Serotonin maintains your mood, helps you sleep, controls your body temperature, and controls your gut. Hushpuppy brain chemical. However cram it into your system the wrong combination of medications, even a dose increase, or a recreational drug thrown into the vortex, and it becomes sideways in a hurry.

Recognizing the Warning Signs

Symptoms may occur within minutes. Or they may sneak in during a few hours of a change of dose, a new prescription or an accidental combination of the drugs. The less severe manifestations are characterized by tremors, wet sweats, a heart rate that cannot be calmed. Add on muscle twitching, agitation and blown wide opening pupils, and you are into moderate territory. At the severe end? The body temperature soars above 41o C and seizures capture and body organs begin to die.

The how by which that escalation occurs is because drugs are able to raise serotonin levels in a variety of ways by inhibiting its reuptake, increasing its release, decreasing its breakdown or activating serotonin receptors directly. Each one of such actions separately perhaps could remain within bounds. Two of them on top of each other, however, and the system collapses. To any individual dealing with addiction and a mental health disorder, the risks of accidental stacking become steeper, as the list of drugs increases and a greater number of prescribers are involved.

The Five Drugs Behind Most Cases

1. SSRIs

Selective serotonin reuptake inhibitors: fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), rank among the most popular drugs prescribed in Canada. They are taken every day by millions of people. They do so by causing serotonin to hang in your synapses than they would normally, and this is precisely the reason why they are useful in cases of depression and anxiety. Individually and at the recommended doses, SSRIs seldom cause full-blown serotonin syndrome.

Problems begin when the patient puts an extra serotonin-affective drug in without even thinking of it. A cough suppressant was picked out of the drugstore. A natural remedy that one of my colleagues vowed. Both shove serotonin a bit higher and all of a sudden the math won’t favour you anymore. Even more unpredictable about those combinations is that the SSRIs also slow the liver enzymes (CYP2D6 and CYP3A4) that causes the metabolism of other drugs. Not so that cold medicine or supplement can simply contribute to its own serotonin load.

2. Opioid Pain Medications

When we mention opioids, pain relief and addiction risk are the two articles that dominate all the attention. What receives a lot less notice? Fentanyl, tramadol, meperidine, and methadone among others that also disrupt serotonin pathways are some of the opioids. And they all do it in their own way. The action of tramadol and meperidine is a direct competition with the serotonin transporter, binding serotonin in the synapse, therefore, acting as a chemical logjam. Instead, Fentanyl follows a different path, where it causes a release of serotonin and binds to 5-HT1A receptors and 5-HT2A receptors concomitantly.

The use of such terms coincides with the current opioid crisis in Canada, which is particularly worrisome. Imagine a person in an antidepressant and illicitly taking fentanyl or even getting it during a normal surgery. And they are seated directly on the risk zone in not knowing it. Four of the patients with a complete diagnostic criteria were reported in a retrospective study of more than 4,500 fentanyl users who took a serotonergic agent. People struggling with fentanyl addiction face this collision constantly, since antidepressants and opioid tapering protocols run in parallel, making medical oversight during recovery non-negotiable.

3. MDMA (Ecstasy/Molly)

MDMA does not prod peptide serotonin. It dumps it. The drug causes a tremendous release and it also inhibits reuptake, both of which flood the synapses, in both directions, simultaneously. The combination of those two biochemical hits is the euphoria and emotional receptivity that looks appealing to recreational users, but also causes the combination of MDMA with any other serotonin-active drug to be a truly life-threatening roulette.

How dangerous? An analysis of the FDA data on adverse events designated serotonin syndrome incidents revealed 20 cases of confirmed serotonin syndrome associated with MDMA consumption. None of them involved MDMA only. All cases involved at least one other substance which was serotonergic: antidepressants, amphetamines, and opioids were the most common. Ten of those patients had been fine taking their antidepressant never before MDMA came into the scene. To make matters worse, the locations where individuals consume MDMA go against them. Bodies have a natural tendency to be taken to extremes by clubs, festivals and overcrowded venues that have insufficient ventilation to eliminate garbage and allow people to move freely and interact.

4. MAOIs

The monoamine oxidase inhibitors take a weird position in the world of psychiatry. They are also no longer prescribed by as many doctors, but to those patients who have developed treatment-resistant depression, drugs such as phenelzine (Nardil) and tranylcypromine (Parnate) still provide a lifeline. They act to prevent the breakdown of serotonin, dopamine and norepinephrine caused by its enzyme, which leaves all the three to be accumulated. It is that action that, however, causes MAOIs to be the most dangerous drug class to use with other serotonergic agents.

Consider: serotonin is irreducible, and a different drug blocks reuptake (or causes excessive release) at the same time. There are no caps to the levels. The MAOI/SSRI combo constitutes the most reported fatal reaction in the whole serotonin toxicity literature. So the risk does not just cease upon the discontinuation of use of the pill. Irreversible MAOI has a retention of two weeks in your system after withdrawal. Two weeks. Wintering patients to a new antidepressant within that washout period have caused serious reactions without the taking of the two drugs on the same day.

5. Over-the-Counter Cough Medications (Dextromethorphan)

Open your drug cabinet. You will most likely be able to find dextromethorphan somewhere in there. It is in Robitussin DM, or Benylin, dozens of store brand cold products on every drugshelf in Canada, they all contain it. DXM works by the action on the brainstem to suppress coughs but promotes serotonin reuptake. One of the side jobs that consumers are completely unaware of.

Those not-so-obvious serotonergic action in the background justifies the continued case reports of serotonin syndrome in people who merely grabbed cold medicine without considering that they were already on antidepressant therapy. DXM abuse, when using high dosages (more commonly known as robotripping), goes further to elevate the risk level, overloading the reuptake pathway that is already blocked by an SSRI or SNRI. No one who reads a box of NyQuil on the back gets their hopes up of an interaction between serotonin. However that is precisely the type of blindspot that brings people to the ER.

Risk Comparison at a Glance

Protecting Yourself

The fact that full disclosure is a last consideration is twice so in the case of individuals who have substance use disorder recovery. Depression and anxiety coexist with addiction more commonly than most individuals can imagine, and the interventions which combine antidepressants with an intervention (counselling and tapering regimens) require close liaison among all physicians making up the team. The last thing to remember is that when you are dealing with one or the other of the addiction and mental health treatment you should ensure that all the prescribers are provided with the overall medication picture including anything out of a clinical environment.