New Psychoactive Substances

Pharmacology: What do we know?

Take-Home Message

We Know Something We don’t Know Something

We never going to know everything

Content

• Definition

• Myth or facts

• Data on NPS

• NPS group of effect

• Pharmacology/Risk of use

Definition

• NPS are defined as “substances of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat”

Myth vs Facts

Myth Facts

All NPS drug = Synthetic Drugs NPS drugs included some plant based illicit drug

New Psychoactive Substance = Newly discovered drug Some of NPS drug are discovered more than 40 years ago

Taking any NPS causing user to be “crazy” Effects of individual NPS drug depends on its structure

NPS drug problem can be solved by banning NPS markets is very revolving market

A synthetic analogue of THC , ‘HU-210’, was first synthesized in 1988 and is considered to have a potency of at least 100 times more than THC.

3,4-methylenedioxypyrovalerone (MDPV), first synthesized in 1969, emerged in 2007 as a new psychoactive substance in Germany

Pyrovalerone, first synthesized in 1964 and marketed for use as an appetite suppressant and in the treatment of chronic fatigue, was later withdrawn due to abuse and dependency in users

Data

Global emergence of new psychoactive substances, up to December 2018:

Receptor

NPS grouping

No single way to categorise, but (almost) all fall into one of four classes:

Stimulants(similar to cocaine, MDMA, amphetamine)

Cannabinoids/SCRAs(synthetic cannabinoid receptor agonists)

Hallucinogens • Dissociatives(similar to ketamine and PCP)

• Psychedelics(similar to LSD, psilocybin)

Depressants • Benzodiazepines

• Opioids

NPS stimulants Mephedrone (‘m-cat’, ‘meph’, ‘drone’ or ‘miaow’), methylone (‘explosion’ or ‘top cat’, MDPV

Mechanism of action • Traditional’ drugs: amphetamines, cocaine, MDMA (ecstasy) • All increase the monoamines receptor interaction : Serotonin (5-HT), Dopamine (DA),

Noradrenaline(NA) • ↑DA: reward & addictive behaviour, mania-like syndrome with euphoria, talkativeness,

disinhibition, agitation, ↑ psychomotor activity (psychosis) • ↑serotonin:entactogenic2, elated mood, ↑ self-confidence, extroversion, psychedelic

experiences (“oceanic boundlessness”) • Ratio of DA:5HT important with all this class • The higher the 5HT ratio, the more like MDMA; ↑DA more like amphetamines

Mode of administration

• Common : Swallowed (Pills), Intranasal(snorting)

• Less Common : Injected, Rectal (Plugging)

Short term risk Agitation, psychotic symptoms, hyperthermia, anxiety, hypervigilance, cardiovascular toxicity, seizures, renal/respiratory failure, Delirium, Serotonin syndrome, stroke

Long term risk Impulsive behavior, Dependency, Depression, Cognitive impairment, Psychosis *Psychological withdrawal effects common after cessation

NPS Cannabinoids

• Modulate G-protein coupled receptors of the endocannabinoid system

• CB1R: predominantly on CNS neurons; CB2R: predominantly in the immune system

• Exogenous activation primarily via partial agonist Δ-tetrahydrocannabinol(THC) on CB1R, produces very different patterns of receptor activation

• Psychotomimetic via mesolimbic DA activation

• SCRA also target CB1R, but generally full agonists: affinity, efficacy varies between agents, many are being shown to be especially potent

• Entirely synthetic: nothing to do with the cannabis plant • Typically sold in mixed potpourris, difficult to quantify: spice, ‘noids • Don’t smell like cannabis, can be smoked in e-vapes, imbued on paper etc

‘Spice Gold’, ‘Spice Silver’, ‘Spice Diamond’, ‘K2’, ‘Bliss’, ‘Black Mamba’, ‘Bombay Blue’, ‘Blaze’, ‘Genie’, ‘Zohai’, ‘JWH -018, -073, -250’, ’Kronic’, ‘Yucatan Fire’, ‘Skunk’, ‘Moon Rocks’, ‘Mr. Smiley’.

• Worryingly, growing evidence that many NPS cannabinoids are more potent: anecdotal but compelling stories of +++agitation, difficult to treat acute psychoses

• Cannabis contains ›50 psychoactive compounds, most notably ΔTHC, but some others are anti-psychotic, e.g. cannabidiol

• SCRAs do not have this antipsychotic component

• Await better longer-term studies, but highly likely to be a considerable cause of morbidity for mental health in the future

• Particular concern about longer-term outcomes in children smoking it

Mode of administration

• Common : Smoked (after being sprayed on herbal mixture), Inhaled (vaporizers)

Short term risk Agitation, psychosis, confusion, slurred speech, cognitive impairment, renal failure, tachycardia, hypertension, myocardial infarction, pulmonary damage, seizures

Long term risk Psychological dependency, addiction potential, psychotic illness *Psychological withdrawal effects likely after cessation

NPS Hallucinogen(Psychdelic)

• Three sub-classes • Phenethylamines (eg: mescaline) • Tryptamines(eg: psilocybin) • Lysergamines (eg: lysergic acid diethylamide)

• Common mechanism of action is 5HT2Areceptor (partial) agonism

• Also bind to other 5HT receptors, which might also produce effects

• Plant-based hallucinogens used entheogenically for millenia

• Many novel drugs synthesised since LSD by Albert Hoffmann in 1938

• Most data on the ‘popular’ 2C &NBOMe series (also have stimulant properties)

NPS Hallucinogen(Dissociative)

• Uncompetitive antagonists of the glutamatergic NMDA receptor

• NPS dissociatives act in a similar manner, but specific pharmacodynamics likely to vary considerably (cfvariation between ketamine and far stronger PCP)

• Novel sensory changes, dissociation, weightlessness, euphoria

• Sense of an absence of time, unusual thought content, loosening associations

• In extremis, enter a ‘K hole’: sense of universal understanding, connecting to cosmic planes; can be hellish nightmare with no sense of end

Mode of administration

• Common : Swallowed (Pills, paper, liquid), Intranasal(snorting)

• Less Common : Injected

Short term risk Accidents/trauma, aggressive/psychotic states, acute cerebellar toxicity, cardiovascular toxicity, respiratory failure

Long term risk Addiction, Problem with mood/ memory, cardiovascular problems, abdominal pain, kidney/bladder/urinary tract damage (ketamine/methoxatamine)

NPS Depressant (Opioid)

• Similar to established recreational opioids (heroin/morphine), but with the potential for much longer durations of action

AH-7921

Novel fentanyls

NPS Depressant (Benzodiapines)

• Sedative, anxiolytic, hypnotic, and anticonvulsant properties–some with long duration of action

Diclazepam

Flubromazepam

• Mode of administration

• Common : Smoked, Swallowed(pills/tablets), Injected, Intranasal (snorting)

Short term risk Overdose, Confusional states, Seizures after withdrawal

Long term risk Addiction Impaired cognition *Potential for withdrawal effects after cessation

Thank you for listening