Transcript Slide 1

Psychedelics (including
dissociative anesthetics, e.g.
Ketamine) mood, and depression
Albert Hoffman
(1906-2008)
In 1943, invented
LSD-25 and took
the first acid trip.
• Albert Hoffman is a different guy from
Abbie Hoffman (1936-1989)—social
activist and member of “The Chicago
Seven” who helped disrupt the Democratic
National Convention in 1968.
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That first trip
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The Guardian, Thursday 1 May 2008
Article history
On April 16 1943, Hofmann administered to himself the first experimental
dose of his creation LSD-25. He recorded what happened on that now
legendary "bicycle day" in his book, LSD - My Problem Child:
"I had to struggle to speak intelligibly. I asked my laboratory assistant, who
was informed of the self-experiment, to escort me home. We went by
bicycle, no automobile being available because of wartime restrictions on
their use.
"On the way home, my condition began to assume threatening forms.
Everything in my field of vision wavered and was distorted as if seen in a
curved mirror.
'I also had the sensation of being unable to move from the spot.
Nevertheless, my assistant later told me that we had travelled very rapidly
• "We arrived at home. I had to lie down on a sofa. My surroundings
had now transformed themselves in more terrifying ways. Everything
in the room spun around, and the familiar objects and pieces of
furniture assumed grotesque, threatening forms ... The lady next
door, whom I scarcely recognised, brought me milk.
• "She was no longer Mrs R, but rather a malevolent, insidious witch
with a coloured mask ... I was taken to another world, another place,
another time. My body seemed to be without sensation, lifeless,
strange. Was I dying?
• "Slowly I came back from a weird, unfamiliar world to reassuring
everyday reality. The horror softened and gave way to a feeling of
good fortune and gratitude ... I could begin to enjoy the
unprecedented colours and plays of shapes that persisted behind
my closed eyes. Kaleidoscopic, fantastic images surged in on me,
alternating, variegated, opening and then closing themselves in
circles and spirals, exploding in coloured fountains."
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5D-ASC The Altered States of Consciousness rating scale 5DASC
(Dittrich, 1998; Dittrich et al., 1999) consists of 94 items
that are visual-analogue scales of 10 cm length. These items
measure alterations in mood, perception, experience of self in relation
to environment, and thought disorder. Scores of each item
range between zero (‘No, not more than usually’) and ten (‘Yes,
much more than usually’). The ASC items are grouped into five
main factors comprising several items. (1) ‘oceanic boundlessness’
(OB) measures derealization and depersonalization accompanied
by changes in affect ranging from heightened mood to
euphoria and/or exaltation as well as alterations in the sense of
time. The corresponding item clusters are ‘positive derealization’,
‘positive depersonalization’, ‘altered time sense’, ‘positive mood’,
and ‘mania-like experience’. (2) ‘anxious ego dissolution’ (AED)
measures ego disintegration associated with loss of self-control,
thought disorder, arousal, and anxiety. The item clusters are
‘anxious derealization’, ‘thought disorder’, ‘delusion’, ‘fear of loss
of thought control’, and ‘fear of loss of body control’. (3) ‘visionary
restructuralization’ (VR) includes the item clusters ‘elementary
hallucinations’, ‘visual (pseudo-) hallucinations’,
‘synesthesia’, ‘changed meaning of percepts’, ‘facilitated recollection’,
and ‘facilitated imagination’. (4) ‘auditory alterations’ (AA)
refers to acoustic hallucinations and distortions in auditory experiences
and (5) the dimension ‘reduction of vigilance’ (RV) relates
to states of drowsiness, reduced alertness, and related impairment
of cognitive function.
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“Quantifying altered states of consciousness was problematic in the early
years of hallucinogen research. Today, however, there are validated
instruments for assessing various aspects of consciousness. According to
Dittrich, hallucinogen-induced altered states of consciousness can be
reliably measured by the five-dimensional altered states of consciousness
(5DASC) rating scale. This scale comprises five primary dimensions and
their respective subdimensions (see the figure). The primary dimensions are
‘oceanic boundlessness’ (shown by orange boxes), referring to positively
experienced loss of ego boundaries that are associated with changes in the
sense of time and emotions – ranging from heightened mood to sublime
happiness and feelings of unity with the environment; ‘anxious egodisintegration’ (shown by purple boxes), including thought disorder and loss
of self-control; ‘visionary restructuralization’ (shown by blue boxes), referring
to perceptual alterations (such as visual illusions and hallucinations), and
altered meaning of percepts; acoustic alterations (not shown), including
hypersensitivity to sound and auditory hallucinations; and altered vigilance
(not shown).”
Magic
Mushrooms
• Some of these states of mind, such as
“boundlessness,” are directly linked to increased
neural activity in fMRI studies. They conclude:
• “The clinical findings and current understanding
of the mechanisms of action of classical
hallucinogens and dissociative anaesthetics
converge on the idea that psychedelics might be
useful in the treatment of major depression,
anxiety disorders and OCD.”
• Recently ketamine was shown to activate
the mTOR (mammalian target of
rapamycin) pathway
mTOR Pathway
The mTOR pathway involves the regulation of a protein kinase variously
known as: FKBP12-rapamycin-associated protein (FRAP); mammalian target
of rapamycin (mTOR) or rapamycin and FKBP12 target 1 (RAFT1) and its
downstream effectors. This kinase is a component of two functional
complexes; TORC1 and TORC2. TORC1 is the rapamycin-sensitive mTOR
complex responsible for regulation of protein translation initiation and
efficiency. TORC1 contains; mTOR, the kinase; raptor (KOG1), a scaffold
protein that mediates the association of mTOR with its substrates; LST8; and
Tco89.
TORC1 is sensitive to nutrients, especially amino acids such as leucine. This
sensitivity involves the small GTPase Ras homologue, Rheb. TORC1 is
activated by phosphatidic acid (PA) that results from the induction of
phospholipase D by mechanical stimuli. TORC1 is activated by growth factor
receptors through the phosphatidylinositol-3-kinase (PI3K); protein kinase D1
(PDK1); protein kinase B (Akt/PKB) pathway.
Activated mTOR (TORC1) phosphorylates protein
phosphatase 2A (PP2A), p70S6K (S6K1) and eIF4E-BP
(PHAS-1). Phosphorylation of PP2A prevents the
dephosphorylation of p70S6K and eIF4E-BP. The
phosphorylation of eIF4E-BP releases eIF4E which can
then participate in the formation of the protein translation
complex involving capped mRNAs. Phosphorylated
p70S6K can phosphorylate the ribosomal S6 subunit
which enhances the translation of 5'-terminal
oligopyrimidine (TOP)-mRNAs. Enhanced translation of
TOP-mRNAs leads to increased synthesis of proteins
required for protein synthetic machinery. The combined
effect of increased translation initiation and increased
ribosomal and other translational proteins leads to
enhanced protein synthesis and cell growth.
Ketamine caused rapid and transient activation of
the mTOR pathway
Phosphorylated eukaryotic initiation factor 4E
binding protein1 (4E-BP1)
Phosphorylated mTOR
Phosphorylated p70S6 kinase
Dose-dependent activation of mTOR pathway by
ketamine
Blockage of AMPA recptors blocks ketamine
activation of mTOR, extracellular regulated kinase (ERK),
and a serine/threonine specific kinase (AKT)
Inhibitors of either ERK or AKT
blocked ketamine activation of mTOR
Ketamine enhanced synaptic proteins via mTOR
pathway
Ketamine enhanced synaptic spines in the
prefrontal cortex 24 hrs after treatment
Ketamine enhanced EPSCs via mTOR
Hypocretin
Rapamycin blocked ketamine
antidepressant effects on
behavioral tests
NR2b antagonist Ro 25-6981 mimics ketamine
Coherence of Antidepressants