Three science ideas you need to know about legal and illegal highs

When someone doesn’t want me to write about something, it makes me curious. So when people tried to warn me off my long-read article on ‘novel psychoactive substances’ (NPS) just published in Chemistry World, I got curious. I was hunting someone who actually made NPS — sometimes called legal highs, now banned in the UK. So I went to the ‘research chemical’ community, who buy substances that may get you high but are too new to have been banned. Some were helpful, some outright hostile. But I now realise they knew some overlooked truths about drugs. The helpful wanted to share them with me. The hostile thought attention would harm them.

Some in the research chemicals world didn’t want me to write about drug laws, even though they didn’t like them.

Two of those ideas became scientific themes in my Chemistry World article. The third did not, but it has changed how I use that widely popular legal high, alcohol. I believe these insights are useful for understanding our relationship with drugs, as a society and individually.

1 — Chemical space

A Reddit user warns me about how research chemical vendors can put chemical space to shady use

The alcohol many of us drink, technically called ethanol, is a remarkable little drug molecule. Just nine atoms, two carbons, six hydrogens and one oxygen. But our livers quickly rearrange these atoms, taking away two hydrogens to make acetaldehyde, a cancer-causing toxin.

The power of such small chemical changes is important to scientists developing drugs, both legally and illegally. And as you add more atoms the number of possible arrangements becomes mindbogglingly enormous. In human history, scientists have made around 70,000,000 molecules. That seems like a lot, until you consider that there are around 10,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000 molecules that could be made using less than 70 atoms. (Most drug structures will have fewer than 70 atoms, but more than the nine of ethanol.)

This vast theoretical playground is known as chemical space. Research into new medicines must pick just the right needles from this haystack. But less fussy research chemical and legal high developers can use the vast number of options to get round laws that ban a specific molecule by making just a few small modifications. That’s why the UK, Ireland and Poland introduced laws making anything that will get you high illegal, with some exemptions.

But this has forced the NPS trade underground — and these laws have therefore got lost in chemical space. Some modifications create more powerful substances, helping illegal traffickers to carry less of such drugs around for the same number of doses, making their lives easier. Yet this is more hazardous for users, as it’s easier to overdose on more powerful substances.

This is now happening, for example with the heroin-like drug fentanyl, and synthetic cannabinoids more commonly known as Spice or K2. Legislating in chemical space forces suppliers towards more dangerous substances, of whose effects little is known, other than that they’re potent. That’s partly why some in the research chemicals world strongly advise people to get tests done on what they are taking, or at least check with others who have taken it.

2 — Locks, keys and taps

The structure of a protein ‘lock’ in purple and an antagonist key molecule in green. Credit: Enzymlogic via Flickr Creative Commons CC BY-SA 2.0 Licence

Our bodies make molecules all the time. Many of them are like keys, fitting into other molecules, known as receptors, that are like locks. Medicinal drug developers are usually hunting the rare key molecules that will hijack such systems with precision, fitting one receptor lock type selectively, to reduce side-effects. Shadier chemists are usually less concerned if their keys fit other locks. This risks interactions with various receptors that in the worst cases could have deadly consequences.

Psychoactive drugs alter our consciousness by fitting into receptors in our nerve synapses. This in turn controls the release of other key molecules, called neurotransmitters, which cause nerve signals and influence our behaviour. NPS molecules’ effects on neurotransmitter release are similar to how taps control water flow. Drugs that cause full flow, releasing all available neurotransmitter molecules, are full agonists. Drugs that prevent any flow are known as antagonists, while those that turn flow part-way are partial agonists.

Beyond whether a key molecule is a full or partial agonist, or an antagonist, it’s important how tightly a key molecule fits into its lock. These factors all influence how much users have to take to get high, and how much to overdose. THC, the key molecule in cannabis, is a partial agonist, making it rare for users to come to immediate harm. While Spice started its journey through chemical space from THC, its modified key molecules have become full agonists, leading to distressing effects. Elsewhere, partial agonists today help people battle heroin and cigarette addictions, and scientists are working on similar partial agonist alcohol replacements.

3 — Time of onset

High purity MDMA, the active chemical in ecstasy, is being supplied in the UK, which can lead to overdosing because there’s a delay between swallowing pills and feeling their effects. Drug charity The Loop therefore advises people to crush large crystals and just dab part of them and break pills into halves and quarters rather than swallowing them whole. Credit: The Loop

It seems to me that illegal drug users have a better sense of how long it takes for substances to work than their legal counterparts. Most ecstasy users, for example, would know to wait for an hour or so to ‘come up’. Meanwhile, some boozers down several alcoholic drinks in a short time before feeling the full effects of the first. I am amongst those boozers, but less so since reading about exactly what alcohol does in our bodies.

Booze triggers noradrenaline release, whose stimulant effect I believe is behind the ‘Let’s have another’ feeling I get shortly after. The next drink then triggers another noradrenaline boost, and another drink, and so on. However, booze also blocks some receptors that are normally unlocked by the neurotransmitter glutamate, making drinkers feel drowsy. I believe the repeated noradrenaline hits override the drowsiness, and stop me realising how drunk I really am. I’ve therefore found some tasty brands of non-alcoholic beer to switch to after a couple of alcoholic ales. Whether my biochemical speculation is right or not, usually I then decide I’ve had enough.

The timing of how substances get into our bodies comes into play with all drugs. Psychoactive drugs that enter our systems particularly quickly can be more addictive, as is the case when injecting heroin or smoking crack. But slower-onset swallowed drugs like ecstasy and alcohol also bring hazards, with their delays opening a window for people to take too much and overdose.

I explore some ways that these ideas should shape how we all look at drugs in my Chemistry World article. But a profound extra point for me is that most of us use substances that alter our consciousness in some way, even if it’s just coffee. Molecules we consume are modifying our minds, influencing our identities, every day. I find that concept awesome.

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