Treatment for Using More Than One Substance: What Changes

Using more than one substance is not one problem twice over. It changes the assessment, the withdrawal plan, the level of care and the medication picture, and it changes them in ways that are easy to miss if you read one substance page at a time.

The Centers for Disease Control and Prevention defines polysubstance use as two or more drugs taken together, either intentionally or unintentionally [1]. In 2022, nearly half of drug overdose deaths involved multiple drugs [1].

If someone is having a seizure, is unresponsive or has trouble breathing, call 911. For a mental-health crisis call or text 988.

This page covers what the term means, why a combination changes the clinical picture, what the assessment asks, how withdrawal is handled, which level of care fits, and how coverage works. Our section on drug addiction covers individual substances.

What polysubstance use is, and why it is so common

The CDC splits it in two, and the split matters because one half is a choice and the other is not.

Intentional polysubstance use is when a person takes a drug to increase or decrease the effects of a different drug, or wants the effects of the combination [1]. Unintentional polysubstance use is when a person takes drugs that have been mixed or cut with other substances, such as fentanyl, without their knowledge [1].

That second one has changed who this page is for. Someone can believe they use one substance and be wrong about it. The supply decided, not them.

Prescriptions count too. The CDC’s advice is to always let your doctor know what drugs you are taking, so that reactions with newly prescribed medications can be avoided, and never to take pills that did not come from a pharmacy and were not prescribed to you [1].

Why mixing changes the clinical picture

The common belief is that an upper and a downer balance each other. They do not.

Mixing stimulants and depressants does not balance or cancel them out [1]. The results of combining drugs are unpredictable, and they often modify or even mask the effects of one or both drugs [1]. That masking is the dangerous part: it may trick a person into thinking the drugs are not affecting them, which makes an overdose easier [1].

Alcohol belongs in this picture more often than people expect. It is a depressant with similar effects to other downers, and mixing it with other drugs can raise the risk of overdose and of serious damage to the brain, heart and other organs [1].

If someone is having a seizure, is unresponsive or has trouble breathing, call 911. For a mental-health crisis call or text 988.

For treatment, the consequence is simple to state and hard to do. A plan has to account for every substance, including the ones nobody thinks of as a drug.

The assessment, and why it takes longer here

The first appointment does more work on this page’s subject than on any other.

Federal guidance describes evaluation as testing for substances, screening for co-occurring mental and physical conditions, and a full assessment of a person’s medical and psychological condition and social situation, in order to decide the level of care that should follow [2]. With one substance, that is a thorough hour. With three, it is the thing the whole plan rests on.

What the clinician is working out is an order of operations. Which withdrawal here could be dangerous. Which will be miserable but not dangerous. What has to be stabilized first, and what can wait. None of that can be settled without knowing everything that is in play.

So name everything on the call. Alcohol, because people leave it out. Prescriptions, because people do not count them. Anything taken irregularly, because irregular is not the same as irrelevant. Our page on withdrawal symptoms covers what each kind tends to involve, and what the treatment process is like covers what follows the assessment.

Withdrawal when more than one substance is involved

Here the differences between substances stop being academic.

Federal guidance draws one line hard. Unlike alcohol and sedative withdrawal, uncomplicated opioid withdrawal is not life-threatening [3]. Seizures and delirium tremens are outcomes in severe alcohol dependence that can lead to fatal consequences [3].

If someone is having a seizure, is unresponsive or has trouble breathing, call 911. For a mental-health crisis call or text 988.

So a combination that includes alcohol or a sedative is a different proposition from one that does not, whatever else is in it. The medication picture changes with it. Guidance says benzodiazepines should be avoided in this setting unless they are required for a concurrent alcohol or sedative withdrawal [3]. A medication that protects in one situation is not a general comfort measure in another.

One risk applies after withdrawal rather than during it, and it is the one that kills people. Most opioid overdose deaths occur in people who have just detoxed, because withdrawal reduces tolerance, so someone who has just been through it can overdose on a much smaller amount than they used to take [4]. Where a combination included opioids, that risk arrives regardless of what else was involved.

This page gives no timeline, deliberately. A withdrawal timeline needs one named drug, and the subject here is combinations. Medical detox describes the setting where that gets worked out for an individual.

Which level of care fits, and why this narrows the options

There is one sentence in the federal guidance that does more work on this page than any other, and most people never see it. It appears in the chapter’s section on benzodiazepines and other sedatives, so read it with that scope attached.

Outpatient withdrawal management should be reserved for patients whose benzodiazepine doses were mainly in therapeutic ranges, who do not have polysubstance dependence, and who are reliable and have reliable people around them to help with monitoring and supervising their progress [3]. The clause in the middle is the one to carry away. Using more than one substance is, in the guidance’s own list, one of the specific things that takes the lightest option off the table.

The wider frame is a ladder rather than a door. Federal guidance sets out five levels of withdrawal management for adults, running from an organized outpatient service, through outpatient care with nurses monitoring for several hours a day, to residential care, and then to round-the-clock medically supervised care on an inpatient or acute unit [5]. Physicians are told to use prudence in deciding who can go through it safely as an outpatient [5], and as a general rule outpatient care is just as effective as inpatient care for people with mild to moderate withdrawal symptoms [5].

After withdrawal, the same idea continues. A continuum of care is a system in which people enter treatment at a level appropriate to their needs, then step up to more intense treatment or down to less intense treatment as needed [6]. Intensive outpatient treatment serves three functions in that system: an entry point into treatment, a step-down from a higher level, and a step-up for someone a standard outpatient program has not held [6].

The hours are worth knowing before you ask about them. The American Society of Addiction Medicine defines intensive outpatient treatment as 9 hours of treatment a week for adults, generally spread over 3 to 5 days, although some programs provide fewer [6]. The consensus panel behind that guidance recommends a range of 6 to 30 hours based on client needs [6]. Our explainers on levels of care, inpatient rehab and outpatient rehab describe what each tier involves.

Medications: where they exist and where they do not

Approved medications exist for some substances and not for others, and there is none for a combination.

That is the practical point people miss. A medication approved for opioid use disorder addresses opioids. It does not address the alcohol, the benzodiazepine or the stimulant alongside it. Treating one substance does not treat the other, and a plan that behaves as though it does has a gap in it with a person standing in the gap.

So the medication conversation on a combination is a set of separate decisions, made in an order, by a prescriber who knows all of them. Our hub on medication-assisted treatment sets out where approved medications exist and what each is for. This page publishes no amounts and no regimens.

Ask a program directly which substances its medication options cover, and what happens with the ones they do not.

Therapy, and what a program does with a combination

The behavioral work is where a combination is actually held together, because it is the part that does not have to be substance by substance.

What changes in practice is less about the content of a session and more about the shape of the plan. One plan rather than two. One team that knows the whole picture rather than two services each holding half of it. A sequence, agreed in advance, for what gets addressed first and what is held.

Ask how the program handles that, and ask who owns the plan. Our pages on types of therapy and cognitive behavioral therapy explain what those sessions involve, and how long treatment takes covers the length question.

Most people need long-term treatment after detox [4]. On a combination, that is not a caution, it is the plan.

Co-occurring mental health conditions

A mental health condition alongside more than one substance changes the level of care, the therapy and the sequence, which is why the assessment asks about it so early.

The practical question to put to a program is the same one that matters for the substances. Do they hold the mental health condition and the substance use on one plan, with one team, or do they hand them to two services that talk to each other occasionally? The answer tells you how the hardest weeks will go.

Federal guidance treats the assessment of co-occurring mental and physical conditions as part of the evaluation itself rather than as a referral made later [2]. A program that treats it that way is doing what the guidance describes.

Paying for treatment and verifying benefits

Coverage is decided per plan and per level of care, and the general rules tell you the shape of the answer rather than the answer.

Under the Mental Health Parity and Addiction Equity Act, a plan that covers mental health and substance use care may not apply harsher limits to it than it applies to medical and surgical care, and that reaches prior authorization and step therapy as well as visit and day caps [7]. The scope is worth knowing: it applies to non-federal governmental plans with more than 50 employees, to group health plans of private employers with more than 50 employees, and to the individual market [7]. Plans from small employers are not covered directly; they get comparable protection through the Affordable Care Act’s essential health benefits requirement [7].

Two boundaries follow. Parity does not by itself oblige a plan to cover this care [7]. And prior authorization is a limit parity governs rather than one it removes [7], so ask whether a step up or down needs a fresh approval.

A verification call produces the numbers this page does not quote: network status, deductible, out-of-pocket maximum and which levels are approved. Our pages on insurance coverage for rehab and what treatment costs explain the terms before you make it, how admission works sets out the steps, and our treatment centers lists the campuses we run.

Frequently Asked Questions

Sources

1. Centers for Disease Control and Prevention. (2024). Polysubstance Use Facts. Stop Overdose. https://www.cdc.gov/stop-overdose/caring/polysubstance-use.html
2. Center for Substance Abuse Treatment. (2006). Detoxification and Substance Abuse Treatment — Chapter 1, Overview, Essential Concepts, and Definitions in Detoxification. Treatment Improvement Protocol (TIP) Series No. 45, SAMHSA, via NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK64119/
3. Center for Substance Abuse Treatment. (2006). Detoxification and Substance Abuse Treatment — Chapter 4, Physical Detoxification Services for Withdrawal From Specific Substances. Treatment Improvement Protocol (TIP) Series No. 45, SAMHSA, via NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK64116/
4. MedlinePlus. Opiate and opioid withdrawal. Medical Encyclopedia, U.S. National Library of Medicine, National Institutes of Health. https://medlineplus.gov/ency/article/000949.htm
5. Center for Substance Abuse Treatment. (2006). Detoxification and Substance Abuse Treatment — Chapter 2, Settings, Levels of Care, and Patient Placement. Treatment Improvement Protocol (TIP) Series No. 45, SAMHSA, via NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK64109/
6. Center for Substance Abuse Treatment. (2006). Substance Abuse: Clinical Issues in Intensive Outpatient Treatment — Chapter 3, Intensive Outpatient Treatment and the Continuum of Care. Treatment Improvement Protocol (TIP) Series No. 47, SAMHSA, via NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK64088/
7. Centers for Medicare & Medicaid Services. The Mental Health Parity and Addiction Equity Act (MHPAEA). https://www.cms.gov/marketplace/private-health-insurance/mental-health-parity-addiction-equity

This page is for general information and is not medical advice. Only a licensed clinician who knows your history can tell you what is right for you. If you or someone you know is in immediate danger, call 911. For free, confidential support 24/7, call or text 988.

Author

Kevin Wandler, MD

Chief Medical Officer, The Recovery Village