Transcript Slide 1

Tell me,
What do you see?
Image from: www.hppdonline.com
HPPD
Hallucinogen Persisting
Perception Disorder
David Hill,
Daryl Bulloch,
Melissa Karnaze
Presentation Outline
1. HPPD Symptoms – David
2. Physiological Changes – Melissa
3. Possible Causes and Treatments
– Daryl
4. Concluding Remarks
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%.
HPPD – What is it?
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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
Symptoms
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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
More Symptoms
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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
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Peripheral field images
Intensified colors
Perceptions of entire
objects
Color confusion
Difficulty reading
Static vision
More acute awareness of
floaters
Afterimages
Images from: http://flickr.com/groups/hppd
Images from: http://flickr.com/groups/hppd
Official DSM-IV Criteria
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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
Early Hallucinogen Research
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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
Postsynaptic Theory
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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)
Hallucinogens Resemble Serotonin
This similarity allows hallucinogens
to act on serotonin receptors
Physiological Changes in the Visual System
Study: EEG coherence in post-LSD visual hallucinations
(Abraham & Duffy, 2001)
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
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
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)
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
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
Methods
• Used quantitative EEG (qEEG)
• Calculated measures of local and medium
distance EEG spectral coherence
• Tested for eyes-open and eyes-closed
states
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
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
Further Results
• Alpha peak frequency increased
• Shortened latency of P2 component of
visual evoked potential (VEP)
How exactly does HPPD work?
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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 receptorinteraction field
How to study HPPD- tons of information on
biochemical and electrical reactions to drugs which
are associated with HPPD
Causes of HPPD- Beyond LSD?
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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
Benzodiazepines, you say?
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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
Klonopin, King of
Benzodiazepines
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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
What do they look like, Dad?
O
N
X
N
O
H
N
O2N
N
X = halogen
Cl
Diazepam a.k.a. Valium
Clonazepam a.k.a. Klonopin
Why did you show us that last
slide, lowly chemist?
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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
You don’t need drugs to have a
good time- other treatments
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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 antipsychotic drugs (these can aggravate visual
disturbances)
Don’t dwell on symptoms in general, but
especially don’t stare at a blank wall
What should I remember about all
of this, Daryl?
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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!
David’s Summary…
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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
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.
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?
References
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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 NR2BNMDA Receptors. Neuropsychopharmacology In press
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