Novel psychoactive substances

Question 1

TIMELINE OF DRUG CONTROL

Answer 1

1803: Morphine was first isolated from opium poppy by Friedrich Surturner
1859: Cocaine first isolated by German chemist Albert Niemann
 Opium wars – Britain tried to trade Opium in China for financial gain which led to conflict, and this war led to the Pharmacy Act
1868: Pharmacy Act stated that Opium could only be sold by pharmacists and records had to be kept on all sales
1874: Heroin first synthesised by English chemist Alder Wright
1908: Pharmacy Act stated Morphine and Cocaine could only be sold by pharmacists
1912: MDMA synthesised but not trialled on humans so psychoactive effects were unknown

1916: Defence of the Realm Act in initiated to ban the selling of cocaine to soldiers in WW1; first time the Home Office got involved
1928: Dangerous Drugs Act criminalised the possession of cannabis – responsibility moved from the Health Ministry to the Home Office
1929: Mephedrone synthesised but only really started getting used in early 2000s
1938: LSD synthesised by Albert Hoffman
1964: Drug Prevention of Misuse Act – Amphetamines criminalised and amended in 1966 to include LSD
1971: Misuse of Drugs Act (Alexander Shulgin experimented on himself with designer psychedelics including MDMA in the 60s-70s)
1977: MDMA made illegal in UK
2003: Mephedrone re-synthesised and became available to the public
 The Misuse of Drugs Act in 1971 categorised drugs into the Class A-C system and prosecution takes place according to the category of the specific drug
 This led to chemists finding loopholes:
1. Chemists would synthesise a new drug – it would have a slightly different structure and be unscheduled so therefore legal
2. Drug sold legally until the government managed to get it into the controlled drugs category – it would then become illegal
3. A new drug would be synthesised, and the cycle continues
4. Was only put to a stop with the Psychoactive Substances Act in 2016

Question 2

What are novel psychoactive substances. State the important act established in 2016

Answer 2

THE PSYCHOACTIVE SUBSTANCES ACT 2016

Novel psychoactive substances (formerly “legal highs”) are compounds designed to mimic existing established recreational drugs e.g. Spice and Black Mamba – synthetic cannabinoids.

 Legislation varies internationally - in the UK it’s illegal to distribute or sell novel psychoactive substances but possession isn’t a criminal offence
 The Act criminalises any substance intended for human consumption with a psychoactive effect.

 Differs from the Misuse of Drugs Act in 1971 as it covers substances by virtue of their psychoactive properties instead of the identity of the drug or its chemical structure:

Question 3

Novel psychoactive substances can be grouped into four main categories…

Answer 3

1. Stimulants – includes cathinone family, such as mephedrone
   - They increase synaptic levels of serotonin, dopamine and/or noradrenaline to produce a sense of euphoria and wellbeing “a high”
   - Commonly swallowed or snorted
2. Depressants – includes opioids and benzodiazepines
   - Opioids have the potential for much longer durations of action
   - Benzodiazepines have sedative, anxiolytic, hypnotic and anticonvulsant properties with some having a long duration of action
   - Commonly smoked, swallowed, injected or snorted
3. Hallucinogens – includes psychedelics and dissociatives
   - Psychedelics produce perceptual alterations and quasi-mystical experiences, with some having stimulant properties
   - Dissociatives produce a euphoric, dissociated state with a perception of disconnection from physical body
   - Both are commonly injected and swallowed with dissociatives also being snorted
4. Cannabinoids – includes spice, black mamba
   - Typically, full agonists of cannabinoid receptors, producing a pleasant state of relaxation and of feeling stoned
   - Commonly smoked and inhaled

Question 4

how do you classify a psychoactive substance

Answer 4

 PSYCHOACTIVE SUBSTANCE: any substance which is capable of producing a psychoactive effect in a person who consumes it
 A substance produces a psychoactive effect if ‘by stimulating or depressing the person’s central nervous system, it affects the person’s mental functioning or emotional state’.
 Psychoactive properties are assessed in different ways, with the first line of response being:

1. RECEPTOR BINDING ASSAY
   - Determines whether the drug binds to a receptor
2. FUNCTIONAL ASSAY
   - Determines whether the drug activates a response following an interaction with the receptor
    Mammalian cell lines (e.g. HEK293T cells) are transfected with a receptor (e.g. GABAA)
    This causes receptor to be expressed by the cell line
    If the receptor is activated by addition of the drug = an intracellular cascade is triggered (usually calcium release)
    The response is then measured to identify the effect of the drug
    The receptors covered within The Act include:
   - CB1: Cannabis and synthetic cannabinoids
   - GABAA: Benzodiazepines
   - 5-HT2A: Psychedelics
   - NMDA: dissociative/hallucinogenic drugs (ketamine)
   - Mu-opioid: opioid drugs (heroin)
   - Monoamine transporters: psychostimulants e.g. MDMA, cocaine
    In some cases, drugs (nitrous oxide, solvents) aren’t responsive to these assays so alternative sources of evidence are required:
3. PUBLISHED LITERATURE
   - Wealth of evidence available both in vitro and in vivo studies by academic researchers which can be referenced by expert witnesses
4. WITNESS ACCOUNTS
   - Accounts from a witness of behaviour exhibited by an individual who has taken the substance may also be relevant
    The Act changed the drugs which were now classed as legal and illegal:
   - Before the Act: illegal drugs only included classes A-C and Schedules 1-5 whereas everything else was legal
   - After the Act: alcohol, caffeine, food, nicotine, medicinal products and controlled substances (depending on who they were being used by) were legal and everything else was illegal

Question 5

What was the effect of introducing the 2016 psychoactive substances act

Answer 5

before the act: A total of 113 shops were found to be selling novel psychoactive substances on the internet in the English language and shipping to the UK

 Only 52% remained open – 65% of these were based overseas, 19% removed them and became a ‘headshop’ and 16% were inactive
 Only 24% of the UK-registered websites remained open after the ban
 It’s unknown whether the UK retailers have ceased selling or have been displaced to underground markets – street level dealing or the hidden web

Question 6

Mephadrone

Answer 6

 A synthetic cathinone that can be known as ‘bath salts’, ‘plant food’ and ‘meow-meow’
 Abused due to their psychostimulant and hallucinogenic effects which are similar to cocaine, MDMA, amphetamines and methamphetamines
 Serious side effects – increased heart rate, chest pain, change in body temp, insomnia, amnesia and seizures
 Classified as a Class B substance under The Misuse of Drugs Act in April 2010 mainly due to the large media interest it attracted

Question 7

Mephedrone mechanism of action

Answer 7

 Mephedrone is a non-competitive blocker of monoamine transporters – Dopamine transporter (DAT), Serotonin transporter (SERT) and Noradrenaline transporter (NET)
 By blocking the transporter = monoamines can no longer be transported back to the presynaptic neurone = causes accumulation of dopamine, serotonin and noradrenaline in the synaptic cleft = increased activation of postsynaptic receptors

Question 8

What is a good way to predict psychoactive activity, the toxic effects, addiction potential of Mephadrone

Answer 8

 The relative serotonin/dopamine (5-HT/DA) activity can be helpful in predicting psychoactive effects, toxic effects and potential for addiction
 This is done by monitoring the DAT:SERT ratio
- A low DAT/SERT inhibition ratio (<0.1) = tenfold greater relative 5-HT vs DA activity (MDMA)
- A high DAT/SERT inhibition ratio (>10) = greater relative DA vs. 5-HT activity (Methamphetamine)
 High dopamine to serotonin ratio = more likely to lead to addiction as dopamine is the neurotransmitter most associated with reward
 Mephedrone falls between MDMA and Methamphetamine ratios which correlates with the psychoactive effects of Mephedrone

Question 9

What are the behavioural effects of Mephedrone

Answer 9

 Mephedrone can cause changes in social behaviour – elated mood, increased impulsivity, psychosis

 Chronic use can impair cognitive function

 Associated with binging tendencies – compulsion to use and addictive behaviours often seen (correlates with rodent studies)

Question 10

2C Drugs

Answer 10

 In 1991, Alexander Shulgin published PIHKAL (Phenethylamines I Have Known and Loved), A Chemical Love Story
 The book detailed synthesis instructions for over 200 psychedelic compounds (including 2C series) including bioassays, dosages and other commentaries
 The ‘Shulgin rating scale’ was used to report the subjective effect of psychoactive substances at a given dosage using: +, ++, +++, ++++
 2C refers to the two carbons between the amino group and the benzene ring in the chemical structure
 Designer substitution to the 2C structure can result in increased hallucinogenic activity e.g. adding methoxy groups at the 2 and 5 positions on the base structure ring or substituting Iodine or Bromine at the 4 position

Question 11

What is the mechanism of action of 2C drugs

Answer 11

 A clear mechanism of action is yet to be established
 However, 2C compounds have been found to be partial agonists for different subtypes of 5-HT receptors – specifically 5-HT2A, 5-HT2B and 5-HT2C receptors
 2C compounds have also been shown to inhibit SERT and to a lesser extent, NET and DAT but have very low potency with these monoamine transporters
 2C-B and 2C-I compounds differ with the halogens in that position
- Alexander Shulgin provided an account of onset and duration of euphoric effects after oral ingestion
- 2C-B had a duration of 4-8 hours with a dosage of 12-24 mg
- 2C-I had a duration of 6-10 hours with a dosage of 14-22 mg

 Other approaches being taken by various countries include having a regulatory approach (grant permits and regulate) and having restricted availability (limited points of sale until harms established)