The summer of 2021 was a liberation for many of us. Clubs, festivals and parties opened after months in the dark. We could dance and laugh together again. We exchanged cheeky glances with strangers on the dancefloor. We could also take drugs with our friends again. Enjoy the highs together, and make the lows more bearable with the most wholesome company.
Drug use changed during the pandemic1. lLast year, we found that about half of people who were already using cannabis, benzos (Valium, Xanax etc), or opioids were using them more during the beginning of the pandemic. Meanwhile, about a third of people who used cocaine or ketamine reported they took less than usual. The supply chains were also impacted by the pandemic. Any other market also suffered the effects of the pandemic. But, unlike other markets, malfunctioning supply chains in the drug market can have harmful or lethal consequences. If your delivery takes a few more days to arrive and it’s a bit more expensive, it’s painful, but you can get over it. However, if your drugs don’t contain what you think they do, it’s not only painful, it could kill you2, 3.
During the summer of 2021, The Loop,4 a drug testing organisation in the UK, found that out of four versions of MDMA pills, only one contained the actual drug, while the three others contained 4-CMC, Eutylone, or Benzocaine. The pills only differed in colour, but the overall design was identical. In some cases, taking imposter pills is benign, you might not enjoy any sort of high. However, in other cases, the consequences can be fatal. Why? Depending on their actual content, these pills can have effects on your brain very different to MDMA’s neuropharmacology. In this article, I will explain the effects of MDMA and compare it to the other drugs, so it will be easier to recognise if you have been given a fake variant. I will also talk about the neuroscience of these substances and help understand how exactly they affect your brain.
So, what exactly are the drugs the Loop found in pills instead of MDMA?
4-CMC and Eutylone are designer drugs, and have effects comparable to MDMA, while the anaesthetic Benzocaine has barely anything in common with it.
Benzocaine
Benzocaine is an outlier among the four substances the Loop reported, as it’s the only one that isn’t psychoactive – it doesn’t change your mental state. It’s used in surgical and dental procedures as a local anaesthetic, and some over-the-counter pain relief medicines also contain it. Benzocaine is an ester anaesthetic, as it has the atoms shown in a red circle. Anaesthetics generally fall into either the category of amides or esters.
Action as an anaesthetic
Neurons transmit information between the brain and periphery (such as limbs and organs) by passing on a signal coming from either end. For example, when you’re in a surgical procedure, pain receptors close to the skin will get activated and create a pain signal. But in order to feel this sensation, the signal needs to be passed on from one neuron to the other, all the way to the brain. Once it reaches the brain, the signal registers, and you feel the pain.
Neurons speak to each other to exchange messages. The speaking neuron releases small molecules, neurotransmitters, that the listening neuron can recognise with its receptors. The listening neuron might activate and speak to other neurons.
The difference between an active (speaking) and inactive (resting) neuron is their electrical charge. An active neuron will become positively charged momentarily compared to its resting state. To become positively charged, neurons open their sodium channels. By opening the sodium channels, they allow positive sodium ions to flow into the cell. This positive charge then travels down on the neuron. The neuron is then ready to speak to other neurons.
Benzocaine binds to these sodium channels, and blocks the sodium inflow. By doing this, it stops neurons from being able to get activated- neurons can’t speak to each other. As the pain signal never reaches the brain, it’s not registered, and you don’t feel pain – this is why Benzocaine works as an anaesthetic.
3,4-Methylenedioxymethamphetamine (MDMA)
MDMA is a well-known party drug that was first synthesised in the 1910s and gained popularity with the emerging rave culture in the 1980s. In the 1970s, MDMA was sometimes used during conventional psychotherapy sessions, to help patients heal from Post Traumatic Stress Disorder (PTSD). The substance later was strictly regulated. Recently, MDMA and its potential therapeutic effects have become a popular topic in scientific communities. New studies are indicating that MDMA-assisted psychotherapy could be more helpful for treatment-resistant PTSD than psychotherapy alone5.
Effects
MDMA has both stimulant and empathogenic properties. As a stimulant, it increases energy, leads to higher blood pressure and heart rate, and decreases appetite. It can also increase teeth-grinding. At the same time, as an empathogen, it gives a sense of relating to others, a sense of emotional connectedness, openness, and sympathy.
Neuropharmacological action
MDMA is known for its ability to increase serotonin, dopamine, and noradrenaline levels in the brain. Serotonin, dopamine and noradrenaline are some of the molecules (neurotransmitters) neurons use to speak to each other. A speaking neuron will release these neurotransmitters, and the listening neuron will understand the message thanks to its receptors. When the message is loud enough, the listening neurons get activated and pass the message to other neurons.
By changing neurotransmitter levels, MDMA alters brain activity. MDMA acts by inhibiting the reuptake of dopamine and serotonin from the space between two neurons that are communicating. Usually, once these neurotransmitters are released and have interacted with the listening neuron, the speaking neuron takes the neurotransmitters back up for recycling. If the reuptake is inhibited, higher levels of neurotransmitters remain in this space between the neurons which are communicating. This is how MDMA increases serotonin, dopamine and noradrenaline in the brain.6
These processes are responsible for the changes in brain activity when people are high on MDMA. MDMA’s effects are mainly due to increases in the levels of serotonin and dopamine in the space between neurons that communicate. Processes that operate through serotonin and dopamine might get enhanced, while other activities get tuned down. For example, MDMA’s interaction with serotonin is responsible for its empathogenic actions, causing feelings of connectedness and empathy. At the same time, its interaction with dopamine is responsible for its stimulant effects such as increased energy and heart rate.
Clearly, Benzocaine and MDMA have little in common, both in mechanism of action and their effects on people. However, the other two substances the Loop found in imposter pills are more similar to MDMA.
4-CMC and Eutylone are both designer drugs. They belong to the family of substituted cathinones. This family is known for their stimulant and empathogenic effects, just like MDMA.
4-Chloromethcathinone (4-CMC)
4-CMC is a stimulant designer drug mostly sold online, and often used as a bulking agent. Its effects resemble Khat, a plant that has been used for centuries as a stimulant in the Arabian Peninsula and southern Africa. The main active component in Khat is Cathinone. Many designer drugs derive from Cathinone, including 4-CMC and Methcathinone. The family of drugs ending in -cathinone are all stimulants, and are closely related to methamphetamine.
Effects
The main target of 4-CMC is dopamine. This drug increases central nervous system function, leading to a higher blood pressure and heart rate, and increased alertness. Compared with MDMA, both share some stimulant features, but they are heightened in 4-CMC. Its interaction with the dopaminergic system makes it similar to methamphetamine. As 4-CMC doesn’t interact with the serotonergic system as much as MDMA, it doesn’t cause effects related to “connectedness and love”.
Neuropharmacology
As a relatively new designer drug, there hasn’t been many studies on 4-CMC. According to a report by the WHO, it stimulates mainly dopamine and serotonin release, but doesn’t interact much with their transporters. This means that, like MDMA, 4-CMC also causes increased levels of dopamine and serotonin in the spaces between the neurons that communicate, but through a different mechanism.7
Eutylone
Like 4-CMC, Eutylone too is a designer drug with stimulant properties. It was designed to mimic the effects of N-Ethylpentylone. In addition to the stimulant effects, Eutylone can also cause feelings of connectedness, similar to MDMA. This is because the subclass of designer drugs ending in -ylone are a hybrid of MDMA and cathinones (like 4-CMC, which I explained above). Their chemical structure is based on MDMA, but its core is modified to get a molecule that also possesses characteristics of cathinones. This can be seen in their physiological effects too, as they are empathogens (mimicking MDMA), but are stronger stimulants than pure MDMA (similar to cathinones).8
Neuropharmacology
Like with many new designer drugs, the neuropharmacology of Eutylone hasn’t been scientifically described. There has been research done on N-Ethylpentylone, the “parent drug” of Eutylone. They are very similar in structure.
N-Ethylpentylone
Its pharmacological action is very similar to MDMA, in that it doesn’t cause any direct neurotransmitter release anywhere. Instead, it inhibits the reuptake of dopamine, serotonin and noradrenaline by interacting with the transporter of neurotransmitters].9
Importantly, it is more potent at the dopamine transporter than MDMA. This can be dangerous and lead to toxicity, and there is a bigger chance of people experiencing stronger, potentially more negative stimulant effects.
Potential risks and benefits of designer drugs
Designer drugs like 4-CMC and Eutylone are synthesised to mimic pharmacological effects of a “parent drug”, but with slightly modified chemical formula. This could be with the aim to modify the potency or effects with respect to the parent drug. As a designer drug gets more widespread and authorities begin to take actions, new drugs are rapidly created that are very similar in structure. Therefore, not much is known about the exact pharmacological and physiological effects of each substance, but speculatively, they are very close to well-established drugs in the same drug class.
Many of the risks of designer drugs are a result of people unknowingly taking them. For example, expecting a specific drug experience, waiting for the expected effects but never experiencing them can induce anxiety. Additionally, people might assume they’re not feeling the desired effects because they haven’t taken enough and re-dose, which can lead to an overdose.
If designer drugs are designed to be more potent than the parent drug, they can cause an overdose. In some cases, the designer drug will have similar characteristics but will be more potent. In others, their potency will be similar to the original drug regarding one neurotransmitter family, but will be more potent on others. For example, Eutylone has similar potency on the serotoninergic system as MDMA, but is more potent on the dopaminergic system. As people are unaware that the substance they are consuming acts differently than expected, even with the most extensive research and preparations, they might unwillingly miscalculate the dosage. Taking a bigger dose than intended can lead to various side effects, from anxiety and paranoia to physiological responses, such as irregular heartbeat or loss of consciousness.
However, most of these scenarios could potentially be avoided if people knew exactly which substances they are taking, and if more scientific research assessed their neuropharmacological properties. The possibility of designing substances that are a chemical hybrid of two parent drug classes might provide drugs more suitable in certain scenarios.
People sometimes take multiple drugs simultaneously to mix their effects. However, combining substances can be dangerous because these drugs might enhance or cancel out each other, and result in unexpected effects. When someone is planning to take different drugs, it might be less harmful if there was a substance available designed to mimic the effects of the chosen drug cocktail. This would eliminate the risk of certain drug-drug interactions. However, for this to be feasible, extensive research would be needed to develop these substances, determine their optimal use and potential risks.
References
1 Drugs and Me (2020) Full report: Recreational drug use during COVID-19 outbreak. Accessed: 9 Jan 2021.
2 Leask, D. (2021). Blues warning as Glasgow suffers "unprecedented" wave of drugs deaths. Accessed: 26 December 2021.
3: Farrell, J. (2021). Drug dealer's warning over deadly batches of illegal party drugs - 'not everything you get is safe, even if you think it's from a reliable source'. Sky News. Accessed: 26 December 2021.
4 The Loop (2021). CAUTION: Pharaoh pills, 4 pills - 4 different drugs. Twitter. Accessed: 26 December 2021.
5 Sessa B (2017). MDMA and PTSD treatment:“PTSD: from novel pathophysiology to innovative therapeutics”. Neuroscience letters, 649:176-80.
6 De la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J. (2004). Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Therapeutic drug monitoring, 26(2):137-44.
7 World Health Organisation (2019). Critical Review Report: 4-CMC (4-CHLOROMETHCATHIONE). Geneva: World Health Organisation. Accessed: 1 December 2021.
8 Krotulski AJ, Papsun DM, Chronister CW, Homan J, Crosby MM, Hoyer J, Goldberger BA, Logan BK (2021). Eutylone intoxications—an emerging synthetic stimulant in forensic investigations. Journal of Analytical Toxicology, 45(1):8-20.
9 Costa JL, Cunha KF, Lanaro R, Cunha RL, Walther D, Baumann MH. (2019). Analytical quantification, intoxication case series, and pharmacological mechanism of action for N‐ethylnorpentylone (N‐ethylpentylone or ephylone). Drug testing and analysis, 11(3):461-71.
After completing a BSc at UCL, Eszter is currently a Master’s student in Liverpool, mainly interested in brain sciences. When she’s not in university, tutoring science or looking after kids, she trains Muay Thai and likes to bake all sorts of sweet creations.