Ketamine An overview of its effects on mental and physical health

1. KetamineAn 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 Ketamine: medical uses • 1964: anaesthetic • Withdrawn from mainstream use because of • ‘emergence phenomena’ • Still key in specialist anaesthesia: veterinary, paediatrics and field medicine.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 >1/3rddo 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 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% .

11. User’s 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 Courtesy of Dr J Corkery UK post-mortem toxicology mentions of ketamine in the UK 1999-2008

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 > 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, perscomm) • 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 (n=29), daily ketamine users (n=21) 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 (N=51) who transitioned to psychosis courtesy of Schultze-Lutter et al, 2007.

35. Cognitive performance

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 K’s 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