Stimulants Flashcards
Stimulants
Stimulants can be described as ‘monoaminomimetics’ as they mimic the effects of the monoamines adrenaline, noradrenaline, 5HT and dopamine.
They can cause direct activation of monoamine receptors, block reuptake mechanisms or cause indirect release of monoamine neurotransmitters.
In a sporting context, stimulants can be inadvertently consumed (e.g. in a proprietary medicine) or deliberately consumed for misuse as recreational drugs or to enhance performance.
Ephedrine
Ephedra sinica, known as ma-huang, was used in traditional chinese medicine (~3000 BCE) for asthma, flu, cough and allergies as a tea. This fits in with adrenaline’s role in bronchodilation.
Active components include ephedrine, norephedrine, pseudoephedrine, norpseudoephedrine…
Ephedrine was synthesised in Japan in 1885.
In the 1920s there was mass manufacture in China. By 1928 export to Europe was >200 tonnes.
In 1948 Vicks Vatronol nose drops for ‘rapid nasal decongestion’ were invented, but have since been withdrawn due to evidence for transient weight loss and increased heart rate. This worked by constricting blood vessels in the nasal cavity.
Pseudoephedrine, the enantiomer of ephedrine, acts as a peripheral sympathomimetic, causing tachycardia and hypertension.
It is a CNS stimulant, acting as an appetite suppressant and reducing fatigue and drowsiness.
It was marketed as a nasal decongestant under the brand names Sudafed, Benadryl and Actifed.
Anecdotally, it is used by long distance drivers to combat fatigue.
It’s also used as a precursor for methamphetamine synthesis.
Due to its risk of misuse, restrictions on sale and supply have been placed on pseudoephedrine in the UK since 2008.
Khat
Khat is Catha edulis, named after qāt.
It was used in Ancient Egypt as a religious plant to ‘achieve divinity’.
It is prominent in East Africa and SW Arabia.
An 11th century Persian text described it as “sour to taste and slenderly made … coolant, relieves biliousness, and is a refrigerant for the stomach and the liver”.
In 1856, Charles Dickens wrote about its use in East Africa, comparing its effects to that of a strong dose of green tea on Europeans, who he believed to be used to stronger stimulants and therefore unaffected by khat.
The cathinone ꞵ-keto-amphetamine, a ‘natural amphetamine’, is found in khat.
There have been many cathinone derivatives synthesised to achieve similar psychoactivity to khat, the first of which was methcathinone.
This shows structural overlap to the synthetic drugs Diethylpropion, an appetite suppressant withdrawn in 2022, and Bupropion, synthesised in 1969 as an atypical antidepressant (less likely to cause sexual dysfunction, weight gain or sleepiness) and used to assist smoking cessation in the UK.
Amphetamine
Amphetamine is amino phenethylamine.
It was synthesised in Germany in 1887 and resynthesised in the US in 1927 by Gordon Alles, who was looking for a synthetic replacement for ephedrine.
In 1933 it was marketed as Benzedrine, an inhaler decongestant and for asthma.
In 1936 Benzedrine sulphate tablets were then marketed for narcolepsy, as well as for obesity, hypotension, low sex drive and chronic pain. The mechanism for chronic pain is not well understood but it might have more to do with easing the emotional burden of pain.
It primarily became associated with its use for combating fatigue and suppressing appetite.
Amphetamine is reported to increase aggression.
In 1937 Benzedrine was reported to improve school performance in children with severe behavioural problems.
Methamphetamine
Methamphetamine (Pervitin) was synthesised in Germany in 1938.
In WW2, amphetamine and methamphetamine were used by the Allied troops and Axis forces.
- Pervitin as ‘Aviator’s chocolate’ or Panzerschokolade (‘Tank chocolates’) to German troops.
- US forces in the North African campaign were supplied with 500,000 Benzedrine sulphate tablets.
- Use probably linked to increased wakefulness and aggression.
Methamphetamine injections may have been used by Germany to win the 1954 world football cup. Team officials said they had injected their players only with vitamin C during the tournament, but vitamin C is not normally injected and Pervitin was widely used in many sports at the time. These injections were also distributed secretly and they only became known because those who got injected contracted jaundice.
Methylphenidate
Methylphenidate was first synthesised in 1944 at CIBA.
In 1954, CIBA filed a patent for Ritalin to treat psychiatric disorders.
It was used in the UK to treat ADHD and narcolepsy.
Methylphenidate’s primary targets are the dopamine transporter (DAT) and the noradrenaline transporter (NET), blocking reuptake and increasing neurotransmitter concentrations in the synaptic cleft. Its affinity for DAT is significantly higher than for NET.
Ritalin had dose-dependent effects on: appetite suppression, dry mouth, anxiety, nausea, insomnia, restlessness, dyskinesia, dizziness, dry eye and hyperhidrosis.
Serious but uncommon adverse effects include psychotic or manic symptoms, growth suppression, and cardiovascular risks.
There was some controversy over its effectiveness.
Evidence suggests that it has a similar addiction/dependence profile to amphetamine. There is therefore controversy surrounding juvenile prescription for ADHD.
Modafinil
Modafinil was developed in 1970s France at Lafon Labs.
In 1998, it gained FDA approval. It is also used in the UK to treat narcolepsy with or without catalepsy.
It has also shown positive results in managing fatigue associated with various conditions, including depression, cancer, and tiredness in military personnel.
Due to its potential for addiction, it is classified as a Schedule IV controlled substance in the United States.
Described as eugeroic (wakefulness-promoting), rather than a stimulant.
It was also approved for shift workers with sleep disorders or sleep apnoea, and it is often used by NHS shift workers.
Adverse effects include: anxiety appetite suppression, cardiac disturbances, confusion, dizziness, dry mouth, etc.
There is unregulated use in US colleges as a nootropic agent, with conflicting evidence to support this interpretation.
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Modafinil increases alertness by influencing dopaminergic neurotransmission, potentially by blocking DAT and increasing DA levels. It also modulates NET and SERT
activity. Modafinil may bind to allosteric sites on the DAT, similar to cocaine.
Additionally, it enhances excitatory glutamatergic neurotransmission, which may link to its possible nootropic effects.
There is also some evidence of its influence on sleep-inducing systems like GABA and adenosine, but these areas require further investigation.
PMA/PMMA - Ecstasy alternative
Seizures of 50 tons of sassafras oil (containing safrole) in 2008 in Thailand lead to reduced production of MDMA in the Netherlands.
Anethole, a flavouring from anise and fennel was substituted for safrole.
This generates a microemulsification in ouzo/anisette upon addition of water.
It cannot quite produce MDMA, but it is used as a precursor for:
- 4-methoxyamphetamine (PMA)
- 4-methoxymethamphetamine (PMMA)
Mephedrone - Ecstasy alternative
4-methylmethcathinone is also known as Mephedrone, or as 4-MMC, MCAT and ‘Meow-meow’.
It is a derivative of cathinone from khat.
Reportedly manufactured in China from 2008 as a legal alternative to ecstasy (MDMA), sold through the internet as ‘plant fertiliser’.
Consumed orally (100-200 mg) or by insufflation (<75 mg)
It has rapid CNS penetration and causes increased locomotor activity and hyperthermia.
The effects of Mephedrone are similar to other amphetamine-type psychostimulants like MDMA, with common emotional effects including euphoria, talkativeness, improved mood, and strong feelings of craving. Notably, it causes stronger cravings than MDMA.
Somatic effects included increased energy and accelerated heartbeat.
The UK press was involved in spreading misinformation about the drug.
In the UK press, an online ‘joke’ (mephedrone.com) suggested that a mephedrone user had ripped off his own scrotum.
A police report noted this and that it could be an unreliable source. However, in November 2009, the Sun reported the statement without the caveat.
Another media report that was recycled during 2010 suggested that mephedrone had led to the deaths of over 20 people, but no forensic toxicology reports were published.
The home secretary Alan Johnsosn announced in 2010 that mephedrone would be made illegal “within weeks”. Eric Carlin, a member of the ACMD and former chairman of the English Drug Education Forum, resigned, claiming the decision made by the home secretary was based on media and political pressure.
α‑PVP (Flakka)
α‑Pyrrolidinovalerophenone, α‑PVP or ‘flakka’, was synthesised in 1963 by Wander as a CNS stimulant.
Chemically similar to cathinone from khat, potent inhibitor of DAT and NET.
It was identified in drug seizures in France and the US in 2011.
Subjectively, consumption results in euphoria, increased alertness, elevated mood and a sense of being ‘sped up’.
There are a lot of ED admissions for psychotic episodes, anxiety, agitation, hallucinations and cardiac disturbance.
Tablets were previously available online. Absorption is rapid, with effects occurring within 10 minutes and lasting for 2-3 hours, although hallucinations can persist longer.
Vaping α-PVP leads to faster absorption and stronger effects.
Withdrawal symptoms include depression, anxiety, and paranoia.
Studies in rodents show dose-dependent hyperlocomotion and self-administration, indicating abuse potential.
Schedule I drug in the US.
Statistics
Amphetamines have been used by 12-7% of the population in the last 20 years, and use seems to have started to fall off.
Methamphetamine use is comparatively a lot lower (<2%). The opposite is true in the US.
There has been a rise in the number of amphetamine-related deaths over the last 30 years, but the total number of deaths in a given year is still below 120 out of >580,000. It is also likely that deaths reported under stimulant use are more complicated, as users normally take other substances at the same time too.
Deaths related to mephedrone and PMA/PMMA (MDMA alternatives) peaked around the mid-2010s (following the fall in MDMA supply in 2008).
Looking at drug overdose death rates in the US, psychostimulants with abuse potential (primarily methamphetamine) have caused 30,000 deaths since 2000, compared to 80,411 deaths involving any opioid in 2021. Stimulant use seems to be more prevalent in the US than the UK.
Molecular targets of stimulants
Some stimulants cause direct activation of monoamine receptors including:
- α1-, α2- and ꞵ2-adrenoceptors
- D1-D5 dopamine receptors
- 5HT1-5HT7 serotonin receptors
- TA1 trace amine receptors
Stimulants can also have indirect actions.
Some act at the cell-surface monoamine transporter family:
- NET/SLC6A2 noradrenaline transporters
- DAT/SLC6A3 dopamine transporters
- SERT/SLC6A4 serotonin transporters
- PMA/SLC29A4 plasma membrane amine transporter
Others act at vesicular amine transporters:
- VMAT1/SLC18A1 vesicular monoamine transporter 1
- VMAT2/SLC18A2 vesicular monoamine transporter 2
Molecular targets for some stimulant drugs, such as modafinil, are yet to be defined.
As these drugs act at a wide range of molecular targets, it is difficult to define their actions and find effective treatments for overdose.
**Aminorex and its analogues
Aminorex is a stimulant drug, previously marketed in 1963 for weight loss as an alternative to amphetamine derivatives.
It was sold over the counter in some European countries but was withdrawn in 1968 due to its association with a significant increase in pulmonary hypertension.
Aminorex interferes with the function of monoamine transporters. Hence, Aminorex and its derivatives share pharmacological and neurochemical similarities with amphetamines and cocaine.
Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists.
Several aminorex analogues exist that are not internationally controlled. Notably, 4-methylaminorex (4-MAR) and 4,4′-dimethylaminorex (4,4′-DMAR) have been associated with adverse events, including death, similar to the dangers highlighted with synthetic cathinones. These have clinical features consistent with serotonin toxicity and noradrenaline-mediated cardiotoxicity.
Self-administration experiments in baboons and rhesus monkeys suggest a significant abuse potential for 4-MAR.
Stimulus generalisation studies in rats indicate that aminorex and 4-MAR produce subjective effects similar to amphetamine and cocaine.
Aminorex and 4-MAR are internationally controlled substances. Following the numerous deaths associated with its use, 4,4′-DMAR was also placed under international control in 2016.
