Synthetic drug
Synthetic drugs refer to substances that are artificially modified from naturally occurring drugs and are capable of exhibiting both therapeutic and psychoactive effects.
In the medical setting, synthetic drugs possess psychotropic effects which can cure insomnia. Since there are limited clinical trials and human studies, the pharmacology and drug effects of most of the synthetic drugs are not well-known. Misuse of synthetic drugs can be fatal so take advice from the professionals before use.
Substances that possess the latter effect are known as New Psychoactive Substances. Their purpose is to mimic the actions of illicit substances by altering the structure of the original drug. By doing so, the "synthesized drug" can appear in the market without being easily detected. However, the uncertainty in the toxic effects of these substances puts the public's health at risk. At present, these drugs are monitored by the Early Warning System.The major categories of NPS include synthetic stimulants, synthetic cannabinoids and synthetic depressants. Common examples from these categories are phenethylamines, cannabinoids and benzodiazepines. To exert the psychoactive effect, specific receptors such as cannabinoid, dopamine and serotonin receptors are either stimulated or inhibited
Common synthetic drugs
Synthetic cannabinoids
There are seven major structural groups, which are naphthoylindoles, naphthylmethylindoles, naphthoypyrroles, naphthylmethylindenes, phenylacetylindoles, cyclohexylphenols and classical cannabinoids respectively. Compared with classical cannabinoids, synthetic cannabinoids differ structurally. Some common synthetic cannabinoids are available in the market such as JWH-018, which is the most well-known naphthoylindole and JWH-250, a phenylacetylindole. They are sold under the brand name "Spice" as a recreational drug over the past decade.Phenethylamines
Phenethylamines can be classified into ring-substituted and non-ring-substituted form. Ring-substituted Phenethylamines include 'D-series' and '2C-series' while common non-ring-substituted Phenethylamines contain Benzodifurans, PMMA, etc.Novel benzodiazepines(Xanax)
is a generic medication derived from benzodiazepines with the brand name Xanax.Medical uses
Synthetic cannabinoids can provide psychotropic effects such as relieving nausea and dizziness. Phenethylamine can relieve depressive symptoms while Alprazolam can treat insomnia, panic attack and anxiety. The most common delivery routes of Alprazolam and Phenethylamine are by oral administration. Both of which are available in the dosage forms of pills and tablets. Synthetic cannabinoids are naturally in solid and oil form and are delivered by smoking.Adverse effects
The adverse effects of synthetic drugs are hard to determine as they usually contain other chemicals with variable concentrations and human studies are limited.Synthetic cannabinoids can cause cardiovascular problems such as tachyarrhythmia, seizures, psychological disorders and potential carcinogenic effects. Addiction and withdrawal symptoms which are linked to chronic use of synthetic cannabinoid include cognitive disturbances, 'profuse sweating', central nervous system and gastrointestinal disturbances.
The adverse effect of Phenethylamines depends on the type of the drug. 'D series' cause more long-lasting effects than other phenylethylamines such as tachycardia. At high doses, '2C series' produce hallucinogenic and entactogenic effects.
Alprazolam can cause central nervous system disturbances and thoughts of suicide.
Contraindications/Precautions
Synthetic cannabinoids are best avoided in users who suffer from rapid heart rate, vomiting, agitation, confusion and hallucination.Pregnant women are also not recommended to take phenethylamines as the effects on fetus are not known. In addition, use of phenethylamine might cause people with bipolar disorder to convert from depression to mania and worsened schizophrenia symptoms. As the drug also affects the central nervous system, administration of such drug before surgery is not recommended.
Benzodiazepines can cross the placenta and can be excreted in breast milk therefore Alprazolam is contraindicated in pregnancy and lactation. Alprazolam is a CYP3As substrate so we should avoid CYP3As inhibitors such as cimetidine which is a CYP3A4 inhibitor.
Pharmacology: Pharmacodynamics/Mechanism of Action(MOA)
Synthetic cannabinoids act as Synthetic Cannabinoid Receptor Agonists by binding to cannabinoid receptors CB1 and CB2. Its binding towards CB1 receptor will lead to receptor phosphorylation that recruits β-arrestin 1 and β-arrestin 2, resulting in a loss of responsiveness and internalization. Stimulation of CB1 receptor causes the dissociation of the βγ subunits of pertussis toxin-sensitive G proteins from the α subunit which then contributes to acute inhibition of synaptic neurotransmitter release. β-arrestin can also stimulate the mitogen-activated protein kinase, thus inducing additional cellular effects. Synthetic cannabinoids can also bind to receptors other than CB1 and CB2 to activate inotropic transient receptor potential channels for cell membrane depolarization and Ca2+ influx.Phenethylamines, which can act as either stimulants or hallucinogens, are indirectly acting sympathomimetic amines. Stimulants can modulate the levels and action of monoamine neurotransmitters such as dopamine, serotonin and noradrenaline for vasoconstriction and elevation in blood pressure. For example, 10-100 μM amphetamine can reach the vasoconstriction effect. Hallucinogen can mediate specific serotonin-receptor activities and produce hallucinations. They may have residue stimulant activity as well. In some animal studies, Phenethylamines have negative inotropism in isolated cardiac tissues of rats due to stimulation of TAAR1, which is in contrast with human pharmacology.
Alprazolam binds to GABA type-A benzodiazepine receptor sites which are the members of the pentameric ligand-gated ion channel superfamily. It mediates phasic inhibition and extrasynaptically to mediate tonic inhibition. Once attached, conformational changes occur which stabilize the receptors and inhibitory signals are produced
Pharmacokinetics
Synthetic cannabinoids are delivered by smoking. In a human study, after 50 μg/kg smoked JWH-018 are delivered, one male and a female have their serum concentration of 8.1 and 10.2 μg/L respectively after 5 minutes, down to 4.6 and 6.1 μg/L after 15 minutes, suggesting the biological half-life of JWH-018 is short. 13 phase 1 metabolites are identified. Monohydroxylated and dihydrodiol metabolites are most prevalent metabolites of synthetic cannabinoids. UGT1A1, UGT1A3, UGT1A9, UGT1A10 and UGT2B7 isoenzymes were primarily responsible for JWH-018 and JWH-073 metabolites' conjugation and had high affinity for hydroxylated metabolites. Generation of JWH-018-N-4- and 5-hydroxypentyl was primarily mediated by CYP2C9 followed by CYP1A2 and CYP2C19. CYP3A4 catalyzed JWH-018-N-4-hydroxypentyl production but with lower activity than CYP1A2 and CP2C19. The drugs are mainly excreted as urine.Phenethylamines are first-order kinetics with half life of 5 to 10 minutes which are absorbed by ingestion. The drugs have low concentration in the brain due to low biological half-life. It is difficult to measure the plasma concentration due to low stability of Phenethylamine. There are two possible metabolism pathways. The first possible pathway is metabolism by MAO-B to form phenylacetic acid due to MAO-B selectivity on non-polar aromatic amines. Then, the metabolites undergo N-methylation by non-specific N-methyltransferase or by phenylethanolamine-N-methyltransferase to form secondary amines and sympathetic neurotransmitter noradrenaline. The second possible pathway is deamination of the drug by the semi-carbazide-sensitive amine oxidases . An alpha-methyl side chain renders the drug immune to deamination in the gut. The drugs are mainly excreted in feces and urine.
Alprazolam has high oral bioavailability in which its maximum plasma concentration is reached after 1 to 2 hours. When taken with food, Cmax is increased by 25%. The half-life profile of this drug for different populations is illustrated in the following table:
| Population | Half-life |
| Healthy individuals | 11.2 |
| Obese | 10.7-15.8 |
| Alcoholic liver disease | 19.7 |
In terms of race, the half-life is 25% higher in Asian patients compared to Caucasians. For the extended-release formulation, it has a half-life of 10.7-15.8 hours in healthy adult patients. Alprazolam has a volume of distribution following oral administration of 0.8-1.3L/kg. Its protein binding in plasma is 80% and capable of crossing the blood-brain barrier. It is metabolized to less effective metabolites by various CYP450 enzymes including CYP3A4, CYP3A5, CYP3A7, and CYP2C9. The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As. 4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha-hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity. The drugs are mainly excreted in urine as unchanged Alprazolam. <10% of the dose is eliminated as alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam.