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Ketamine An overview of its effects on mental and physical health

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Title: Ketamine An overview of its effects on mental and physical health


1
Ketamine An overview of its effects on mental
and physical health
  • Val Curran
  • SSA 8th November 2012

2
  • NMDA-receptor antagonist

3
  • NMDA-receptor antagonist
  • Snorted, effects within 5 mins
  • Short half life, duration of effects about 1-2
    hours.

4
  • NMDA-receptor antagonist
  • Snorted, effects within 5 mins
  • Short half life, duration of effects about 1-2
    hours.

5
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  • Withdrawn from mainstream use because of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).

6
Ketamine medical uses
  • Acute chronic pain
  • particularly neuropathic pain (Lynch et al 2005)
    complex regional pain syndrome (Correll et al
    2004)

7
Ketamine medical uses
  • Depression (Berman et al 2000)
  • Antidepressants take weeks to produce a response,
    are only moderately effective and gt1/3rd 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.

8
  • Ketamine may also be effective for treatment
    resistant bipolar depression (Diazgranados et al,
    2010).
  • And decrease suicidal ideation (Machado-Vieira
    et al, 2012)
  • Krupitsky Evidence from Russia (1980 2008)
    effective adjunct to psycho-therapy for alcohol
    and heroin dependence.

9
Ketamine recreational use
  • 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

10
Extent of last year illicit drug use for most
prevalent drugs among young people aged 16 to 24,
2011/12 Crime Survey for England and Wales
Chart notes Source Home Office, Illicit drug
use among 1624s 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 .
11
Users acute experiences
Emergence phenomena
  • 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

DOSE
12
What do you like about taking ketamine?
  • 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
13
What do you like about taking ketamine?
  • 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
14
What do you like about taking ketamine?
  • 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
15
Acute reinforcing effects
  • In ketamine-naïve
  • volunteers, get U-shaped
  • reinforcement curve
  • (Morgan et al., 2004)

16
Acute physical risks
  • Able to maintain airway
  • Increased cardiac output
  • Gag reflex preserved, less chance of aspiration
    BUT commonly used with alcohol (Dillon et al.,
    2003)

17
Acute Physical Risks
  • Safety Ratio (Gable, 2004)

18
Ketamine - Deaths
  • UK post-mortem toxicology mentions of ketamine in
    the UK 1999-2008

Courtesy of Dr J Corkery
19
Acute Intoxication
  • 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)?

20
Chronic effects
21
Ketamine-induced ulcerative cystitis
22
Ketamine-induced ulcerative cystitis
  • Now gt 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)

Healthy 7 years 4 years
Cystoscopic findings of two daily ketamine
abusers showing varying degrees of inflammation
and neovascularization
A
B
C
23
Ketamine-induced ulcerative cystitis
  • CT scans small bladder capacity
  • Marked thickening of the bladder wall and severe
    inflammation
  • Some symptom relief upon cessation varying
    degrees

24
Ketamine-induced ulcerative cystitis
  • Prevalence unknown
  • 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
  • Unlikely to be adulterants as seen in chronic
    pain (Gregoire et al., 2008).
  • Can get kidney damage as secondary problem.
  • IF EXPERIENCING SYMPTOMS, STOP USING

25
K-cramps
  • 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

26
Neurological Changes
  • 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).

27
Cognitive Impairment
  • Clear evidence with frequent ketamine users
  • short and long term memory deficits (Morgan et
    al., 2010).
  • 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)

28
Schizophrenia-like symptoms
  • 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?

29
  • The Schizophrenia Proneness Instrument (SPIA -
    Schultze-Lutter et al., 2001 in press).
  • Clinical interview/symptom rating - predicts
    later schizophrenia and distinguishes between
    non-psychotic affective disorders and
    schizophrenia (Klosterkötter et al, 1996 2001)
  • SPIA Produces a profile of Basic symptoms

30
SPIA Basic symptoms
  • Affective-Dynamic Disturbances
  • e.g. reduced tolerance of stress, decreased
    emotional responsiveness
  • Cognitive-Attentional Impediments
  • e.g. attention and short term memory deficits,
    concentration problems.
  • Cognitive disturbances
  • e.g. indecisiveness, thought interference and
    blockages, odd speech
  • Disturbances in Experiencing Self
    Surroundings
  • e.g. self-reported pressure of thought and
    unstable ideas of reference
  • Body Perception Disturbances
  • e.g unusual bodily perceptual experiences
  • Perception Disturbances
  • e.g. changes in the intensity or quality of
    perceptual stimuli.

31
  • Given link between cannabis and psychosis, we
    compared ketamine users with high potency
    cannabis users.
  • Daily skunk users (n29), daily ketamine users
    (n21) and controls (n 30) naïve to illicit
    drugs.

32
Daily skunk users
33
Daily ketamine users
34
Prodromal individuals who later transitioned to
psychosis
Data for prodromal group (N51) who transitioned
to psychosis courtesy of Schultze-Lutter et al,
2007.
35
Cognitive performance
  Non-drug Skunk Ketamine   F(3,125), p
Immediate prose 7.93 (2.82) 5.57 (2.27) 5.88 (2.32)     4.637, 0.002
Delayed prose 6.53 (3.25) 3.72 (2.02) 4.70 (2.10)     4.518, 0.002
Verbal fluency 17.70 (6.82) 12.28 (2.64) 13.40 (3.99)     5.472, lt0.001
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, lt0.001
           
36
Depression
  • Increased depression in frequent ketamine users
    (Morgan et al., 2009).
  • BUT subclinical and not related to change in dose
    (Morgan et al., 2010)

37
Dependence Tolerance
  • Tachyphylaxis rats, monkeys and man.
  • Frequent ketamine users increased dose 600
    (Morgan et al., 2010)
  • Hair concentration doubled in recreational users
    (baseline 21.82 46.27 1 year follow-up 48.43
    104.56 )

38
Dependence
  • Attentional bias towards Ketamine related
    images
  • Ketamine related cues overshadow other
    predictors of reward in an associative learning
    task (Freeman et al, 2012)

39
Dependence Withdrawal?
  • 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).
  • Case studies Critchlow et al., 2008 Lim et al.,
    2003 Blatchut et al., 2009.

40
Educational and professional achievement
  • 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)

41
Criminal activities
  • Criminal - unknown
  • No DTOs
  • Ketamine smuggling -organised crime
  • Ketamine arrests increased over past 4 years

42
Cost to the Health Service
  • Cystoscopies
  • Cather insertion
  • Cystectomy
  • Lifetime follow-up
  • Cost of treating dependence

43
  • When the ketamine supply diminished...
    Methoxetamine stepped in

44
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 Ks severe chronic effects.
45
Conclusions
  • Chronically, mainly in frequent users, bladder
    problems, cognitive/neurological impairment and
    difficulty in stopping use are the major
    concerns.

46
Conclusions
  • 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.

47
Conclusions
  • 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.

48
Conclusions
  • 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.

49
THANK YOU!
Celia Morgan Leslie Muetzelfeldt Tom
Freeman
Morgan Curran (2011) Ketamine use a
review. Addiction
50
(No Transcript)
51
  • Harms rated by 6,000 in an International Drug
    Survey (Morgan et al, in press).

52
  • 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.
  • 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.
  • 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.
  • 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.
  •  

53
To add
  • 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?

54
  • 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.

55
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.
56
Propensity for I.V. use
  • Low hospital workers and psychonauts
  • Awaiting Data
  • Drugscope (2009)
  • Bristol Drugs Project I.M. pers comm
  • Suggestions on the increase little evidence

57
  • Thanks for listening!

58
  • Depression Berman et al 2000 - below Zarate et
    al 2010

59
e.g. self surroundings
  • 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.

60
Basic symptoms SPIA
Basic symptoms
  • Affective-Dynamic Disturbances
  • e.g. reduced tolerance of stress, decreased
    emotional responsiveness
  • Cognitive-Attentional Impediments
  • e.g. attention and short term memory deficits,
    concentration problems.
  • Cognitive disturbances
  • e.g. indecisiveness, thought interference and
    blockages, odd speech
  • Disturbances in Experiencing Self
    Surroundings
  • e.g. self-reported pressure of thought and
    unstable ideas of reference
  • Body Perception Disturbances
  • e.g unusual bodily perceptual experiences
  • Perception Disturbances
  • e.g. changes in the intensity or quality of
    perceptual stimuli.

61
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
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