CNS Depressants: How They Work and Why Mixing Is Dangerous

Alcohol is a central nervous system depressant rather than a stimulant, and per MedlinePlus alcohol is a drug that slows down brain activity, changing mood, behavior, self-control, memory and coordination.

The sociable, energized feeling early in a drinking session is disinhibition rather than stimulation. Combining depressants, rather than any single one, produces the overdose risk that matters most.

Key Takeaways

• Alcohol depresses the central nervous system at every blood alcohol concentration and never becomes a stimulant.
• NIDA’s CNS depressant class covers benzodiazepines, non-benzodiazepine sedative hypnotics and barbiturates, and NIDA classes opioids separately.
• Benzodiazepines increase the frequency of GABA-A chloride channel opening, while barbiturates extend its duration and act on two further mechanisms.
• FDA added boxed warnings to nearly 400 products in 2016 over opioid and benzodiazepine co-use, and a class-wide boxed warning to all benzodiazepines in 2020.
• Per SAMHSA TIP 45, the substances whose withdrawal can prove fatal are alcohol and the sedative-hypnotics.

When Is Depressant Use a Medical Emergency?

Unusual dizziness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness after taking a depressant requires immediate medical attention. Per FDA, patients taking opioids with benzodiazepines, other CNS depressant medicines or alcohol should seek medical attention immediately for those symptoms.

A suspected overdose requires 911, and naloxone where an opioid may be involved, given even when opioid involvement is uncertain.

Crisis resources. The 988 Suicide and Crisis Lifeline answers three ways: call 988, text 988, or chat at 988lifeline.org/chat. Spanish-language support answers by pressing 2, and the Lifeline’s videophone option serves ASL users.

Understanding which substances carry that risk starts with the question people search for most.

Is Alcohol a Stimulant or a Depressant?

Alcohol is a central nervous system depressant, and alcohol’s classification does not change as blood alcohol concentration rises. No authoritative source classifies alcohol as a stimulant at any dose.

The confusion is genuine and carries a documented explanation. Per NIAAA-published research, short-term alcohol consumption depresses brain function by altering the balance between inhibitory and excitatory neurotransmission, acting by increasing inhibitory neurotransmission, decreasing excitatory neurotransmission, or both. Suppressing inhibitory systems first produces the appearance of stimulation: per the same source, alcohol’s excitatory actions, including the reduction of social inhibitions, arise at least in part from suppression of inhibitory neurotransmitter systems.

Timing within a session matters too, and the research there concerns subjective effects rather than drug class. Every blood alcohol concentration below a session’s peak occurs twice, once while rising and once while falling, and research finds alcohol producing a predominant stimulant effect during the ascending limb of the blood alcohol curve and a predominant sedative effect during the descending limb. Those measures describe how people feel and behave rather than what the drug is.

Per NIAAA, continued acute consumption progresses through lethargy, confusion, amnesia, loss of sensation, difficulty breathing and death. Nothing in that sequence is stimulant. Three prescription classes sit alongside alcohol.

Which Drugs Are CNS Depressants?

NIDA’s class list names three groups: benzodiazepines, non-benzodiazepine sedative hypnotics, and barbiturates. Per NIDA, CNS depressants are medicines including sedatives, tranquilizers and hypnotics that slow brain activity, useful for treating anxiety, panic, acute stress reactions and sleep disorders.

• Benzodiazepines: diazepam (Valium), clonazepam (Klonopin), alprazolam (Xanax), triazolam (Halcion), estazolam (Prosom).
• Non-benzodiazepine sedative hypnotics, commonly called z-drugs: zolpidem (Ambien), eszopiclone (Lunesta), zaleplon (Sonata).
• Barbiturates: mephobarbital (Mebaral), phenobarbital (Luminal), pentobarbital sodium (Nembutal).

Two entries people expect to find sit outside that list. NIDA classes opioids separately, treating opioids, CNS depressants and stimulants as the three medication classes most commonly misused, and opioids still depress the nervous system pharmacologically: FDA states that both opioids and benzodiazepines depress the central nervous system. Alcohol is a depressant and not a prescription medicine, so alcohol does not appear on a list of prescription drug classes, and FDA guidance on these medicines directs patients not to drink alcohol with any of them because alcohol also depresses the central nervous system.

FDA’s working list runs wider than NIDA’s and is explicitly non-exhaustive. Alongside benzodiazepines, FDA includes other sleep drugs and tranquilizers, muscle relaxants such as baclofen, carisoprodol, cyclobenzaprine and tizanidine, and antipsychotics. Anyone taking a muscle relaxant alongside a sleep aid combines two depressants without necessarily knowing it. All of them converge on one inhibitory system.

How Do CNS Depressants Work?

CNS depressants act on the GABA inhibitory system, and per NIDA most CNS depressants increase activity of gamma-aminobutyric acid, a chemical that inhibits brain activity. Per FDA, they bind to GABA receptors in the brain, which produces drowsiness or calming effects.

The GABA-A receptor is a protein of five transmembrane subunits, two alpha, two beta and one gamma, which together form a central chloride channel. GABA binds where the alpha and beta subunits meet, and benzodiazepines bind at a separate site formed by the alpha and gamma subunits. Where the classes diverge is what each does to that channel, and the difference explains their relative danger.

Benzodiazepines Change the Frequency of Channel Opening

Per StatPearls, benzodiazepines increase the frequency of GABA-A receptor chloride channel opening in the presence of GABA, and in the absence of GABA, benzodiazepines have no effects on GABA-A receptor function. Benzodiazepines amplify a signal that has to already be there.

Barbiturates Change the Duration and Act on Two Further Systems

Per StatPearls, barbiturates enhance activation of GABA-A receptors by extending the duration for which the chloride channels stay open, hyperpolarizing the postsynaptic membrane. Barbiturates also diminish responses to the excitatory neurotransmitter glutamate by inhibiting the AMPA receptor subtype, and barbiturates decrease calcium conductance. Three mechanisms rather than one, and the same source states the consequence: barbiturates carry a narrow therapeutic index, prove highly addictive and carry a high risk for toxicity.

Alcohol Acts on Both Sides of the Balance

Alcohol increases inhibitory GABA-A signaling and inhibits excitatory glutamate signaling, and the GABA-A half is less uniform than commonly written. Per NIAAA-published research, some reports suggest short-term alcohol exposure increases the inhibitory effect of GABA-A receptors, while other research shows alcohol not increasing GABA-A receptor function in some brain regions and under certain experimental conditions. The glutamate side is clearer: short-term exposure to intoxicating concentrations of alcohol appears to inhibit both NMDA and non-NMDA receptor activity. Rising alcohol tolerance reflects the nervous system adapting to that suppression.

Two depressants acting on the same system at once is where the deaths happen.

Why Is Combining CNS Depressants So Dangerous?

Two depressants suppress the same respiratory control system by different routes, and the observed overdose death rate for opioid and benzodiazepine co-dispensing reached 10 times that of opioids alone. Per FDA, concomitant use may result in profound sedation, respiratory depression, coma and death.

FDA acted on 31 August 2016, adding boxed warnings and patient Medication Guides to nearly 400 products. Six figures from that review:

• Scale of exposure. In 2014, 81 million US patients received an opioid and 30 million received a benzodiazepine.
• Growth in overlap. Between 2002 and 2014, the proportion of opioid analgesic recipients receiving an overlapping benzodiazepine prescription increased by 41 percent.
• Death rate. In a North Carolina cohort, overdose death rates among patients co-dispensed opioids and benzodiazepines reached 7.0 per 10,000 person-years against 0.7 among patients dispensed opioids alone.
• Hazard ratio. Patients taking opioids with a current benzodiazepine prescription carried a hazard ratio of 3.86 for fatal overdose, and risk rose as the daily benzodiazepine dose rose.
• Trend. Benzodiazepine involvement in opioid analgesic overdose deaths rose from 18 percent in 2004 to 31 percent in 2011.
• Alcohol. Analysis of 2010 data found alcohol involved in 18.5 percent of opioid analgesic abuse-related emergency department visits and 22.1 percent of opioid analgesic-related deaths.

FDA’s 2020 benzodiazepine review reached the conclusion that matters most here: benzodiazepine abuse and misuse are common and the associated harms are substantial, and those harms occur primarily when people use benzodiazepines in combination with other drugs. Between 2013 and 2017, 55 percent of benzodiazepine-involved overdose deaths also documented prescription opioid involvement. The same additive suppression applies to mixing alcohol and benzodiazepines. National mortality data shows how routine the pattern is.

How Often Does More Than One Depressant Show Up in an Overdose?

Most opioid overdose deaths involve a second drug: per CDC, 62.6 percent of 13,415 opioid overdose deaths across 25 states and DC in early 2018 co-occurred with at least one common non-opioid drug.

Benzodiazepines were present in 32.5 percent of those deaths, cocaine in 34.0 percent and methamphetamine in 12.1 percent. National trend data covering 399,230 opioid poisoning deaths from 1999 to 2017 found alcohol co-involvement rising from 12.4 to 14.7 percent and benzodiazepine co-involvement rising from 8.7 percent to a peak of 26.2 percent in 2010 before settling at 21.0 percent in 2017.

Those two benzodiazepine percentages differ because the years, geographies and death definitions differ, and both describe the same picture: a depressant overdose is usually more than one depressant. Sleep medicines carry a distinct hazard of their own.

What Are the Risks of Prescription Sleep Medicines?

Z-drugs carry a boxed warning added on 30 April 2019 for eszopiclone, zaleplon and zolpidem, after FDA identified 66 cases of complex sleep behaviors over 26 years that resulted in serious injuries including death.

Those cases covered accidental overdoses, falls, burns, near drowning, hypothermia, motor vehicle collisions with the patient driving, and self-injury. The detail relevant here is FDA’s own framing: these behaviors have occurred in patients with and without a history of them, even at the lowest recommended doses, and can occur after just one dose, with or without alcohol or other sedating CNS depressants.

FDA also added a contraindication, its strongest warning: these three medicines are contraindicated in patients who report an episode of complex sleep behavior after taking them. Scale gives context, with an estimated 26.6 million zolpidem prescriptions dispensed in 2018. Stopping any of these substances carries its own danger.

Which CNS Depressant Withdrawals Can Kill You?

Alcohol withdrawal and sedative-hypnotic withdrawal can both prove fatal. Per SAMHSA TIP 45, the substances with the most serious withdrawal syndromes, those where the withdrawal syndrome can be fatal, are alcohol and the sedative-hypnotics.

The same source states that unlike alcohol and sedative withdrawal, uncomplicated opioid withdrawal is not life-threatening, and that where opioid withdrawal is not life-threatening, withdrawal from barbiturates can be. For benzodiazepines the current authority is FDA’s 2020 class boxed warning: stopping abruptly or reducing the dosage too quickly can result in serious withdrawal reactions, including seizures, which can be life-threatening. The severe reactions FDA lists include catatonia, seizures, delirium tremens, hallucinations, mania, psychosis, and suicidal ideation and behavior.

Two further points from the 2020 warning change how quickly this becomes relevant. Physical dependence can occur when benzodiazepines are taken steadily for several days to weeks, even as prescribed. And protracted withdrawal syndrome persists beyond 4 to 6 weeks after initial withdrawal, with symptoms lasting weeks to as long as 12 months. Alprazolam is the most commonly dispensed benzodiazepine and the drug behind most Xanax addiction, accounting for 38 percent of the 92 million benzodiazepine prescriptions dispensed in 2019.

Alcohol withdrawal is the only depressant withdrawal with published mortality figures. Per StatPearls, 3 to 5 percent of people with alcohol withdrawal syndrome progress to alcohol withdrawal delirium, historically carrying a mortality rate as high as 20 percent, now around 1 percent with advances in critical care, prompt diagnosis and treatment. No comparable published mortality percentage exists for benzodiazepine or barbiturate withdrawal. Two beliefs about depressants cause the most avoidable harm.

Which Beliefs About CNS Depressants Are Wrong?

Two widely held beliefs about depressants fail against the primary sources, and both lead people to underestimate a combination or a taper.

Common misconception	What the evidence shows
“Alcohol is a stimulant at low doses and only becomes a depressant later.”	Per MedlinePlus, alcohol is a central nervous system depressant that slows brain activity, and no authoritative source classifies alcohol as a stimulant at any dose. Per NIAAA-published research, alcohol’s apparently excitatory actions arise at least in part from suppression of inhibitory neurotransmitter systems, which is disinhibition rather than stimulation.
“A prescribed benzodiazepine is safe because a doctor prescribed it.”	Per FDA’s 2020 class boxed warning, even when taken at recommended dosages their use can lead to misuse, abuse and addiction, and physical dependence can occur when benzodiazepines are taken steadily for several days to weeks, even as prescribed. Stopping abruptly can produce withdrawal reactions including life-threatening seizures.

Both corrections argue for the same thing, which is clinical supervision when stopping.

Where Can You Get Depressant Detox in Los Angeles?

New Spirit Recovery provides medically monitored detox for alcohol, benzodiazepine and opioid use disorders at its Tarzana, Northridge and Encino locations, with 24-hour medical and nursing supervision.

Clinicians monitor withdrawal from alcohol or a sedative-hypnotic because both can prove fatal, and stopping more than one depressant at once changes the clinical picture rather than simply adding to it. Medically supervised detox runs 7 to 10 days on average.

The admissions evaluation establishes which depressants the taper has to account for.

“The hardest admissions to monitor are the ones where more than one depressant is involved, because stopping two at once does not behave like stopping one. That is a question for the medical providers before it is a question for anybody else.” Cynthia Prieto, LVN, Director of Nursing at New Spirit Recovery.

Frequently Asked Questions

Is alcohol a stimulant or a depressant?

A depressant. Per MedlinePlus, alcohol slows brain activity. The energized feeling early in a session is disinhibition: per NIAAA-published research, alcohol’s apparently excitatory actions arise at least in part from suppressing inhibitory neurotransmitter systems.

Does alcohol become a depressant only after a few drinks?

No. Alcohol is a central nervous system depressant at every blood alcohol concentration and its classification never changes. What changes within a session is the balance of subjective effects, which research finds more stimulant-like on the rising limb of the blood alcohol curve and more sedative on the falling limb.

What are examples of CNS depressants?

Per NIDA: benzodiazepines such as diazepam, clonazepam and alprazolam; non-benzodiazepine sedative hypnotics such as zolpidem, eszopiclone and zaleplon; and barbiturates such as phenobarbital and pentobarbital. Alcohol is also a depressant, and FDA’s wider list adds muscle relaxants and antipsychotics.

Are opioids CNS depressants?

Opioids depress the central nervous system, and NIDA classes opioids separately from CNS depressants. FDA states that both opioids and benzodiazepines depress the central nervous system, which is the basis of its 2016 boxed warning on combining them.

Why is mixing alcohol with benzodiazepines dangerous?

Both depress the same respiratory control system by different routes. Per FDA, combining opioids, benzodiazepines, other CNS depressants or alcohol may result in profound sedation, respiratory depression, coma and death, and the observed overdose death rate for opioid and benzodiazepine co-dispensing reached ten times that of opioids alone.

How quickly can you become dependent on benzodiazepines?

Per FDA’s 2020 boxed warning, physical dependence can occur when benzodiazepines are taken steadily for several days to weeks, even as prescribed. Stopping abruptly or reducing too quickly can produce withdrawal reactions including life-threatening seizures.

References

1. MedlinePlus, National Library of Medicine. Alcohol.
2. Valenzuela, C. F. Alcohol and neurotransmitter interactions. Alcohol Health and Research World, National Institute on Alcohol Abuse and Alcoholism.
3. National Institute on Drug Abuse. Prescription CNS Depressants DrugFacts; and Misuse of Prescription Drugs Research Report.
4. US Food and Drug Administration. (2016). FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines. Drug Safety Communication, 31 August 2016.
5. US Food and Drug Administration. (2020). FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. Drug Safety Communication, 23 September 2020.
6. US Food and Drug Administration. (2019). FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. 30 April 2019.
7. Jones, C. M., McAninch, J. K. (2015). Emergency department visits and overdose deaths from combined use of opioids and benzodiazepines. American Journal of Preventive Medicine, 49(4), 493-501.
8. Centers for Disease Control and Prevention. (2019). Drug overdose deaths involving opioids, by type of opioid. MMWR, 68(34).
9. Tori, M. E., Larochelle, M. R., Naimi, T. S. (2020). Alcohol or benzodiazepine co-involvement with opioid overdose deaths in the United States, 1999-2017. JAMA Network Open.
10. Substance Abuse and Mental Health Services Administration. (2006). Detoxification and Substance Abuse Treatment. Treatment Improvement Protocol (TIP) Series, No. 45.
11. Bounds, C. G., Patel, P. Benzodiazepines; Suddock, J. T., Cain, M. D. Barbiturate Toxicity; Newman, R. K., et al. Alcohol Withdrawal Syndrome. StatPearls, National Library of Medicine.