The Game Changer: the impact of ‘novel highs’ Dr Russell Newcombe HIT Hot Topics Conference, Liverpool UK 15th November 2013 www.3Dresearch.org.uk

Overview of presentation 1. Definitions: legal highs and NPS 2. Types: by source and effects 3. Legal response 4. Recent research: prevalence, trends Conclusions

Definitions: legal highs Chemicals which alter the normal functioning of the brain (neurotransmitters and brain-waves), thus producing changes in our experience and behaviour - a ‘high’ (2) Specifically, a legal high is a chemical which is: (a) not controlled by the 1971 Misuse of Drugs Act; (b) not licensed for legal use (like alcohol and tobacco); (c) not advertised/sold – and therefore not regulated - as a medicine (Medicines Act 1968) – see next 2 slides; (d) mimics the effects of popular controlled drugs [?] Thus, a legal high is a substance which is not legally regulated – a more accurate term would be ‘legal loophole’ drugs.

Novel psychoactive substances (NPS) Over the last few years, the term ‘legal high’ has become replaced by ‘novel psychoactive substance’ (NPS) – because if and when possession and trafficking of a particular new drug is prohibited by the government, it literally ceases to be a ‘legal high’. For example, use of the term ‘NPS’ allows us to avoid the confusion which currently exists in relation to drugs like mephedrone (meow/m-cat), which was banned by the UK government in April 2010 - but it is still referred to as a ‘legal high’ by some sources (notably the mass media). However, it could also be argued that labels like new drugs or novel highs are enough for many purposes.

In short: Legal highs: uncontrolled, but can be new drugs (eg. 6-APB) or older drugs (eg. nitrous oxide) NPS: new, but can be uncontrolled (eg. 6-APB) or controlled (eg. mephedrone)

The legal loophole used by NPS Headshops and online retailers of ‘legal highs’/NPS get round the 1968 UK Medicines Act by stating that their products are not for human consumption, i.e. by definition not a medicine. So: no tests/trials required. Instead product packaging typically contains a cross/bones (sign of toxicity), and a warning not to consume the substance – using euphemisms such as bath salts, pond cleaner, room odoriser, incense, cream dispenser refills – and the vaguer product descriptors ‘souvenirs’ and ‘research chemicals’. Packaging also typically states ‘for sale to adults only’.

Headshops: famous UK chain Sell ‘legal highs’ and drug-related paraphernalia and literature Dr Hermans at Bold Street in Liverpool, UK

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50 of the 73 new NPS in 2012 were synthetic cannab-inoid products

Google results (August 2012): ‘buy legal highs’ = 2.74 million ‘buy research chemicals’ = 6.91 million http://m.londonlovesbusiness.com/3267.article

Problems with legal high/NPS sales Headshops/websites cannot give out information about the safer use of the drugs they sell No testing/trials of risks & harms of NPS sold No guarantee that different batches of same product will contain (a) same dose of drug, or (b) even same drug Huge variety of NPS available, with different chemical/ trade/slang names, making drug/health service responses & research work very difficult

2. Types of legal high/NPS Based on last-year prevalence of use among young adults in 2012/13 in England & Wales (British Crime Survey): What are the most popular legal highs? What are the most popular NPS among those banned since 2005? www.gov.uk/government/uploads/system/uploads/attachment_data/file/225122/Drugs_Misuse201213.pdf

Most popular legal highs & NPS - last-year use: 16-24s, E&W, 2012/13 Legal highs nitrous oxide 6.1% 2nd poppers 1.2% 7th salvia 1.1% 8th NPS banned mephedrone 1.6% 5th since 2005 ketamine 0.8% 9th magic mushrooms 0.6% 10th Traditional cannabis 1st, cocaine 3rd, ecstasy 4th, Illegal drugs amphets 6th, LSD & tranx 11th/12th Top 10 drugs: 3 are legal highs, 3 are NPS [steroids 13th; crack & khat 14th/15th; opiates 16th] Poppers = alkyl nitrites

Nitrous oxide used by 350,000 young people in past year Home Office figures show 'hippy crack' is second most popular drug among 16- to 24-year-olds. Guardian, 25 July 2013 “sniffing balloons full of the gas has become the summer recreational drug of choice, particularly for festival goers”

Nitrous oxide: whippets

Nitrous oxide (N2O, laughing gas) Young adults in UK report N2O as most popular legal high in online and media surveys (see later slides on prevalence) 16-24 year olds: N2O is 2nd most popular of all drugs used in last year in 2012/13 CSEW – reported by about 400,000 (6%) in E&W – only cannabis use is more prevalent Yet: Gets no or very little attention from mass media Coverage by educational publications poor/missed Relatively little research compared to other NPS

3 TYPES OF NPS BASED ON SOURCE Herbal highs: plant/fungi or animal part/product Synthetic highs: substance made by means of chemistry (semi-synthetic if started with natural precursors) Mixed herbal/synthetic: synthetic drugs mixed into natural drugs, esp. herbal material + cannabinoids ------------------------------------------------------------------------------------------------------- Electronic highs: perceptual, electrical (eg. brain tuners)

Herbal Highs: Chewed, smoked or brewed/drank Salvia divinorum Khat: cathinone (stimulant) Salvia divinorum salvinorin A (hallucinogen) Kratom: mitragynine (stimulant/ opioid-like)

Synthetic highs: white powders & pills BUBBLE ------------------- UPPERS or TRIPS

Some common NPS/legal highs Accessed: 5th March 2013

Mephedrone: methylmethcathinone 4MMC m-cat meph drone fert

Mephedrone injecting problems Photograph of left upper limb of Patient 3 post debridement Dorairaj J, Healy C, McMenamin M, Eadie P (2012). The untold truth about “bath salt” highs: A case series demonstrating local tissue injury. Journal of Plastic, Recon-structive & Aesthetic Surgery, 65, 37-41.

Synthetic opioids: bromadol Bromophenyldimethylaminophenylethylcyclohexanol 500 times stronger than morphine: 20 mg morphine / 10 mg heroin = 0.04 mg bromadol [40 mcg] Short-term effects include analgesia, sedation, euphoria, constipation, itching & respiratory depression Longer-term effects include tolerance and dependence VX-Chem http://www.vxchem.com/buy/bromadol Bromadol: C22H28BrNO  Purity: 99% Minimum Order Quantity: 500 grams Price: $3,440 for 500 grams ($6.88 a gram)

Herbal products containing synthetic cannabinoids Usually sold as herbal preparations containing inert herbal material (leaf etc.) saturated with synthetic cannabin- oids (SCs) & other drugs. The pure SC powder can also be obtained online.

New legal synthetic cannabinoids Latest batch of legal synthetic cannabinoids sold online include: 5F-PB22, AKB-48F, STS-135 & BB-22: from £15 a gram to £3,000 a kg – e.g. http://chemicalwire.com/cannabinoids.html

“Acute Kidney Injury Associated with Synthetic Cannabinoid (SC) Use” In 2012, Wyoming Department of Health investigated 16 cases of Acute Kidney Injury (AKI) following SC use, across 6 states. 5 of the 16 patients had used a new SC called XLR-11 Also: SCs are 2 to 3 times more likely than cannabis to produce sympathomimetic effects (tachycardia, hypertension), and 5 times more likely to produce hallucinations – with an increased risk of seizures. “No antidote exists” ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Morbidity & Mortality Weekly Report, Vol. 62 (6), 93-8 (February 15, 2013) http://www.cdc.gov/mmwr/pdf/wk/mm6206.pdf

Types of novel psychoactive drugs Main illegal drugs being mimicked Phenethylamines ecstasy (MDMA), amphetamines Piperazerines ecstasy, amphetamines Cathinones ecstasy, amphetamines, cocaine Tryptamines LSD, psilocin, DMT Cannabinoids THC, hallucinogens, sedatives Miscellaneous stimulant/sedative/hallucinogen/opioid Source: EMCDDA-Europol Annual Report on the implement-ation of Council Decision 2005/387/JHA [April 2012]

Recent guide to NPS, Nov 2013 http://www.kfx.org.uk/drug_facts/drug_facts_images_and_pdfs/researchchemicals2013.pdf

3. Legal responses to NPS Misuse of Drugs Act amendments (see Appendices) Temporary Class Drug Orders - ban trafficking for 1 year while ACMD review (max 14 years prison) > methoxetamine (made class B, 2013) > June 2013: 5APB & 6APB (Benzo Fury) & NBOMe Importation bans: 2DPMP, phenazepam (class C, 2012) Intoxicating Substances Supply Act 1985 (2008-11: 0) Trade/consumer legislation Anti-social Behaviour, Crime & Policing Bill 2013

Response of NPS marketers to NPS bans Continuing to sell banned NPS in countries which have not yet banned them ‘Tweaking’ banned chemical to produce new legal version with similar effects Producing new NPS in unbanned groups Banned NPS move into illicit drug market, usually with rise in price & adulterants and fall in purity, eg. mephedrone banned in 2010 but still 5th most popular last-year drug for 16-24s in 2012/13 BCS (after cannabis, nitrous oxide, cocaine and ecstasy)

4. Recent research and notable studies New Musical Express Drugs Survey – October 2013 Sample: 5,295 respondents: 63% male, 56% in FT education, 55% 18-24 years (20% U-18) Lifetime drug use: 78% - 4 in 10 had tried legal highs Last-year drug use: 74%: legal highs 2.6%, mephedrone 1.1 % First drug used: legal highs 1.6%, mephedrone 1.2% Attitudes: 54% believed legal highs should not be banned

Global Drug Survey 2013 Online survey advertised in Mixmag, Guardian & Gay Times 2012, n = 22,000 (80% aged 18-30) NPS/Legal Highs – 12% had ever used Unknown drugs – 14% had used a drug at a party/club without knowing what it was Bought drugs online: 22% Past-month use in UK (n = 7,000+) Nitrous oxide 26.9% Mephedrone 13.8% Poppers 13.6%

NPS obtained from internet, UK, late 2011 A total of 22 ‘legal high’ products were purchased from 5 different internet sites in late 2011, and each substance was screened to determine its active ingredients. Six products - 4 sold as Benzo Fury & 2 as NRG3 - contained 6-APB; three contained MDAI; three contained 5-IAI; three contained methoxetamine; three contained benzocaine; two (labelled NRG2) contained cathinones, including the banned mephedrone; and two contained MPA. Overall, 23% did not contain the listed active ingredients Source: Ayres T & Bond J (2012). A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet and their impact on public (ill)health. Legal highs or illegal highs? BMJ Open, July 31, 2012; 2(4).

Emergence of multi-drug NPS products, e.g. 11 drugs in E tablet Analysis of RockStar ecstasy tablet in 2013 found ELEVEN different drugs present, including MDMA, amphetamine, cathinones, BZPs & methoxetamine Scottish Police Authority, reported by Crew2000 pic.twitter.com/6MPb2DfoZR

The NPS are mutating… Many new NPS identified in Japan in 2012, including a product containing both URB-754* (inhibitor of an endo-cannabinoid deactivating enzyme) & 4-Me-MABP (cathinone derivative) Also, a 3rd unknown compound - N,5-dimethyl-N-(1-oxo-1-(p-tolyl)butan-2-yl)-2-(N′-(p-tolyl)ureido)benzamide) – was also found in the product, and deduced to be an unexpected reaction between URB-754 and 4-Me-MABP. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ * 6-methyl-2-[(4-methylphenyl)amino]-1-benzoxazin-4-one ~ 4-methylbuphedrone . Uchiyama N et al. (2012). URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products. Forensic Science International, October 2012.  

Deaths related to NPS, England & Wales   2008 2009 2010 2011 2012 mephedrone/cathinones 0 0 6 6 18 BZP/TFMPP 0 9 5 2 .. GHB/GBL 20 16 12 20 .. novel psycho. substances 25 26 22 29 52 NPS includes current legal highs and former legal highs like mephedrone Office of National Statistics (2013). Deaths related to drug poisoning in England & Wales, 2012 Deaths related to NPS, Scotland novel psycho. substances 0 2 8 9 17 NPS: substances which were legally available at the time of the death National Records of Scotland (2013). Drug-related deaths in Scotland, 2012.

Deaths from legal highs in 2012 An average of: one death per week in England & Wales One death every 3 days in Scotland Given differences in population size, this means that the annual mortality rate for legal highs is three times higher in Scotland (about 1 in 300,000) compared with England & Wales (about 1 in a million)

5. Conclusions NPS are a ‘game-changer’ - they have: > hugely expanded the number of psychoactive drugs > sidestepped drug-related laws (legal loophole), and banned NPS are rapidly replaced by more legal NPS > introduced new drug-related risks and harms; > caught many drug services unprepared/untrained > AND they require a harm-reduction approach more than a recovery approach – but the UK drug strategy’s primary aim is recovery

Legal high users = guinea pigs Source: Lifeline (2013). “Big Blue Book of Drugs”. [Available from: Exchange Supplies]

WTF should we do next? Take an evidence-based approach Take a principled approach: theory & models – not common-sense or counter-productive bans Cross-national/regional comparisons: especially New Zealand – Psychoactive Substances Act 2013 Take a harm-reduction approach based on categories of NPS - stimulant, sedative, hallucinogen etc. – as well as the effects/harms of specific substances Involve NPS users: representation, participation

NPS/legal high use interventions: need consultation with and representation of NPS users on policy-making and drug service groups

Dr Russell Newcombe www.3Dresearch.org.uk director@3Dresearch.org.uk Research, Training & Consultancy on Drugs, Disorder & Deviancy

Appendices

Visual hallucinations: animated simulation – OPTICAL SPIRAL Look at the circle at the centre of the animated spiral, and keep your eyes focused on it for at least half a minute. When I stop it and say OK, look at the back of your hand from about 12 inches away. You will experience a brief visual hallucination. This exercise is voluntary: do not take part if you suffer from epilepsy, anxiety, migraines or any other health conditions which this could affect

NZ Psychoactive Substances Act 2013 Unlike the previous law, where substances were only banned after they started causing harm, this Act reverses the onus of proof onto manufacturers to prove products are ‘low risk’ before they can be sold. Ministry of Health authority administers a legal framework for the testing, licensing of manufacture and sale, and general regulation of NPS. The clinical testing process costs manufacturers up to $2 million and provides information about each substance including its risk levels. Penalties for importation or manufacture without a license: maximum sentence 2 years imprisonment, or, for a company, a fine up to $500,000. Penalty for selling: imprisonment for up to 3 months or fine up to $40,000. Penalty (civil) for possession of unapproved substance: fine up to $500. Communities will be consulted over where NPS stores are allowed to open. The Authority will be able to recall products that turn out to cause harm not detected in clinical trials, by simply revoking the license. .

National Poisons Information Service Report 2012/13 NPS drugs (legal highs or banned since 2005) involved in telephone enquiries & TOXBASE accesses during 2012/13 [% change compared to 2011/12] Of 32 drugs listed, NPS comprised 20 (63%) Telephone queries (n = 1,021) Toxbase queries Number Rank (n = 49,390) . legal highs 103 [up 34%] 5 8,432 [up 36%] mephedrone 76 [down 3%] 7 alkyl nitrites 57 [up 36%] 10 ketamine 11 2,993 [down 14%] methcathinone 12 alphamethyltryptamine (AMT) 13 synthetic cannabinoids 15 5/6-APB 16 methylenedioxyaminoindane (MDAI) 20 magic mushrooms 21 251-NBOMe 22 methoxetamine 23 methiopropamine (MPA) 24 gammabutyrolactone (GBL) 26 trifluoromethylphenylpiperazerine (TFMPP) 27 benzylpiperazerine (BZP) 28 1,574 [down 5%] methedrone 29 methylenedioxypyrovalerone (MDPV) 30 5-2-aminopropylindole (5-IT) 31 2-aminoindane (2-AI) 32

Local responses in UK by late 2013 Swansea: organized response to legal highs, including education, training, conference etc. Brighton: a specialist drug service for legal high users has been launched Lincolnshire: police have announced that they want consultation with legal high users

Changes in perception of drugs over time: medicines, Illegal drugs, legal highs…

Why have legal highs/NPS become so popular over the last 5 years? Not just because of price – many illegal drugs are cheaper than they were 20 years ago, and NPS can cost more. Main reasons seem to be: (1) the drop in the purity of several popular drugs (next slide) (2) the drop in availability of some popular drugs (eg. skunk) (3) the advent of the Internet and headshops as new ways of buying psychoactive drugs (4) Entrepreneurs prepared to research, produce and market many new legal substances for getting ‘high’ (notably China) (5) Modern society: consumer-oriented, pleasure-oriented

Nitrous oxide (N2O) Nitrous oxide (laughing gas), when inhaled, causes 1-2 minutes of mild to moderate intoxication - including hilarity, lateral thinking & the ‘eureka experience’. Effects include dizziness and loss of coordination, so its safest to do when sitting/laying down. Boost the effects of hallucinogens like ecstasy & LSD. Most users inhale it from balloons filled from whippets – refills for whipped cream dispensers.

Electronic/Technological Highs Brain-Wave Tuners: computer programs that, via electrodes attached to skull, produce direct changes in electrical brain-waves, & so stimulation, sedation or hallucinations Perception Tuners: notably visual, tactile & sound-based (eg. binaural sounds, visual animations, Dream Machine) The Chemputer (Cronin): makes molecules from atoms – and psychoactive drugs typically comprised of 2 or more of just four atoms: carbon, hydrogen, oxygen and nitrogen http://www.guardian.co.uk/science/2012/jul/21/chemputer-that-prints-out-drugs

MODA amendments, from 2001 to 2014 2001 35 phenethylamines [ecstasy-type] A1 2003 GHB (gammahydroxybutyrate) C4 2005 psilocin-based mushrooms (live/fresh) A1 ketamine C4 2009 GBL (gammabutyrolactone), 14BD (butanediol) C(R4b) BZP (benzylpiperazine) & other piperazines C1 some synthetic cannabinoids B1 2010 mephedrone & substituted cathinones B1 2012 phenazepam C2 2013 more synthetic cannabinoids B1 methoxetamine & some analogues B1 2014 khat C1 R4b: paragraph 4b of MoDA 2011 Regulations makes it legal to possess or supply GBL/14BD “except where a person does so knowing or believing that they will be used for the purpose of human ingestion” 2001: one of 35 phenethylamines was a stimulant, placed in Class B: hydroxyamphetamine Synthetic cannabinoids, eg. JWH-018 (Spice) – but excludes nabilone (Cesamet) Oripavine (synthetic opioid) also made class C in December 2009

Temporary Class Drug Orders 2011 Police Reform & Social Responsibility Act 2011 (Nov.) Home Office can place a drug in a Temporary Class if the ACMD advise that (a) it is or is likely to be misused and (b) it has or could have harmful effects – and that a fast response is required to protect public. Covers all MoDA offences for 12 months – except possession, though police can still confiscate TCDs. Penalties as for class B/C (max. 14 years custody). In first 2 years, just 3 drugs have been placed under a TCDO: methoxetamine (banned 2013), 6APB & NBome Section 151 & Sch. 17

European Union Survey, June 2011 Out of 27 EU countries in 2011: The UK was ranked fourth for legal high use (Ireland was first) The UK ranked top for the proportion of legal high users who were offered them in clubs & parties 670,000 15-24 olds in England & Wales reported that they had used legal highs in 2011/12 survey

British Crime Survey: 2009/10 - 2011/12 Adults in England & Wales reporting last-year use of 5 drugs:   ^ 367,000 ~ 220,000 16-59 16-24 . 09/10 10/11 11/12 09/10 10/11 11/12 Mephedrone .. 1.4 1.1^ .. 4.4 3.3 ~ Spice * 0.4 0.2 0.1 1.2 0.4 .. BZP 0.5 0.1 0.1 1.4 0.2 .. Khat 0.2 0.2 0.2 0.5 0.3 .. GBL/GHB 0.1 0.0 0.1 0.5 0.1 .. _____________________________________________________________________ All five drugs were ‘legal highs’ until controlled by the UK Misuse of Drugs Act in 2010 – the exceptions being GHB (banned in 2005) & khat (still uncontrolled) * and other synthetic cannabinoids .. not reported E&W = England & Wales ~ 95% CI: 173,000 to 267,000 last-year mephedrone users in E&W: 16-24s, 2011/12 ^ 95% CI: 317,000 to 416,000 last-year mephedrone users in E&W: 16-59s, 2011/12 Note: the BCS (now called CSEW) does not include poppers or solvents in its definition of ‘legal highs’ or ‘recently controlled drugs’

Characteristics of mephedrone users British Crime Survey 2011/12: levels of last-year use in E&W Age: 16-19 (2.9%) & 20-24 (3.6%) vs 25-59 (0.5%) Sex: men 1.5% vs women 0.7% Ethnic group: white (1.2%) & mixed (1.9%) vs other races (0.3%) Marital status: single (2.7%) vs others (0 to 1%) Occupational status: students (2.7%) & unemployed (2.2%) vs others (0-1.3%) Area: city-dweller (2.8%) vs others (0.5%-1.4%) Past-month nightclub attendance: 9+ (9.7%) vs none (0.5%) Past-month pub/bar attendance: 9+ (4.7%) vs none (0.3%)

Levels of use of legal highs in England & Wales, 2012/13 British Crime Survey 2012-13 (E & W, n = 21,600) % Last-year use 16-59s 16-24s Nitrous Oxide 2.0 6.1 Poppers 0.8 1.2 Salvia divonorum 0.3 1.1 Poppers = amyl nitrites (sic); Nitrous O. = nitrous oxide; Salvia Div. = salvia divinorum

Range of drug contents in 44 synthetic cannabinoid products NPS are often multi-drug products. Research in Japan tested 44 synthetic cannabinoid products & found that most contained one or both of 2 SCs: cannabicyclohexanol & JWH-018. 7 of 44 ( 1 in 6) also contained oleamide, a CNS sleep chemical. Concentration ranges across products Cannabicyclohexanol 1.1 to 16.9 mg/g JWH-018 2.0 to 35.9 mg/g Oleamide 7.6 to 210.9 mg/g Uchiyama N et al. (2010). Chemical analysis of synthetic cannabinoids as designer drugs in herbal products. Forensic Science International, 198, 31–8.

UK Forensic Early Warning System FEWS was set up to identity New Psychoactive Substances (NPS) more promptly to enable Government “to take action before a harmful substance takes a foothold in the UK”, and to feed into the UK-wide Drugs Early Warning System (DEWS). Analysis of 1,300 samples tested during January 2011 to March 2012 found 17 NPS (9 already banned in UK): 5 synthetic cannabinoids, 4 tryptamines, 2 phenethylamines, 1 cathinone & 5 other NPS. 6 specific new drugs were: 5-IAI, methoxyphenamine, ethylphenidate, camfetamine, JWH-022 and etizolam. Source: ANNUAL REPORT ON THE HOME OFFICE FORENSIC EARLY WARNING SYSTEM (FEWS). A SYSTEM TO IDENTIFY NEW PSYCHOACTIVE SUBSTANCESIN THE UK (May 2012, Home Office)

‘Tweaking, bombing, dabbing & stock-piling: the emergence of mephedrone and the perversity of prohibition’ “One thing is certain: no matter how wide the net is cast in terms of framing legislation to control mephedrone use, the ‘research chemists’ and cyber-entrepreneurs are likely to remain one step ahead … Until people no longer want to take drugs to experience altered states of intoxication and until the poss-ibilities for chemically tweaking molecules are exhausted, the ‘cat and mouse’ antics witnessed with ‘meow’ will continue” Measham F, Moore K, Newcombe R, Welch Z. (2010). Drugs & Alcohol Today, 10(1), 14-21