lecture 5 - Psychedelic drugs Flashcards
classic Psychedelics
LSD (lysergic acid diethylamide; made from lysergic acid found in rye ergot fungus)
- Psilocybin (found in ‘magic mushrooms’)
definitions
-psychedelic
-hallucinogen
-psychotomimetic
Psychedelic = ‘mind revealing’ . A type of drug that changes a persons perception of reality
- Hallucinogen = ‘causing hallucinations’
— psychedelics can cause hallucinations; more often, they cause distortions of perception - Psychotomimetic = ‘mimicking psychosis’
— they can trigger (new) or increase (existing) psychotic effects
(hallucinations, delusions)
— these effects can persist long-term
acute subjective affects of psychedelics
-effects the person taking them will notice
altered perception - increased vividness of colours; distortions
of apparent size of objects; synaesthesia (sensory cross over - read a word and have a certain flavour associate with it) ; illusions of movement; hallucinations, ranging from simple geometric patterns to complex images of objects & people
- Subjectively pleasant effects – incl. ‘loss of self’: feelings of ‘boundlessness’, ‘undifferentiated unity’; altered sense of time &
space; often described in mystical or religious terms - Subjectively unpleasant effects – incl. ‘loss of self’: ‘anxious ego
dissolution’ – frightening feelings of ‘depersonalization’ & ‘derealization’; ideas of reference & paranoia; fear, panic & dangerous behaviour
what is the mechanism for psychedelic effect
-how do they work according to structure (what is a shared structure)
indole ring structure
mechanism for psychedelic effect
-what does the shared indole ring structure suggest
Suggests psychedelic effects involve serotonin (5-HT) receptors, but…:
– simply increasing 5-HT activity throughout the brain (e.g., with
SSRI) doesn’t produce similar effects,
– and neither does simply reducing 5-HT activity (e.g., using ATD).
does increasing / decreasing 5HT activity (by ssris) produce similar results to psychedelics
simply increasing 5-HT activity throughout the brain (e.g., with
SSRI) doesn’t produce similar effects,
– and neither does simply reducing 5-HT activity (e.g., using ATD)
how many types of 5HT receptor is there
At least 14 distinct sub-types of serotonin (5-HT) receptor
Psychedelic drugs are 5HT ______ , but only for some 5HT receptor types (and could be antagonists for others)
Psychedelic drugs are 5-HT agonists, but only for some 5-HT
receptor types (& could be antagonists at others)
-they mimic the effects of serotonin
-these drugs interreact with serotonin receptors in a selective manner
what is the main site of agonistic action for 5HT 2A receptors
-explain how the disruption of these sites could be the bases for ‘psychedelic’ experiences
5-HT 2A receptors in prefrontal cortex & thalamus are main site of
agonistic action
-PFC = high-level cognition, conceptual thinking, sense of self
– thalamus = sensory ‘relay station’, with inputs from sense organs & outputs to sensory cortex
so,,Disruption of these systems could be basis for ‘psychedelic’
experiences (disrupted sense of self, alterations in perception,
synaesthesia
neural correlates of the psychedelic state
-what does psilocybin do to cortical and sub cortical brain areas
Psilocybin (v. placebo) significantly decreased neural activity
in a number of cortical (e.g. PFC) & sub-cortical (e.g. thalamus)
brain areas.
- Intensity of subjective experience correlated significantly with
observed reductions in neural activity (more intense the more decrease of the brain activity)
imaging studies show that psychedlic drugs do what to
-brain areas
-functional connectivity
imaging studies show that psychedelic drugs:
‒ reduce neural activity in brain areas involved in
maintaining a sense of self (the ‘default mode
network’);
‒ increase functional connectivity between brain areas
that usually don’t communicate much.
- Again, these neurophysiological changes correlate
with subjective intensity of experience
Griffiths et al 2006 study
-effects of a single dose of psilocybin
-who participated
-study design
-placebo?
-acute effects
-expectancy effects?
- a study he carried out to test the effects of a single dose of psilocybin in selected healthy, religious/spiritual volunteers
Volunteers were not general population: highly educated (majority
post-grad); healthy & low risk; religious/spiritual, interest in effects
of drugs & extensive self-reflection opportunity.
Used methylphenidate (stimulant; non-psychedelic) as “active
placebo” in a double-blind, within-subjects design.
- Acute effects of psilocybin (v. methylphenidate): changes in
perception (visual pseudo-hallucinations, synaesthesia) & cognition (sense of meaning, ideas of reference); highly labile mood
(alternating between intense joy, sadness & anxiety) - More participants reported mystical experiences and persisting
positive effects following psilocybin than following methylphenidate - BUT there were effects of methylphenidate too, suggesting
expectancy effects in both groups…
Griffiths et al 2006 study
-effects of a single dose of psilocybin
-after 7 hours
-after 2 months
-after 2 months self reported
- After seven hours, reports of a “complete” mystical experience:
– 61% following psilocybin
– 11% following methylphenidate - After two months, ratings of experience being “among top five
most spiritually significant experiences”:
– 38% following psilocybin
– 8% following methylphenidate - After two months, self-reported “moderate” increase in well-being
/ life satisfaction:
– 50% following psilocybin
– 17% following methylphenidate
Griffiths et al 2006 study
-effects of a single dose of psilocybin
-precautions taken to avoid negative effects
-what negative effects were still observed?
Stringent safety precautions (incl. screening of volunteers; clinician
involvement before, during, after) to avoid/manage potentially
dangerous negative drug effects.
Nevertheless:
– 11/36 volunteers reported strong/extreme fear following psilocybin
(none following methylphenidate); two compared it to being in a
war.
– 6/36 experienced ideas of reference/ paranoid thinking following
psilocybin.
“Blinding” to conditions may have been ineffective.
psychedelics in therapy
-what can the benefit?/ positive effects
Long & controversial history (N.B., LSD & psilocybin remain illegal in UK)
- There are (somewhat inconsistent) reports of possible positive effects for LSD- & psilocybin-assisted
psychotherapy in treating:
– addictions (including alcohol & tobacco),
– obsessive-compulsive disorder, and
– depression & anxiety in patients with life-threatening or terminal illnesses
- Currently very active area of research
how are psychedelics used in psychotherapy currently
Current approach uses administration as part of a carefully
monitored, on-going programme of psychotherapy –
– psychedelics are used to “facilitate & intensify ongoing therapeutic
processes, but not to replace them
what is the ‘afterglow period’
Some studies have identified an “afterglow period” (possibly lasting
for weeks) when effectiveness of psychotherapy is enhanced – the
experience seems to challenge patient’s current world-view &
increase openness to alternative perspectives suggested by therapist.
Possibly distinct therapeutic mechanisms for SSRIs and
psychedelics
-basic action
-functions reduced
-functions enhanced
SSRIS - post synaptic 5HT1AR mediated emotional moderation and modulated by SSRIS
basic action
-post synaptic 5ht signalling up, limbic responsivity down
functions reduced
-stress, impulsivity,agression. anxiety
functions enhanced
-resilience
-emotional ‘blunting’
5HT2AR mediated emotional release and modulated by psychedelics
basic action
-5HT2AR signalling up
-cortical entropy down
functions reduced
-rigid thinking
functions enhanced
-environmental sensitivity
-emotional release
what is cortical entropy and whats its role in psychedlic therapy etc
Cortical entropy’: complexity of interactions between brain areas
usually ‘segregated’ from each other – its increase in psychedelic drug
states is hypothesised to be mechanism for reducing ‘rigid thinking’
recently published clinical trials
Carhart-Harris et al., NEJM, 2021 [Link]
– 25mg psilocybin and daily placebo versus 1mg psilocybin and daily
escitalopram (SSRI). Both with psychological support.
– No sig. difference on primary outcome measure (change on self-report depression scale). Did both work or did neither work?
- Goodwin et al., NEJM, 2022 [Link]
– Three doses of psilocybin compared: 25mg, 10mg, 1mg, all with psychological support.
– Sig. greater improvement on primary outcome measure (other-rated MADRS) with 25mg versus 1mg, but not with 10mg versus 1mg.
– Adverse events noted. - Both recommend larger and longer trials
what are some unresolved issues with psychedelics use in psychotherapy
1)Too few studies, often with small sample sizes
2) Obvious acute subjective effects means blinding is compromised: it is practically impossible to ‘control
for’ expectancy / placebo effects, and many studies do not assess expectancy (e.g., via asking participants to guess which group thought they were in).
3) Unclear how the effects are produced: direct pharmacological mechanism (independent of mystical experience), or non-pharmacological (psychological)
reaction to a mystical experience?
what is ketamine and what does it do
Ketamine is a synthetic glutamate antagonist that blocks excitatory effects of glutamate at NMDA
receptors (see Lecture 1).
- It is used as general anaesthetic & sedative.
what effects does ketamine have
It also has hallucinogenic & dissociative effects at lower (sub-anaesthetic) doses (but not consistently classed as a psychedelic drug).
– hallucinogenic = causing hallucinations or perceptual
distortions
– dissociative = producing a ‘dream-like’ feeling of being ‘detached from reality’ (incl. depersonalisation &
derealisation)
what are the acute effects of ketamine
Sometimes described as similar to being drunk (euphoria, dizziness, nausea) with disordered thought & speech.
- Memory impairments across wide range of tasks.
- Perceptual distortions & ‘dissociation’ – objects & surroundings seem ‘unreal’.
- Delusional thinking – often of a paranoid nature.
- Similar to symptoms in schizophrenia. (Hence, the “glutamate hypothesis” of schizophrenia, as mentioned briefly in Lecture 3
