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

KetamineKetamine

An overview of its effects on mental and An overview of its effects on mental and

physical health physical health

Val Curran Val Curran SSA 8SSA 8thth November 2012 November 2012

NMDA-receptor antagonistNMDA-receptor antagonist

NMDA-receptor antagonistNMDA-receptor antagonist Snorted, effects within ~ 5 minsSnorted, effects within ~ 5 mins Short half life, duration of effects about Short half life, duration of effects about

1-2 hours.1-2 hours.

NMDA-receptor antagonistNMDA-receptor antagonist Snorted, effects within ~ 5 minsSnorted, effects within ~ 5 mins Short half life, duration of effects about Short half life, duration of effects about

1-2 hours.1-2 hours.

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Withdrawn from mainstream use because of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 withoutketamine 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)



Depression Depression (Berman et al 2000) (Berman et al 2000)

Antidepressants take weeks to produce a Antidepressants take weeks to produce a response, are only moderately effective and response, are only moderately effective and >1/3>1/3rdrd do not respond. do not respond.

Ketamine improves mood within hours in Ketamine improves mood within hours in treatment resistant depressed patients.treatment resistant depressed patients.

Review by Duman & Aghajanian (2012) Science Review by Duman & Aghajanian (2012) Science calls this “perhaps the mostcalls this “perhaps the most

important discovery in half a century.”important discovery in half a century.”

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.

Ketamine: recreational useKetamine: recreational use Prevalence increased and Prevalence increased and

price decreased since price decreased since 2005/6 (Drugscope, 2008; 2005/6 (Drugscope, 2008; BCS 2008/2009)BCS 2008/2009)

Mixmag surveys ketamine Mixmag surveys ketamine ever used ever used

2001 25.5% 2001 25.5% 2010 67.8% 2010 67.8% 2012 (Guardian) 2012 (Guardian)

48%48%

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 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 experiencesUser’s acute experiences

StimulantStimulant Sense of melting into people Sense of melting into people

or thingsor things Distorted perceptions e.g. Distorted perceptions e.g.

feeling "as big as the feeling "as big as the universe" or "as small as an universe" or "as small as an electron", often electron", often simultaneously simultaneously

Visions and hallucinationsVisions and hallucinations Spiritual and out of body Spiritual and out of body

experiencesexperiences K-holeK-hole

DOSE

Emergence phenomena

What do you like about What do you like about taking ketamine?taking ketamine?

““I love the ego dissolution, my I love the ego dissolution, my consciousness becomes intertwined consciousness becomes intertwined with divine entities and all semblance with divine entities and all semblance of the physical realm disappears.”of the physical realm disappears.”

Muetzelfeldt et al (2008) Drug & Alc Dependence


““I love the ego dissolution, my I love the ego dissolution, my consciousness becomes intertwined consciousness becomes intertwined with divine entities and all semblance with divine entities and all semblance of the physical realm disappears.”of the physical realm disappears.”

““The numbness and detachment and The numbness and detachment and the enhancement of music. Combined the enhancement of music. Combined with E it is warm and glowy”with E it is warm and glowy”



““I love the ego dissolution, my consciousness I love the ego dissolution, my consciousness becomes intertwined with divine entities and all becomes intertwined with divine entities and all semblance of the physical realm disappears.”semblance of the physical realm disappears.”

““The numbness and detachment and the The numbness and detachment and the enhancement of music. Combined with E it is enhancement of music. Combined with E it is warm and glowy”warm and glowy”

““It is cheap and it gets me really off my headIt is cheap and it gets me really off my head””


Acute reinforcing effectsAcute reinforcing effects

In ketamine-naïve In ketamine-naïve

volunteers, get U-volunteers, get U-shapedshaped

reinforcement curve reinforcement curve (Morgan et al., 2004)(Morgan et al., 2004)

Acute physical risksAcute physical risks

Able to maintain airwayAble to maintain airway Increased cardiac outputIncreased cardiac output Gag reflex preserved, less chance of Gag reflex preserved, less chance of

aspiration BUT commonly used with aspiration BUT commonly used with alcohol alcohol (Dillon et al., 2003)(Dillon et al., 2003)

Acute Physical RisksAcute Physical Risks Safety Ratio (Gable, 2004)Safety Ratio (Gable, 2004)

Ketamine - DeathsKetamine - Deaths

UK post-mortem toxicology mentions of ketamine in the UK 1999-2008

Courtesy of Dr J Corkery

Acute IntoxicationAcute Intoxication AccidentsAccidents

Data scarce; 2 of 30 frequent users died in our Data scarce; 2 of 30 frequent users died in our 12month longitudinal study. 12month longitudinal study.

DrivingDriving Hong Kong 9% of fatal vehicle crashes involving Hong Kong 9% of fatal vehicle crashes involving

drugs or alcohol involved ketamine (Cheng et al., drugs or alcohol involved ketamine (Cheng et al., 2005) 2005)

Increased risk of unprotected sex in gay men Increased risk of unprotected sex in gay men More than any other class of drug (Rusch et al., More than any other class of drug (Rusch et al.,

2004)?2004)?

Chronic effectsChronic effects

Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis

Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis Now > 10 papers detailingNow > 10 papers detailing Occurs mainly in frequent usersOccurs mainly in frequent users Symptoms frequency, urgency, urge Symptoms frequency, urgency, urge

incontinence and occasionally painful incontinence and occasionally painful haematuria (blood in urine) haematuria (blood in urine) (e.g. Chu et al. 2008) (e.g. Chu et al. 2008)

Cystoscopic findings of two daily ketamine abusers showing varying degrees of inflammation and neovascularization

C BA

Healthy 7 years 4 years

Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis

CT scans: small bladder CT scans: small bladder capacitycapacity

Marked thickening of the Marked thickening of the bladder wall and severe bladder wall and severe inflammationinflammation

Some symptom relief upon Some symptom relief upon cessation: varying degrees cessation: varying degrees

Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis Prevalence unknownPrevalence unknown

30% of ketamine users experienced it (Muezelfeldt et al., 30% of ketamine users experienced it (Muezelfeldt et al., 2008)2008)

Survey of UK urologists suggests that one third may recover Survey of UK urologists suggests that one third may recover upon cessation, one third will not change, one third will upon cessation, one third will not change, one third will continue to worsen (Cotrell & Gillatt, 2008)continue to worsen (Cotrell & Gillatt, 2008)

Aetiology unknown Aetiology unknown Unlikely to be adulterants as seen in chronic pain Unlikely to be adulterants as seen in chronic pain (Gregoire et (Gregoire et

al., 2008al., 2008).). Can get kidney damage as secondary problem.Can get kidney damage as secondary problem.

IF EXPERIENCING SYMPTOMS, STOP USING IF EXPERIENCING SYMPTOMS, STOP USING

K-crampsK-cramps

Spontaneously reported in 33% of 90Spontaneously reported in 33% of 90 ketamine users interviewed ketamine users interviewed (Muetzelfeldt et al., 2008)(Muetzelfeldt et al., 2008)

Frequent usersFrequent users Severe gastric painSevere gastric pain Some evidence users take ketamine to avoidSome evidence users take ketamine to avoid

Neurological ChangesNeurological Changes

Emerging evidence of frontal-temporal Emerging evidence of frontal-temporal reduction in grey matter reduction in grey matter (Fletcher, Morgan, pers comm)(Fletcher, Morgan, pers comm)

White matter density reduction noted in White matter density reduction noted in frontal and parietal regions.frontal and parietal regions.

Evidence of differences in neural correlates of Evidence of differences in neural correlates of associative learning DLPFC and OFC associative learning DLPFC and OFC (Morgan et al., in (Morgan et al., in prep). prep).

Cognitive ImpairmentCognitive Impairment Clear evidence with frequent ketamine usersClear evidence with frequent ketamine users

short and long term memory deficits short and long term memory deficits (Morgan et al., (Morgan et al., 2010).2010).

Spatial working memory & pattern recognition Spatial working memory & pattern recognition memory deficits related to increase over a year in memory deficits related to increase over a year in extent of ketamine use (longitudinal study - extent of ketamine use (longitudinal study - Morgan et al., 2010).Morgan et al., 2010).

Few cognitive deficits seen in infrequent users Few cognitive deficits seen in infrequent users (Morgan & Curran, 2006)(Morgan & Curran, 2006)

Schizophrenia-like symptomsSchizophrenia-like symptoms Acute ketamine is the best pharmacological Acute ketamine is the best pharmacological

model of schizophrenia.model of schizophrenia. Brings back symptoms in patientsBrings back symptoms in patients Anecdotal reports of ketamine-induced Anecdotal reports of ketamine-induced

psychosis psychosis (Lilly, 1979; Jansen, 1991) (Lilly, 1979; Jansen, 1991) but little evidencebut little evidence Sub-clinical psychotic symptoms – especially Sub-clinical psychotic symptoms – especially

delusions – are increased in ketamine users delusions – are increased in ketamine users (inc. infrequent: Morgan et al., 2010). (inc. infrequent: Morgan et al., 2010).

The schizophrenia prodrome? The schizophrenia prodrome?

The Schizophrenia Proneness Instrument The Schizophrenia Proneness Instrument (SPIA - Schultze-Lutter et al., 2001; in (SPIA - Schultze-Lutter et al., 2001; in press). press).

Clinical interview/symptom rating - predicts later Clinical interview/symptom rating - predicts later schizophrenia and distinguishes between non-schizophrenia and distinguishes between non-psychotic affective disorders and schizophrenia psychotic affective disorders and schizophrenia (Klosterkötter (Klosterkötter et alet al, 1996; 2001), 1996; 2001)

SPIA Produces a profile of ‘SPIA Produces a profile of ‘Basic symptoms’Basic symptoms’

SPIA Basic symptomsSPIA Basic symptoms Affective-Dynamic Disturbances’Affective-Dynamic Disturbances’

e.g. reduced tolerance of stress, decreased emotional responsivenesse.g. reduced tolerance of stress, decreased emotional responsiveness

‘‘Cognitive-Attentional ImpedimentsCognitive-Attentional Impediments’’ e.g. attention and short term memory deficits, concentration problems.e.g. attention and short term memory deficits, concentration problems.

‘‘Cognitive disturbancesCognitive disturbances’’e.g. indecisiveness, thought interference and blockages, odd speech e.g. indecisiveness, thought interference and blockages, odd speech

‘‘Disturbances in Experiencing Self & Surroundings’Disturbances in Experiencing Self & Surroundings’ e.g. self-reported pressure of thought and unstable ideas of referencee.g. self-reported pressure of thought and unstable ideas of reference

‘‘Body Perception DisturbancesBody Perception Disturbances’’`̀ e.g unusual bodily perceptual experiences e.g unusual bodily perceptual experiences

‘‘Perception Disturbances’Perception Disturbances’

e.g. changes in the intensity or quality of perceptual stimuli.e.g. changes in the intensity or quality of perceptual stimuli.

Given link between cannabis and psychosis, Given link between cannabis and psychosis, we compared ketamine users with high we compared ketamine users with high potency cannabis users. potency cannabis users.

Daily ‘skunk’ users (n=29), daily ketamine Daily ‘skunk’ users (n=29), daily ketamine users (n=21) and users (n=21) and controls (n= 30) naïve to controls (n= 30) naïve to illicit drugs.illicit drugs.

Daily skunk users Daily skunk users

0

2

4

6

8

10

12

14

16

18

AffectiveDynamic

Cognitive-Attentional

CognitiveDisturbances

Self andSurroundings

Body Perception PerceptionDisturbances

Me

an

SP

I-A

sc

ore

Cannabis

Non-drug

Daily ketamine usersDaily ketamine users

0

2

4

6

8

10

12

14

16

18

20

AffectiveDynamic




BodyPerception

PerceptionDisturbances

Me

an

SP

I-A

sc

ore

Ketamine

Cannabis

Non-drug

Prodromal individuals who Prodromal individuals who later transitioned to later transitioned to

psychosispsychosis

0

2

4

6

8

10

12

14

16

18

20

AffectiveDynamic




Body Perception PerceptionDisturbances

Me

an

SP

I-A

sc

ore

Prodromal

Ketamine

Cannabis

Non-drug

Data for prodromal group (N=51) who transitioned to psychosis courtesy of Schultze-Lutter et al, 2007.

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,

<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

Cognitive performance

Depression Depression

Increased depression in frequent ketamine users Increased depression in frequent ketamine users (Morgan et al., 2009).(Morgan et al., 2009).

BUT subclinical and not related to change in dose BUT subclinical and not related to change in dose (Morgan et al., 2010)(Morgan et al., 2010)

Dependence: ToleranceDependence: Tolerance

Tachyphylaxis – rats, monkeys and man.Tachyphylaxis – rats, monkeys and man. Frequent ketamine users increased dose 600% Frequent ketamine users increased dose 600%

(Morgan et al., 2010)(Morgan et al., 2010)

Hair concentration doubled in recreational Hair concentration doubled in recreational users users (baseline 21.82 ± 46.27; 1 year follow-up 48.43± (baseline 21.82 ± 46.27; 1 year follow-up 48.43± 104.56104.56 ) )

DependenceDependence

Attentional bias & towards Ketamine related Attentional bias & towards Ketamine related images images

Ketamine related cues overshadow other Ketamine related cues overshadow other predictors of reward in an associative learning predictors of reward in an associative learning task (Freeman et al, 2012)task (Freeman et al, 2012)

Dependence: Dependence: Withdrawal?Withdrawal?

‘‘Discontinuation syndrome’Discontinuation syndrome’ 28 out of 30 daily users tried but failed to give 28 out of 30 daily users tried but failed to give

up – all reported K craving as the reason - up – all reported K craving as the reason - mainly to alleviate pain (bladder; K-cramps).mainly to alleviate pain (bladder; K-cramps).

12 out of 30 of the same group reported 12 out of 30 of the same group reported withdrawal symptoms characterised by withdrawal symptoms characterised by anxiety, shaking, sweating, palpitations anxiety, shaking, sweating, palpitations (Morgan et (Morgan et al. 2009).al. 2009).

Case studies: Case studies: Critchlow et al., 2008; Lim et al., 2003; Blatchut et al., Critchlow et al., 2008; Lim et al., 2003; Blatchut et al., 2009.2009.

Educational and professional Educational and professional achievementachievement

General risks associated with addictive illegal General risks associated with addictive illegal drugs?drugs?

Ketamine dependent individuals often on Ketamine dependent individuals often on margins of mainstream societymargins of mainstream society

Significantly less time in education frequent Significantly less time in education frequent users compared to infrequent, poly-drug & users compared to infrequent, poly-drug & controls controls (Morgan et al., 2009)(Morgan et al., 2009)

20% employment related problems in 20% employment related problems in recreational users recreational users (Dillon et al., 2003)(Dillon et al., 2003)

Criminal activitiesCriminal activities

Criminal - unknown Criminal - unknown No DTOsNo DTOs

Ketamine smuggling -Ketamine smuggling -organised crimeorganised crime

Ketamine arrests Ketamine arrests increased over past 4 increased over past 4 yearsyears

Cost to the Health ServiceCost to the Health Service

CystoscopiesCystoscopies Cather insertionCather insertion CystectomyCystectomy Lifetime follow-upLifetime follow-up Cost of treating dependenceCost of treating dependence

When the ketamine supply diminished... When the ketamine supply diminished... Methoxetamine stepped inMethoxetamine 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.

ConclusionsConclusions

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.




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.

Morgan & Curran (2011) Ketamine use: a review. Addiction

Celia Morgan Leslie Muetzelfeldt Tom Freeman

THANK YOU!

Harms – rated by 6,000 in an Harms – rated by 6,000 in an International Drug Survey International Drug Survey (Morgan et al, in (Morgan et al, in press).press).

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.

To add 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 - Schedule 1 - Drugs belonging to this schedule are thought Drugs belonging to this schedule are thought to have no therapeutic value and therefore cannot be to have no therapeutic value and therefore cannot be lawfully possessed or prescribed. These include LSD, lawfully possessed or prescribed. These include LSD, MDMA (ecstasy) and cannabis. Schedule 1 drugs may be MDMA (ecstasy) and cannabis. Schedule 1 drugs may be used for the purposes of research but a Home Office used for the purposes of research but a Home Office licence is required.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?

Berman et al 2000 – 7 patients; decrease Berman et al 2000 – 7 patients; decrease of 14 on HAM-D after K; 0 after placebo.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.

“Recent studies report what is arguably the most important discovery in half a century: ketamine produces rapid antidepressant action in treatment resistant depressed patients.”

October 5th 2012

Propensity for I.V. usePropensity for I.V. use

Low : hospital workers and Low : hospital workers and psychonautspsychonauts

Awaiting DataAwaiting Data Drugscope (2009)Drugscope (2009) Bristol Drugs Project I.M. – pers commBristol Drugs Project I.M. – pers comm

Suggestions on the increase – little Suggestions on the increase – little evidenceevidence

Thanks for listening!Thanks for listening!

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

e.g. self & surroundingse.g. self & surroundings

Do you sometimes feel that things going Do you sometimes feel that things going on around you have special meaning for on around you have special meaning for you, even though you know this is you, even though you know this is improbable or impossible?improbable or impossible?

Do you sometimes feel as if random Do you sometimes feel as if random things were meant especially for you e.g. things were meant especially for you e.g. comments on rasdio or TV? comments on rasdio or TV?

Rating – frequencyRating – frequency If needed – severity, subjective burden, If needed – severity, subjective burden,

areas of life.areas of life.

Basic symptoms: SPIABasic symptoms: SPIA Affective-Dynamic Disturbances’Affective-Dynamic Disturbances’

e.g. reduced tolerance of stress, decreased emotional responsivenesse.g. reduced tolerance of stress, decreased emotional responsiveness

‘‘Cognitive-Attentional ImpedimentsCognitive-Attentional Impediments’’ e.g. attention and short term memory deficits, concentration e.g. attention and short term memory deficits, concentration problems.problems.

‘‘Cognitive disturbancesCognitive disturbances’’e.g. indecisiveness, thought interference and blockages, odd speech e.g. indecisiveness, thought interference and blockages, odd speech

‘‘Disturbances in Experiencing Self & Surroundings’Disturbances in Experiencing Self & Surroundings’ e.g. self-reported pressure of thought and unstable ideas of referencee.g. self-reported pressure of thought and unstable ideas of reference

‘‘Body Perception DisturbancesBody Perception Disturbances’’`̀ e.g unusual bodily perceptual experiences e.g unusual bodily perceptual experiences

‘‘Perception Disturbances’Perception Disturbances’

e.g. changes in the intensity or quality of perceptual stimuli.e.g. changes in the intensity or quality of perceptual stimuli.

Basic symptoms

Acute Physical Risks: National Acute Physical Risks: National Poisons ServicePoisons Service

• 570 000 TOXBASE sessions (online poisons database): 0.3 % ketamine: 1710 cases

• Up six-fold from 2000: 0.05% - 285 cases

Documents

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