Transcript Reviewing the harms of ketamine - Society for the Study of Addiction

Ketamine
An overview of its effects on mental and
physical health
Val Curran
SSA 8th November 2012
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NMDA-receptor antagonist
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NMDA-receptor antagonist
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Snorted, effects within ~ 5 mins
Short half life, duration of effects about
1-2 hours.
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NMDA-receptor antagonist
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Snorted, effects within ~ 5 mins
Short half life, duration of effects about
1-2 hours.
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Ketamine: medical uses
 1964: anaesthetic
 Withdrawn from mainstream use because of
‘emergence phenomena’
 Still key in specialist anaesthesia: veterinary,
paediatrics and field medicine.
 WHO K report, June 4-8th 2012: “Anaesthesia without
ketamine in this part of the world is unthinkable.”
(Africa).
Ketamine: medical uses
 Acute & chronic pain
 particularly neuropathic pain (Lynch et al 2005) &
complex regional pain syndrome (Correll et al 2004)
Ketamine: medical uses
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Depression (Berman et al 2000)
Antidepressants take weeks to produce a
response, are only moderately effective and
>1/3rd do not respond.
Ketamine improves mood within hours in
treatment resistant depressed patients.
Review by Duman & Aghajanian (2012)
Science calls this “perhaps the most
important discovery in half a century.”
 Ketamine may also be effective for
treatment resistant bipolar depression
(Diazgranados et al, 2010).
 And decrease suicidal ideation (MachadoVieira et al, 2012)
 Krupitsky: Evidence from Russia (1980
– 2008) – effective adjunct to psychotherapy for alcohol and heroin
dependence.
Ketamine: recreational use
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Prevalence increased and
price decreased since
2005/6 (Drugscope, 2008;
BCS 2008/2009)
Mixmag surveys ketamine
ever used
2001 25.5%
2010 67.8%
2012 (Guardian) 48%
Chart notes
Source: Home Office,
Illicit drug use among 16–24s tables: Tables EY.02 and EY.04
British Crime Survey 2011/2: 16-24 year olds England
& Wales last year use of drugs.
Ketamine: 2006/07 0.8%; 2008/09 1.9%; 2011/12
1.8% .
User’s acute experiences
Emergence phenomena
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DOSE
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Stimulant
Sense of melting into people
or things
Distorted perceptions e.g.
feeling "as big as the universe"
or "as small as an electron",
often simultaneously
Visions and hallucinations
Spiritual and out of body
experiences
K-hole
What do you like about taking
ketamine?
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“I love the ego dissolution, my consciousness
becomes intertwined with divine entities and all
semblance of the physical realm disappears.”
Muetzelfeldt et al (2008) Drug & Alc Dependence
What do you like about taking
ketamine?
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“I love the ego dissolution, my consciousness
becomes intertwined with divine entities and all
semblance of the physical realm disappears.”
“The numbness and detachment and the
enhancement of music. Combined with E it is
warm and glowy”
Muetzelfeldt et al (2008) Drug & Alc Dependence
What do you like about taking
ketamine?
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“I love the ego dissolution, my consciousness
becomes intertwined with divine entities and all
semblance of the physical realm disappears.”
“The numbness and detachment and the
enhancement of music. Combined with E it is
warm and glowy”
“It is cheap and it gets me really off my head”
Muetzelfeldt et al (2008) Drug & Alc Dependence
Acute reinforcing effects
In ketamine-naïve
volunteers, get U-shaped
reinforcement curve
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(Morgan et al., 2004)
Acute physical risks
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Able to maintain airway
Increased cardiac output
Gag reflex preserved, less chance of aspiration
BUT commonly used with alcohol (Dillon et al., 2003)
Acute Physical Risks
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Safety Ratio (Gable, 2004)
Ketamine - Deaths
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UK post-mortem toxicology mentions of
ketamine in the UK 1999-2008
Courtesy of Dr J Corkery
Acute Intoxication
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Accidents
 Data scarce; 2 of 30 frequent users died in our
12month longitudinal study.
Driving
 Hong Kong 9% of fatal vehicle crashes involving
drugs or alcohol involved ketamine (Cheng et al.,
2005)
Increased risk of unprotected sex in gay men
 More than any other class of drug (Rusch et al.,
2004)?
Chronic effects
Ketamine-induced ulcerative cystitis
Ketamine-induced ulcerative cystitis
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Now > 10 papers detailing
Occurs mainly in frequent users
Symptoms frequency, urgency, urge
incontinence and occasionally painful
haematuria (blood in urine) (e.g. Chu et al. 2008)
Cystoscopic findings of two
daily ketamine abusers
showing varying degrees of
inflammation and
neovascularization
Healthy
A
7 years
B
4 years
C
Ketamine-induced ulcerative cystitis
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CT scans: small bladder
capacity
Marked thickening of the
bladder wall and severe
inflammation
Some symptom relief upon
cessation: varying degrees
Ketamine-induced ulcerative cystitis
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Prevalence unknown
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30% of ketamine users experienced it (Muezelfeldt et al.,
2008)
Survey of UK urologists suggests that one third may recover
upon cessation, one third will not change, one third will
continue to worsen (Cotrell & Gillatt, 2008)
Aetiology unknown
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Unlikely to be adulterants as seen in chronic pain (Gregoire et
al., 2008).
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Can get kidney damage as secondary problem.
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IF EXPERIENCING SYMPTOMS, STOP USING
K-cramps
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Spontaneously reported in 33% of 90
ketamine users interviewed (Muetzelfeldt et al., 2008)
Frequent users
Severe gastric pain
Some evidence users take ketamine to avoid
Neurological Changes
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Emerging evidence of frontal-temporal
reduction in grey matter (Fletcher, Morgan, pers comm)
White matter density reduction noted in
frontal and parietal regions.
Evidence of differences in neural correlates of
associative learning DLPFC and OFC (Morgan et al., in
prep).
Cognitive Impairment
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Clear evidence with frequent ketamine users
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short and long term memory deficits (Morgan et al.,
2010).
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Spatial working memory & pattern recognition
memory deficits related to increase over a year in
extent of ketamine use (longitudinal study Morgan et al., 2010).
Few cognitive deficits seen in infrequent users
(Morgan & Curran, 2006)
Schizophrenia-like symptoms
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Acute ketamine is the best pharmacological
model of schizophrenia.
Brings back symptoms in patients
Anecdotal reports of ketamine-induced
psychosis (Lilly, 1979; Jansen, 1991) but little evidence
Sub-clinical psychotic symptoms – especially
delusions – are increased in ketamine users
(inc. infrequent: Morgan et al., 2010).
The schizophrenia prodrome?
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The Schizophrenia Proneness Instrument (SPIA Schultze-Lutter et al., 2001; in press).
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Clinical interview/symptom rating - predicts later
schizophrenia and distinguishes between non-psychotic
affective disorders and schizophrenia (Klosterkötter et al,
1996; 2001)
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SPIA Produces a profile of ‘Basic symptoms’
SPIA Basic symptoms
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Affective-Dynamic Disturbances’
e.g. reduced tolerance of stress, decreased emotional responsiveness
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‘Cognitive-Attentional Impediments’
e.g. attention and short term memory deficits, concentration problems.
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‘Cognitive disturbances’
e.g. indecisiveness, thought interference and blockages, odd speech
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‘Disturbances in Experiencing Self & Surroundings’
e.g. self-reported pressure of thought and unstable ideas of reference
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‘Body Perception Disturbances’
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e.g unusual bodily perceptual experiences
‘Perception Disturbances’
e.g. changes in the intensity or quality of perceptual stimuli.
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Given link between cannabis and psychosis,
we compared ketamine users with high
potency cannabis users.
Daily ‘skunk’ users (n=29), daily ketamine
users (n=21) and controls (n= 30) naïve to
illicit drugs.
Daily skunk users
18
16
Mean SPI-A score
14
12
Cannabis
10
Non-drug
8
6
4
2
0
Affective
Dynamic
CognitiveAttentional
Cognitive
Disturbances
Self and
Body Perception Perception
Surroundings
Disturbances
Daily ketamine users
20
18
Mean SPI-A score
16
14
Ketamine
12
Cannabis
10
Non-drug
8
6
4
2
0
Affective
Dynamic
CognitiveAttentional
Cognitive
Disturbances
Self and
Surroundings
Body
Perception
Perception
Disturbances
Prodromal individuals who later
transitioned to psychosis
20
18
Mean SPI-A score
16
14
Prodromal
12
Ketamine
10
Cannabis
Non-drug
8
6
4
2
0
Affective
Dynamic
CognitiveAttentional
Cognitive
Disturbances
Self and
Body Perception Perception
Surroundings
Disturbances
Data for prodromal group (N=51) who transitioned to psychosis courtesy of SchultzeLutter et al, 2007.
Cognitive performance
Immediate prose
Non-drug
Skunk
Ketamine
7.93 (2.82)
5.57 (2.27)*
5.88 (2.32)*
F(3,125), p
4.637, 0.002
Delayed
6.53 (3.25)
3.72 (2.02)***
4.70 (2.10)
prose
Verbal fluency
4.518, 0.002
17.70 (6.82)
12.28 (2.64)**
13.40 (3.99)**
5.472, <0.001
Category fluency
18.10 (6.43)
16.93 (4.58)
14.40 (4.44)
2.155, 0.078
Digit Forwards
9.87 (2.24)
9.51 (2.37)
8.75 (2.36)
0.979, 0.422
Digit Backwards
7.27 (2.39)
6.21 (1.84)
4.75 (2.12)**
5.998, <0.001
Depression
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Increased depression in frequent ketamine users
(Morgan et al., 2009).
BUT subclinical and not related to change in dose
(Morgan et al., 2010)
Dependence: Tolerance
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Tachyphylaxis – rats, monkeys and man.
Frequent ketamine users increased dose 600%
(Morgan et al., 2010)
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Hair concentration doubled in recreational
users (baseline 21.82 ± 46.27; 1 year follow-up 48.43±
104.56 )
Dependence
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Attentional bias & towards Ketamine related
images
Ketamine related cues overshadow other
predictors of reward in an associative learning
task (Freeman et al, 2012)
Dependence: Withdrawal?
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‘Discontinuation syndrome’
28 out of 30 daily users tried but failed to give
up – all reported K craving as the reason mainly to alleviate pain (bladder; K-cramps).
12 out of 30 of the same group reported
withdrawal symptoms characterised by
anxiety, shaking, sweating, palpitations (Morgan et
al. 2009).
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Case studies: Critchlow et al., 2008; Lim et al., 2003; Blatchut et
al., 2009.
Educational and professional
achievement
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General risks associated with addictive illegal
drugs?
Ketamine dependent individuals often on
margins of mainstream society
Significantly less time in education frequent
users compared to infrequent, poly-drug &
controls (Morgan et al., 2009)
20% employment related problems in
recreational users (Dillon et al., 2003)
Criminal activities
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Criminal - unknown
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No DTOs
Ketamine smuggling organised crime
Ketamine arrests
increased over past 4
years
Cost to the Health Service
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Cystoscopies
Cather insertion
Cystectomy
Lifetime follow-up
Cost of treating dependence
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When the ketamine supply diminished...
Methoxetamine stepped in
Marketed as ‘Bladder friendly ketamine’.
First drug ACMD put under a Temp Control Drug Order (TCDO).
18th Oct 2012 ACMD recommended most K analogues put in
Schedule 1 (having no medical use).
Will hamper research on non-ketamine agents which may be
anti-depressants/analgesics without K’s severe chronic effects.
Conclusions
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Chronically, mainly in frequent users, bladder
problems, cognitive/neurological impairment and
difficulty in stopping use are the major concerns.
Conclusions
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Chronically, mainly in frequent users, bladder
problems, cognitive/neurological impairment and
difficulty in stopping use are the major concerns.
Ketamine remains an important medicine in
anaesthesia and pain management.
Conclusions
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Chronically, mainly in frequent users, bladder
problems, cognitive/neurological impairment and
difficulty in stopping use are the major concerns.
Ketamine remains an important medicine in
anaesthesia and pain management.
Its antidepressant, psychotic and chronic prodromal
effects are now key in mental health research.
Conclusions
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Chronically, mainly in frequent users, bladder
problems, cognitive/neurological impairment and
difficulty in stopping use are the major concerns.
Ketamine remains an important medicine in
anaesthesia and pain management.
Its antidepressant, psychotic and chronic prodromal
effects are now key in mental health research.
Ketamine's mind-altering properties may be far more
useful than any clubber ever imagined.
THANK YOU!
Celia Morgan
Leslie Muetzelfeldt
Tom Freeman
Morgan & Curran (2011) Ketamine use: a review. Addiction
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Harms – rated by 6,000 in an International Drug
Survey (Morgan et al, in press).
Class A
Class B
2.5
Class C
No Classification
2
1.5
1
0.5
0
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ACMD report of 18th October 2012 recommends that a large number of ketamine analogues should be made
Schedule 1 controlled drugs, to reduce possible future abuse.
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Although ketamine and one analogue [methoxetamine = Mexxy] is abused, the plan to ban so many analogues,
some with already proven research utility, seems extreme.
the long-term use of ketamine is associated with an inflammatory cystitis and possibly cognition impairments,
so there is a real need to find safer and more effective alternatives. This research will be made extremely
difficult under the new proposals since virtually no research or clinical site in the UK has a Schedule 1 license.
Moreover experience shows that almost no producers can comply with Schedule 1 requirements, so access to,
and development of novel test compounds will almost certainly cease.
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While Schedule 1 status has a massive impact on research and clinical use it has no impact on “illicit” use,
being just a residual beurocratic category from the old and out of date 1961 UN convention. So we must at all
costs avoid putting drugs with clinical potential into it, for the reasons stated above. Also experience tells us
that removing a drug from Schedule 1 is extremely difficult even when it has proven utility [cf cannabis].
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David Nutt proposes to exempt hospitals and universities from Schedule 1 requirements but this will not affect
the production issue. The best way to limit damage to research for patients benefit is to stop potentially useful
drugs being made Schedule 1 in the first place.
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To add
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ACMD review of MXE. Temp Control Drug Order – TCDO MXE was the first so we are reviewing the process.
First we need to know how ketamine causes bladder pain and the
ability to study analogues will be useful for that goal so why
make this analogue Schedule 1.
Schedule 1 - Drugs belonging to this schedule are thought to
have no therapeutic value and therefore cannot be lawfully
possessed or prescribed. These include LSD, MDMA (ecstasy)
and cannabis. Schedule 1 drugs may be used for the purposes of
research but a Home Office licence is required.
Second, I am not convinced of the reasoning behind having
different drugs in this chemical class in Class A, B & C. Is the
message that ketamine is the least harmful?
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Berman et al 2000 – 7 patients; decrease of 14
on HAM-D after K; 0 after placebo.
Depression affects over 120 million people worldwide, making it the fourth
largest contributor to the global burden of disease, according to the World
Health Organization. At some point in their lives 13 per cent of Americans
experience major depression, and globally 850,000 depressed people kill
themselves every year.
Zarate et al () 17 patients “Ketamine somehow reboots the brain”. Effects
last 7-10 days.
Acts on neuroplasticity. Works on pain too. (Antids often prescribed for
pain).
Ketamine's mind-altering properties may be far more useful than any clubber
ever imagined.
October 5th 2012
“Recent studies report what is arguably the most important discovery in
half a century: ketamine produces rapid antidepressant action in
treatment resistant depressed patients.”
Propensity for I.V. use
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Low : hospital workers and psychonauts
Awaiting Data
Drugscope (2009)
 Bristol Drugs Project I.M. – pers comm
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Suggestions on the increase – little evidence
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Thanks for listening!
•Depression: Berman et al 2000 - below Zarate et al 2010
e.g. self & surroundings
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Do you sometimes feel that things going on
around you have special meaning for you, even
though you know this is improbable or
impossible?
Do you sometimes feel as if random things were
meant especially for you e.g. comments on
rasdio or TV?
Rating – frequency
If needed – severity, subjective burden, areas of
life.
Basic symptoms
Basic symptoms: SPIA
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Affective-Dynamic Disturbances’
e.g. reduced tolerance of stress, decreased emotional responsiveness
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‘Cognitive-Attentional Impediments’
e.g. attention and short term memory deficits, concentration problems.
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‘Cognitive disturbances’
e.g. indecisiveness, thought interference and blockages, odd speech
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‘Disturbances in Experiencing Self & Surroundings’
e.g. self-reported pressure of thought and unstable ideas of reference
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‘Body Perception Disturbances’
`
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e.g unusual bodily perceptual experiences
‘Perception Disturbances’
e.g. changes in the intensity or quality of perceptual stimuli.
Acute Physical Risks: National
Poisons Service
• 570 000 TOXBASE sessions (online poisons database): 0.3 %
ketamine: 1710 cases
• Up six-fold from 2000: 0.05% - 285 cases