD to be an aid to psychotherapy • Psycholytic therapy (Europe) • Psychic loosening or opening • Release repressed memories and enhance communication with the therapist • Psychedelic therapy (US, Canada, Britain) • Give LSD to patient to help them gain insight through a drug-induced spiritual experience

12. US government explored the possibilities of LSD as a psychological weapon • MK-ULTRA (CIA program) • Designed to investigate LSD as a mind control agent • At one point they gave LSD to unsuspecting members of the public to observe behavioral reactions. • http://soundmedicine.iu.edu/segment.php4?seg=1644 • Check out the above link for a segment from NPRs Sound Medicine that discusses MK-ULTRA

13. As you know LSD was extremely popular in the hippie culture of the 1960s • There was a backlash against its use • Federal laws in 1965 restricted new research on LSD • Sandoz stopped distributing LSD for research purposes • Recreational use of LSD was banned in 1967 • There has been a resurgence in the interest in LSD research recently

14. LSD is usually taken orally • A single dose of LSD in crystalline form is barely visible to the naked eye • Larger amounts of LSD are dissolved in water and then droplets are applied to a sheet of paper and dried (a “blotter”) • Individual squares of the blotter are sold as a single dose “tabs”

15. Potency and time course of action of Hallucinogenic Drugs • The potency of hallucinogenic drugs vary • Most are taken orally, but as mentioned earlier DMT is usually smoked • For the drugs taken orally onset of effects usually takes 30-90 minutes • The trip can take 6-12 hours • Psilocybin maybe less • The effects of smoked DMT are felt within seconds. Peak effects occur within 5-20 minutes • Effects are over in an hour or less • “businessman’s trip

16. Psychological and physiological response to hallucinogenics • Similar across different forms • Text focuses on LSD • Four phases of the “trip” • Onset - 30 minutes to an hour after ingestion • Visual effects • Intensification of colors • Appearance of geometric patterns and strange objects can be seen with eyes closed • Plateau phase – next 2 hours or so • Sense of time begins to slow • Visual effects become more intense

17. Peak phase – about 3 hours into trip; lasts another 2 or 3 hours • May feel like in another world in which time has been suspended • Continuous stream of bizarre distorted images • Can be beautiful, or menacing • May experience synesthesia • Crossing over of senses – colors heard • Come down phase – 2 more hours or so • Most effects are gone by the end • User may not feel completely normal until the next day

18. hallucinogens can produce other psychological effects in addition to the phases of sensory-perceptual effects above • Emotional shifts • Euphoria • Anxiety • Fear • Feelings of depersonalization • Being outside oneself • Disruption of logical thought

19. Sometimes the LSD experience is viewed as mystical or spiritually enlightening • Good trip • Sometimes it can be disturbing and frightening • Bad trip • Good trip or bad trip may depend in part on • The dose • Individuals personality • Expectations • Previous experience • Social setting • Can’t really predict the outcome of an LSD trip in advance

20. Physiological response to hallucinogens • LSD effects reflect activation of the sympathetic response • Pupil dilation • Increased • Heart rate • Blood pressure • Body temperature • Can cause • Dizziness • Nausea • Vomiting • These effects are more likely with peyote and psilocybin

21. Indoleamine hallucinogens • Most hallucinogens have either a serotonin-like or a catecholamine-like structure • Serotonin-like or indolamine hallucinogens • LSD, Psilocybin, psilocyn, DMT, 5-MeO-DMT, synthetic tryptamines

22. Phenethylamine hallucinogens • Catecholamine-like hallucinogens • Notice their similarity to Norepinephrine • of course they are also structurally similar to DA • Remember Amphetamine chapter • Mescaline is the catecholamine-like hallucinogen that we have discussed • but there are also forms of amphetamines that have hallucinogenic properties • DOM • TMA • Together these drugs are known as phenethylamine hallucinogens

23. Hallucinogens are 5-HT2 receptor agonists • How hallucinogens cause dramatic cognitive and perceptual effects is not well understood • Evidence for serotonergic effects • LSD binds with high affinity to multiple serotonergic receptor subtypes • 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT6, 5-HT7

24. If we compare the indolamine and phenethylamine hallucinogen families we find that both bind to only a couple of serotonin receptor subtypes • 5-HT2A and 5-HT2C • This suggests those receptor subtypes may play a key role

25. There is not a lot of human experimental work on the hallucinogens • Here is 1 nice study • Vollenweider et al. (1998) studied psilocybin. • Found that visual illusions and hallucinations produced by these drugs were blocked by antagonists of the 5-HT2A receptor. • Ketanserin • Risperidone • Also blocks D2 receptors • Note in next graph that haloperidol (another D2 antagonist) did not block these effects • Ruling out D2 effects

26. 14.7 Blockade of psilocybin-induced visual illusions and hallucinations

27. Since there is not a lot of human work, animal studies are very important. • Drug discrimination studies are quite useful here • Train to discriminate LSD from saline injection • LSD lever • Saline lever

28. Then the animals were tested with various doses of particular 5-HT2A receptor antagonists • Notice all 3 antagonists decreased responding to The LSD lever. • Switched to saline lever • Implies these antagonists blocked the subjective effects of LSD • Drugs that have higher affinity for 5-HT2A do a better job of blocking these effects

29. Tolerance • Most hallucinogenic drugs cause rapid tolerance with repeated use • Humans taking LSD for 4 days showed nearly complete tolerance by day 4 • Likely the result of down regulation of 5-HT2A receptors • A 2005 study with mice showed down regulation of 5-HT2A receptors after repeated LSD exposure • Takes 3 or 4 days for tolerance to go away

30. Neural Mechanisms of hallucinations • One theory is that the locus coeruleus plays an important role • Remember- dense cluster of NE neurons in the pons • Receives information from all the major sensory systems and sends that information to all areas of the cortex.

31. Neural Mechanisms of hallucinations • Aghajanian et al found that LSD and mescaline decreased spontaneous firing of neurons in the rat LC • However, they also found that the LC cells were more easily excited by sensory information • Put together, these effects make the LC far more sensitive to sensory input. • Baseline is lowered • Responsivity increased

32. Neural Mechanisms of hallucinations • Perhaps the increased sensitivity of the LC is the mechanism of perceptual distortion and hallucination following ingestion of LSD • Studies using fMRI with shizophrenic patients experiencing hallucinations show increased activity in cortical regions that normally code that sense • Visual – occipital • Auditory – temporal

33. Other researchers posit that areas such as the prefrontal cortex, striatum, and thalamus (fronto sub-cortical circuits) might serve as a gating mechanism for sensory information. • The idea is that the hallucinogens may open the gate, thus, flooding the cortex with information • These researchers believe that this might also explain the cognitive disturbances common with hallucinogenic drugs as well

34. Addiction? • Hallucinogens are not considered addictive • People usually do not binge • Do not cause cravings • Do not cause physical dependence or withdrawal • Do not support self-administration in animals • Doesn’t seem possible to overdose • No documented human deaths • Eight individuals have been documented as taking massive doses • Snorted crystaline form (mistaken for cocaine) • Remember a barely visual grain is psychoactive • Comatose state • Vomiting • Hyperthermia • Light gastric bleeding • Respiratory problems • They all survived without residual effects

35. Despite lack of addictive potential and lack of overdose issues, the use of LSD can have consequences • Bad trips • Flashbacks • Hallucinogen persisting perception disorder (HPPD) • Long lasting flashbacks causing major impairment or disturbance • Few documented cases • Psychotic breakdown? • Prolonged psychotic episodes following LSD use invariably involve individuals • Already diagnosed with a psychiatric disorder • That exhibited prepsychotic symptoms prior to taking the drug

36. PCP and Ketamine • PCP and ketamine were both initially developed as anesthetics. • PCP • 1-(1-phenylcyclohexyl) piperdine • AKA phencylclidine • Developed in the 1950s as an anesthetic • Produced unusual anesthesia • No responsiveness to nociceptive stimuli • But, not typical relaxed unconsciousness (like seen with barbiturates). • Trance-like or catatonic-like state • Vacant expression • Fixed staring eyes • Maintenance of muscle tone • Not uncommon to have rigidity or waxy flexibility like seen in catatonic schizophrenics

37. PCP was initially considered a promosing anesthetic • Did not produce respiratory depression like seen with barbiturates • High therapeutic index • But some patients had problematic reactions • Agitation – rather than quieting • Postoperative effects ranging from blurred vision, dizziness, and mild disorientation…to hallucinations, severe agitation, and violence. • Clinical use of PCP was terminated in 1965

38. PCP became a more popular illicit drug in 1967. • AKA – “Angel dust”; “hog” • Never was as popular as marijuana or even cocaine or heroin

39. Ketamine was developed as a safer alternative to PCP • First synthesized in 1962 • CI-581 ---- later renamed ketamine • Less potent and shorter acting than PCP • Valuable anesthetic particularly for children • Also animals • Currently available with prescription • Ketaset • Ketalar • Vetalar

40. Route of administration • PCP is generally obtained in powder form • Can be ingested by any common route • Orally • Intranasally • IV • IM • Smoked • Applied as a liquid to a cigarette

41. Route of administration • Ketamine is marketed as an injectable liquid • Street sellers commonly evaporate the liquid to yield a powder. • Can be snorted • Compressed into a pill • AKA: “K,” “special K,” and “cat valium.”

42. Studies form the 50s and 60s found that subanesthetic doses of PCP produce • Feeling of being detached from body • Dissociation • Sensations of vertigo or floating, numbness. • Dream like state • Affective changes • Drowsiness, apathy, negativism • Sometimes hostility toward experimenters • Sometimes euphoria • Cognitive disorganization • Difficulty maintaining concentration • Deficiency in abstract thinking • Halting speech

43. Subjective effects of ketamine • Low doses of ketamine produce reactions similar to what occurs with PCP • High doses can produce dissociative anesthesia • Lose mental contact with environment for 10 minutes or so • Eyes open • Maintain muscle tone • Some have described the dissocative state as a “near-death” experience • Sometimes called “K-hole” • Sometimes spiritually uplifting • Sometimes terrifying

45. Reinforcement • PCP and ketamine support self-administration in several species • Rhesus monkeys self-administered PCP at levels to maintain continuous intoxication • Could not stand up. • Lying or sitting on floor near lever • PCP and ketamine activate midbrain DA cell firing. • Stimulate DA release particularly in prefrontal cortex • Rats will self-administer PCP directly in the NA • This affect may be driven by inhibition of glutamatergic input to the NA rather affecting the DA system

46. PCP and Ketamine’s action at the NA • Cocaine and amphetamine are indirect DA agonists • DA normally inhibits NA • Slowing NA activity = reinforcement • PCP and ketamine are antagonists of Glutamate (at NMDA receptor) • Glutamate normally excites NA • Slowing NA activity = reinforcement

47. 14.12 Self-administration of PCP into the nucleus accumbens shell by rats (Part 1)

48. PCP and ketamine are noncompetitive antagonists of the NMDA receptor • NMDA is an ionotropic receptor that responds to glutamate • NMDA and ketamine block at the receptor by binding to a site different from where glutamate binds • Making them noncompetitive antagonists • Remember the binding site is inside the channel • NMDA receptors found throughout the brain including the cerebral cortex and hippocampus • This probably leads to the cognitive deficits

49. The use of ketamine seems to be increasing • Studies of ketamine use indicate that it can cause strong addiction • People also take increasing doses indicating tolerance

50. Model of schizophrenia • Acute PCP or ketamine exposure causes perceptual, cognitive, and affective responses closely resembling symptoms of schizophrenia • Can cause positive and negative symptoms • Positive • Hallucinations • Bizarre thought content • Negative • Blunted affect • Emotional withdrawal • Slowed motor response • Some of the symptoms can persist for days • Perceptual distortion • Magical ideation