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Tell me, What do you see?

Tell me, What do you see?. Image from: www.hppdonline.com. HPPD. H a l l u c i no g e n P e r s i s t i ng P e r c e p t io n Di s o r d e r. David Hill, Daryl Bulloch, Melissa Karnaze. Presentation Outline. 1. HPPD Symptoms – David 2. Physiological Changes – Melissa

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Tell me, What do you see?

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  1. Tell me,What do you see? Image from: www.hppdonline.com

  2. HPPD Hallucinogen Persisting Perception Disorder David Hill, Daryl Bulloch, Melissa Karnaze

  3. Presentation Outline 1. HPPD Symptoms – David 2. Physiological Changes – Melissa 3. Possible Causes and Treatments – Daryl 4. Concluding Remarks

  4. Disclaimer: This presentation covers the drug-induced disorder HPPD, as classified in the DSM-IV. Therefore, it does not cover possible therapeutic uses of hallucinogens, which is another topic altogether. We are not advocating the use or abstinence of hallucinogens, but merely exploring this disorder, which has a reported incidence among LSD users ranging from 15% to 80%.

  5. HPPD – What is it? • Hallucinogen Persisting Perception Disorder • Perception of visual hallucinations long after taking a hallucinogen, not better attributable to another medical or psychiatric condition • Not really “flashbacks” – it is more of a continuous distortion of perception

  6. Symptoms • Different from what are commonly thought as hallucinations – won’t see imaginary people • Instead, symptoms include: trailing of moving images, geometric hallucinations, flashes of color, halos around objects • These perceptual defects can cause great distress while mental mindset is intact • Depression is often comorbidly present

  7. Macropsia (objects appear unnaturally large) Micropsia (objects appear unnaturally small) Aeropsia (a sense of bright whiteness in the air between individuals and observed objects Imagistic phosphenes Illusions of movement Peripheral field images Intensified colors Perceptions of entire objects Color confusion Difficulty reading Static vision More acute awareness of floaters Afterimages More Symptoms

  8. Images from: http://flickr.com/groups/hppd

  9. Images from: http://flickr.com/groups/hppd

  10. Official DSM-IV Criteria • A. The re-experiencing, following cessation of use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen • B. The symptoms in Criterion A cause clinically significant distress in social, occupational, or other important areas of functioning • C. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder

  11. Early Hallucinogen Research • Serotonin has been the main focus of study of hallucinogens, due to increased serotonin levels and structural similarity • Researchers used to hypothesize that hallucinogens worked by suppressing serotonin neurons (Aghajanian) • Further research found flaws in this theory

  12. Postsynaptic Theory • Hallucinogens work at receptor sites on serotonin target neurons (Jacobs) • In particular, the 5-HT receptor has been identified as the most affected • 5-HT receptor has been found to enhance extracellular GABA levels in prefrontal cortex, which could lead to hallucinations (Lambe)

  13. Hallucinogens Resemble Serotonin This similarity allows hallucinogens to act on serotonin receptors

  14. Physiological Changes in the Visual SystemStudy: EEG coherence in post-LSD visual hallucinations(Abraham & Duffy, 2001)

  15. Previous Studies: • HPPD subjects demonstrate behavioral, psychophysical, electrophysiological evidence for abnormal visual system functioning • Neurophysiological data show evidence for above normal occipital function (shorter flash VEP latency compared to normal, LSD-naive control subjects) • There is no correlation between the number of episodes of hallucinogen exposure and the presence of flashbacks

  16. Flashbacks: • EEG study deals with one aspect that may trigger flashbacks  dark environment - heightened but isolated visual system functioning amplifies minor aspects of visual stimulation - facilitates production of illusions and hallucinations

  17. Flashbacks: • Other flashback triggers may involve: 1. biological co-factors that combine with residual effects of hallucinogens (e.g. cannabis) 2. lasting memories from unusually distinct and powerfully emotional experiences induced under hallucinogen intoxication (Shick & Smith, 1970; Wesson & Smith, 1976; Fischer, 1977; McGee, 1984) 3. manifestations of learned, imaginative role-playing (Matefy & Krall, 1974; Matefy, 1980) 4. heightened awareness of normal visual phenomena (Horowitz, 1969; Wesson & Smith, 1976) • Flashbacks may be perceptual, somatic, and/or emotional (study focuses on perceptual)

  18. Subjects • People with psychosis and other brain disorders, or a history of spontaneous hallucinations prior to LSD use were excluded • Drug screens, all subjects passed • 33 control subjects • male/female ratio 4:7

  19. HPPD Subjects • 38 HPPD subjects • male/female ratio 17:2 • First mean LSD use 18.1+/- 16.0 years • Lifetime use median of 16 times (1-450) • Mean of 9.7 years with persistent visual hallucinations • At time of study, still daily visual hallucinations all used LSD prior to HPPD onset • Majority reported intensity of hallucinations in dark environment

  20. Methods • Used quantitative EEG (qEEG) • Calculated measures of local and medium distance EEG spectral coherence • Tested for eyes-open and eyes-closed states

  21. Results: Coherence • HPPD subjects, compared to control group: • eyes-open  reduction of coherence • eyes-closed  increase of coherence in broad occipital region (R more than L) and within broad region and midline parietal and mid-temporal regions  increase over many frequencies (slightly more marked in theta range)  reduced coherence of occipital region to more anterior regions

  22. What these results mean… • In eyes-open: • widespread cortical inhibition • In eyes-closed: • localized and isolated cortical disinhibition • occipital visual system functioning more in isolation than normal • occipital visual system more internally synchronized and less influenced by other regions • This may be a pattern to facilitate hallucinations

  23. Further Results • Alpha peak frequency increased • Shortened latency of P2 component of visual evoked potential (VEP)

  24. How exactly does HPPD work? • Mechanism is unknown! (well, that was easy) • May be a “disinhibition of visual processing related to a loss of serotonin receptors on inhibitory interneurons” (Abraham et al., 1996) • Probably association with GABA receptors- needs more studying, since such a broad receptor-interaction field • How to study HPPD- tons of information on biochemical and electrical reactions to drugs which are associated with HPPD

  25. Causes of HPPD- Beyond LSD? • LSD is the most prominent drug noted in cases of HPPD, however MDMA and mescaline may also cause symptoms as seen by Abraham • Drugs that cause HPPD may not yield as much information as drugs used to treat the symptoms • Class of drugs used to treat HPPD symptoms: Benzodiazepines

  26. Benzodiazepines, you say? • Active at GABA-A receptors- acutely block/reduce symptoms of HPPD • Benzodiazepines include diazepam (valium), chlordiazepoxide (Librium), clorazepate (Tranxene), prazepam (as Prazepam), and medazepam (as Medazepam)- metabolized into long-lasting primary metabolite nordazepam, which is also available directly under the brand names Calmday, Stilny, Madar, and Vegesan

  27. Klonopin, King of Benzodiazepines • Clonazepam is currently the most prescribed drug for reducing the symptoms of HPPD • Has longest half-life in the body out of drugs in its class • Not a cure, and not without a heavy price- like many of its class, is habit forming, withdrawal follows if usage stops • Normal dose is 0.5 mg 1-3 times per day

  28. What do they look like, Dad?

  29. Why did you show us that last slide, lowly chemist? • Structural analysis studies between receptors and modified benzodiazepines may elucidate mechanism of HPPD • 7 different conformationally mobile binding points • Probable reason for different effects over the class of diazepines

  30. You don’t need drugs to have a good time- other treatments • Meditation and relaxation techniques- let your mind drift to a far away fluffy cloud • Wear sunglasses all the time (Blues Brothers) • Avoid stimulants (such as caffeine) and anti-psychotic drugs (these can aggravate visual disturbances) • Don’t dwell on symptoms in general, but especially don’t stare at a blank wall

  31. What should I remember about all of this, Daryl? • No one’s really sure how HPPD works- needs more time and attention to elucidate mechanism • There’s no panacea- most drugs do not prevent all visual disturbances and are habit-forming • Good news- don’t need medicine to stop it!

  32. David’s Summary… • HPPD, in the most severe cases, continuously distorts the subjects perception • This alteration of perception can cause the individual great distress if not treated • Hallucinogens act on the 5-HT serotonin receptor, which then affects GABA levels in the prefrontal cortex – this is believed to be the source of hallucinations

  33. Melissa’s Summary… • HPPD may involve psychological or emotional triggers, but there is still a physiological basis according to studies done. • If we use the definition of a hallucinogen as being any agent that causes alterations in perception, cognition, and mood as its primary psychobiological actions in the presence of an otherwise clear sensorium, then HPPD is basically a case where a person has the internal mechanisms to replicate the effects of a hallucinogen.

  34. Continued… • Some HPPD subjects experience their symptoms as part of their everyday conscious experience. Their baseline consciousness would be considered an altered state of conscious to those without HPPD, so consciousness is unique to the physical and psychological makeup that is responsible for how one perceives and constructs reality. • What makes someone susceptible to HPPD? Is it brain structure alone? How much does AMY and other structures involved with emotion and affect play a role in a person’s susceptibility to recurring flashbacks?

  35. References • Abraham, HD, Aldridge, AM, & Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology, 14(4), 285-98. • Abraham, HD, & Duffy, FH. (2001). EEG coherence in post-LSD visual hallucinations. Psychiatry research, 107(3), 151-63. • Aghajanian, GK, Foote, WE, & Sheard, MH. (1968). Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe. Science, 161(842), 706-8. • Aldurra, G. (2001). Improvement of Hallucinogen-Induced Persistent Perception Disorder by Treatment With a Combination of Fluoxetine and Olanzapine: Case Report. Journal of clinical psychopharmacology, 21(3), 343. • Codding, PW, & Muir, AK. (1985). Molecular structure of Ro15-1788 and a model for the binding of benzodiazepine receptor ligands. Structural identification of common features in antagonists. Molecular pharmacology, 28(2), 178-84. • Halpern, JH, & Pope HG, J. (2003). Hallucinogen persisting perception disorder: what do we know after 50 years?. Drug and alcohol dependence, 69(2), 109-19. • Lambe, EK, & Aghajanian, GK. (2005). Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors. Neuropsychopharmacology In press • <hppdonline.com>

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