Does Naltrexone Block Benzos? What the Science Says

Naltrexone does not block benzodiazepines in the pharmacological sense. It is an opioid receptor antagonist, meaning it physically occupies opioid receptors and prevents opioids from activating them. Benzodiazepines work through an entirely different receptor system, so naltrexone cannot intercept their primary effects the way it intercepts those of heroin or oxycodone. The relationship between the two drugs is more nuanced than a simple yes or no, though, because opioid and GABA signaling overlap in parts of the brain that regulate anxiety and reward.

Why This Question Comes Up

People prescribed naltrexone for alcohol or opioid use disorder are sometimes also taking a benzodiazepine for anxiety or sleep, and they understandably want to know whether one drug will cancel out the other. Others wonder whether naltrexone could serve as an emergency antidote for benzodiazepine overdose the way it reverses opioid overdose. In both cases, the answer hinges on the fact that naltrexone and benzodiazepines act on completely different molecular targets in the brain.

Naltrexone binds tightly to mu-opioid receptors, blocking the effects of opioid drugs and also blocking some of the brain’s own endorphins. Benzodiazepines, on the other hand, enhance the activity of GABA-A receptors, the brain’s main inhibitory system. These are separate locks requiring separate keys. Naltrexone does not fit the GABA-A lock, so it cannot directly undo what a benzodiazepine does at that receptor.

What Actually Blocks Benzodiazepines

The true pharmacological antagonist for benzodiazepines is flumazenil, a drug that competes with benzodiazepines at their specific binding site on the GABA-A receptor. Flumazenil can reduce or terminate benzodiazepine effects in a dose-dependent manner by directly displacing the benzodiazepine molecule from the receptor.¹ It is used in emergency rooms for benzodiazepine overdose, although its use is more limited than naloxone’s role in opioid overdose because abruptly reversing benzodiazepines in a dependent person can trigger seizures.

Animal research confirms flumazenil’s specificity. When researchers administered flumazenil to rats that had been given anxiety-reducing compounds acting through the GABA-benzodiazepine system, the anxiolytic effects were abolished.² Flumazenil is, in short, the mirror image of benzodiazepines at their receptor. Naltrexone is not.

The Partial Overlap Between Opioid and GABA Systems

Even though naltrexone cannot directly block benzodiazepines, the opioid and GABA systems are not completely independent of each other. They share circuitry in brain regions involved in anxiety, stress, and reward. This overlap is where the story gets more interesting and where much of the confusion originates.

One well-cited line of animal research tested whether naloxone, a short-acting opioid antagonist closely related to naltrexone, could interfere with the anti-anxiety effects of benzodiazepines like diazepam. The results were striking: naloxone blocked the anti-anxiety effect of benzodiazepines in a dose-dependent manner across two different anxiety models. But it did not block the motor-impairing effects of those same drugs. The researchers concluded that the brain’s own opioid system plays a role in producing the anxiety-relieving properties of benzodiazepines, but not their sedative or muscle-relaxant properties.³

This is an important distinction. When someone takes diazepam, the calming feeling and the physical sedation appear to be driven by partially different neural circuits. The endorphin system seems to contribute to the emotional relief but not to the drowsiness and coordination problems. Blocking opioid receptors with naloxone or naltrexone therefore chips away at part of the benzodiazepine experience without undoing the whole thing.

A separate lab study found that naloxone, naltrexone, and even morphine all acted as weak negative modulators of GABA-A receptor function in brain tissue preparations, reducing the response to GABA at high concentrations.⁴ The concentrations needed were far above what you would see at normal clinical doses, so this effect is probably not relevant to someone taking a standard naltrexone prescription. It does, however, illustrate that there is a faint chemical crosstalk between the two systems at the receptor level.

What Happens When People Take Both

The most directly relevant human study gave volunteers either naltrexone or a placebo before administering diazepam. Naltrexone did not block the cognitive effects of diazepam: performance on a standardized test battery was the same in both groups. But naltrexone changed how diazepam felt. People on naltrexone reported more negative mood states like fatigue and anxiety, and fewer positive states like friendliness and feeling high. They liked the diazepam experience less.⁵

In other words, naltrexone did not reverse the sedation or impairment caused by diazepam, but it stripped away some of the pleasurable quality. This aligns neatly with the animal findings described above: the opioid system contributes to the rewarding and anxiety-relieving aspects of benzodiazepines, so blocking it makes the experience less enjoyable without eliminating the drug’s core pharmacological effects.

The same study found something unexpected on the pharmacokinetic side. Naltrexone delayed the time it took for diazepam to reach peak blood levels. In the placebo group, diazepam peaked at about 75 minutes; in the naltrexone group, it peaked at about 135 minutes.⁵ That is close to double the absorption time. The mechanism behind this delay is not entirely clear, but it means that taking both drugs together can alter how quickly the benzodiazepine kicks in, even though naltrexone does not block its effects at the receptor.

Naltrexone’s Influence on Drug Metabolism

Beyond the receptor story, naltrexone can influence how the liver processes other drugs, including some benzodiazepines. Many benzodiazepines are broken down by liver enzymes in the cytochrome P450 family, particularly CYP3A4. Naltrexone has been shown to inhibit several of these enzymes in lab studies using human liver tissue. At a concentration of 1 micromolar, naltrexone reduced CYP3A4 activity by roughly 38%, CYP2C9 by about 37%, and CYP2D6 by about 32%.⁶

CYP3A4 is the enzyme responsible for breaking down benzodiazepines like alprazolam, midazolam, and triazolam. If naltrexone slows that enzyme down, those benzodiazepines could linger in the body longer or reach higher blood levels than expected. This does not mean naltrexone “blocks” benzos; paradoxically, it could make them slightly stronger or longer-lasting by slowing their clearance. The delayed diazepam peak observed in the human study mentioned earlier may partly reflect this metabolic interference.

Not all benzodiazepines are metabolized by CYP3A4. Lorazepam and oxazepam, for instance, skip the cytochrome P450 pathway and are eliminated through a different process called glucuronidation. For those drugs, naltrexone’s enzyme-inhibiting properties are largely irrelevant. This is one reason the interaction between naltrexone and benzodiazepines is not uniform across the class. Which specific benzodiazepine is involved matters.

The Low-Dose Naltrexone Question

A growing number of people take low-dose naltrexone (LDN), typically between 0.5 and 4.5 milligrams per day, for chronic pain, autoimmune conditions, and other off-label uses. Standard naltrexone for addiction treatment is prescribed at 50 milligrams per day, so LDN is roughly a tenth of the usual dose or less. People on LDN who also take a benzodiazepine sometimes wonder whether the interaction concerns described above still apply at such low doses.

At LDN doses, the drug produces only a brief and partial blockade of opioid receptors rather than the sustained, near-complete blockade seen with the full 50-milligram dose. The proposed mechanisms of LDN are thought to involve modulation of immune signaling and glial cell activity rather than GABAergic neurotransmission.⁷ In practical terms, this means LDN is far less likely to interfere with the subjective effects of a benzodiazepine in the way that a full 50-milligram dose can. The enzyme-inhibition effects on CYP3A4 would also be smaller at lower concentrations, though they have not been formally studied at LDN-specific doses.

That said, the clinical evidence on LDN and benzodiazepine co-use specifically is thin. Most LDN research focuses on pain and inflammation endpoints, not on drug interactions with other central nervous system medications. If you are taking both, the risk of a dramatic interaction is low based on what we know about the pharmacology, but it is not zero and has not been rigorously tested in controlled trials.

Practical Implications for People on Both Drugs

If you are prescribed naltrexone for alcohol or opioid use disorder and also take a benzodiazepine, the combination is not considered dangerous in the way that mixing benzodiazepines with opioids is dangerous. Naltrexone does not amplify the respiratory depression that makes opioid-benzodiazepine combinations potentially fatal. The main things to be aware of are subtler.

First, naltrexone may reduce how much emotional relief the benzodiazepine provides. The anti-anxiety effect might feel blunted compared to what you experienced before starting naltrexone. This is not because the benzodiazepine is not working pharmacologically. Your cognitive and motor impairment will still be present. But the subjective sense of calm and well-being can be diminished when the opioid system is blocked.

Second, for benzodiazepines processed through CYP3A4, naltrexone could modestly alter the timing and intensity of effects. The onset might be slower, and the drug may persist longer. This is unlikely to be clinically significant for most people at standard doses, but it is worth mentioning to your prescriber so they can monitor your response.

Third, and perhaps most important clinically: naltrexone is not a substitute for flumazenil in a benzodiazepine emergency. If someone has overdosed on a benzodiazepine, giving naltrexone will not reverse the sedation or respiratory depression. Only flumazenil can do that, and even flumazenil is used cautiously because of seizure risks in dependent individuals.

Benzodiazepine Use During Addiction Treatment

One context where the naltrexone-benzodiazepine question becomes especially relevant is in treatment for opioid use disorder. People entering treatment often have histories of polysubstance use, and benzodiazepines are commonly among the substances involved. Research on treatment outcomes has found that sedative use before and during treatment is associated with worse results. In one large study, the proportion of days of pretreatment sedative use was linked to increased likelihood of opioid relapse, and sedative use during the first four weeks of treatment was associated with greater opioid craving.⁸

This finding does not mean that naltrexone and benzodiazepines are pharmacologically incompatible. Rather, it suggests that ongoing benzodiazepine use during addiction treatment complicates recovery, possibly because the partial overlap in reward circuitry means that benzodiazepine use keeps activating some of the same pathways that sustained the addiction. Some clinicians interpret this as a reason to taper benzodiazepines when possible in patients starting naltrexone, though this needs to be balanced against the risk of benzodiazepine withdrawal, which can be medically serious.

Why the Mood Change Matters More Than It Sounds

The human finding that naltrexone makes diazepam less pleasurable might seem like a footnote, but it has real implications. For someone taking a benzodiazepine recreationally, naltrexone reduces the rewarding quality of the high. This is the same principle behind using naltrexone for alcohol use disorder: alcohol triggers endorphin release, and naltrexone blunts that endorphin reward, gradually weakening the reinforcement loop. The evidence suggests a similar partial dampening occurs with benzodiazepines.

For someone taking a benzodiazepine as prescribed for a legitimate anxiety disorder, this mood-altering effect is less welcome. If the emotional relief from the benzodiazepine feels weaker, the person may be tempted to take a higher dose to achieve the same subjective effect, even though their cognitive impairment is already at the expected level. This mismatch between how impaired someone feels and how impaired they actually are can be a subtle safety issue, particularly for tasks like driving.

The animal research showing that opioid antagonists selectively block the anti-anxiety but not the motor effects of benzodiazepines supports this concern. If naltrexone removes the calming feeling while leaving the coordination problems intact, a person might take more of the benzodiazepine chasing the anxiety relief, unaware that they are already significantly sedated and impaired. Prescribers managing patients on both drugs should be alert to this dynamic and set clear dosing expectations.

Benzodiazepines That Bypass the Interaction

As mentioned in the section on drug metabolism, not all benzodiazepines pass through the same liver pathways. The ones most likely to be affected by naltrexone’s CYP3A4 inhibition are those heavily metabolized by that enzyme, such as alprazolam, midazolam, and triazolam. These could theoretically have slightly elevated blood levels or delayed clearance when taken alongside naltrexone.

Lorazepam, oxazepam, and temazepam are metabolized primarily through glucuronidation and do not rely on CYP3A4. For these drugs, the pharmacokinetic interaction with naltrexone is expected to be minimal. The indirect effect on subjective mood would still apply because that operates through the opioid receptor, not through metabolism. But the timing and intensity of sedation should be less affected.

If you and your prescriber are weighing which benzodiazepine to use while you are on naltrexone, these metabolic differences are worth factoring in. A benzodiazepine that avoids the CYP3A4 pathway removes one layer of interaction from the equation, leaving only the mood-dampening effect through the opioid system. That simplifies monitoring and reduces the chance of unexpected changes in how the benzodiazepine hits.