Abuse of Medications That Theoretically Are Without Abuse Potential

Roy R. Reeves, DO, PhD; Mark E. Ladner, MD; Candace L. Perry, MD; Randy S. Burke, PhD; Janet T. Laizer, MD


South Med J. 2015;108(3):151-157. 

In This Article

What Types of Noncontrolled Medications Are Abused and How?

Any pharmaceutical that may induce psychoactive effects of any kind may be abused. Effects that may occur include relaxation, sedation, intoxication, euphoria, increased energy, and hallucinations. A range of medications is capable of producing such effects to some degree if taken in large enough doses; therefore, a variety of common medications may theoretically be abused.

Many medications such as antihistamines, quetiapine, olanzapine, tricyclics, gabapentin, skeletal muscle relaxants, and clonidine are abused to take advantage of their sedating effects. Others, including pseudoephedrine, tranylcypromine, bupropion, fluoxetine, and venlafaxine are abused for their stimulant effects. Anticholinergic agents and tricyclics are abused for their euphoric effects, whereas dextromethorphan and anticholinergic agents are taken for their dissociative and hallucinogenic effects. It may be difficult to categorize clearly these medications by their desired primary effects because many may have more than one effect. Medication may be abused in different ways: to experience a pharmacological property of the medication; to augment or prolong the effect of another drug, or produce a synergistic effect when combined with another drug (eg, taking quetiapine with narcotics for a more intense effect than would be obtained with narcotics alone); and to alter the effect of another drug (eg, curbing the effects of cocaine with a sedating medication).[10] When medications are abused, dosages are often much larger than clinically indicated, and routes of administration are sometimes changed for the purposes of abusing the drugs (eg, intranasal abuse of bupropion). Cooper[1] classifies harmful effects of medication abuse into three categories: harm related to pharmacological or psychological effects of the medication, harm related to the adverse effects of another active ingredient in a compound formulation, and harm from other consequences such as progression to abuse of other substances, economic costs, and effects on personal/social life.

Cough/Cold Preparations and Antihistamines

Readily available, medications for cough and the "common cold" are frequently abused, particularly among minors.[11] Cough preparations contain several constituents that may be abused, including decongestant, antitussive, and antihistamine components.

Of particular concern is the decongestant pseudoephedrine, a sympathomimetic drug that promotes dopamine release and may be abused for stimulatory effects.[12] Abuse to lose weight and improve athletic performance has occurred, and abuse via intravenous routes rarely has occurred.[13] Pseudoephedrine is used to manufacture methamphetamine, resulting in classification as a controlled substance in several states. Interventions targeting minors and controlling the sale of pseudoephedrine has been shown to decrease methamphetamine abuse by hindering the manufacturing of the latter.[14] Although less notable, decongestants with stimulant properties such as ephedrine and oxymetazoline possess abuse potential if used in large doses.[15] Sympathomimetic agents in medications other than cough preparations (eg, weight loss drugs) could likewise have abuse potential.

Dextromethorphan (DXM), a widely used OTC cough/cold remedy, is a congener of levorphanol, an opiate agonist analgesic, and increasing illicit use has been reported. When abused in large doses (>2 mg/kg), DXM produces intoxicating, hallucinogenic, and dissociative effects.[16] DXM appears to be popular among adolescents who intoxicate themselves with 5 to 10 times the recommended dose. Extraction procedures are available online for the home manufacture of concentrated DXM powder from cough preparations. Large doses of DXM have physiological and psychological effects similar to phencyclidine,[11] and physical dependence and withdrawal have occurred.[17]

Reports of abuse of antihistamines have been increasing. In the 1980s tripelennamine was taken with the opioid pentazocine to produce heroin-like intoxication.[18] Abuse of antihistamines such as chlorpheniramine, cyclizine, diphenhydramine (Benadryl), and Coricidin, which contains chlorpheniramine and DXM and is widely abused by minors, is a problem.[19–21] Antihistamine abuse appears to be targeted at sedation resulting from H1 receptor antagonism; however, antihistamines also may affect dopaminergic transmission, resulting in a cocaine-like effect.[22]


Reports of the abuse of anticholinergic agents such as diphenhydramine, which has both anticholinergic and antihistaminic properties, and benztropine (Cogentin) by more than 100 patients have been published and reviewed.[23] Although all anticholinergics may be abused, this occurs most frequently with trihexyphenidyl (Artane). Anticholinergics are abused for the stimulant, euphoriant, and hallucinogenic effects they can produce when taken in large doses,[24] with the most frequent reason for abuse given by patients being "to get high." Rates of inappropriate use of anticholinergic drugs by people with serious mental illness may be as high as 18%.[25]


Older antipsychotic drugs such as chlorpromazine (Thorazine) have significant anticholinergic and sedating effects and may be abused. Newer atypical antipsychotics affect many different neuroreceptors with a variety of potential effects. People have taken advantage of these effects by consuming excessive amounts of the drugs, or by combining them with other medications or substances.

Quetiapine (Seroquel)

Quetiapine may be abused for its sedating and anxiolytic effects. Drug-seeking behaviors, compulsive use, and diversion (diversion of licit drugs for illicit purposes) have occurred.[26,27] Oral abuse occurs by consuming 800 to 1200 mg at a time; however, quetiapine powder is sometimes snorted intranasally[28,29] and taken intravenously.[30]

Dependence and withdrawal have been described in a 38-year-old man who was hospitalized because he could not control his intake of quetiapine and experienced withdrawal symptoms when he tried to stop the medication.[31] Quetiapine is sometimes referred to as "quell" or "baby heroin" by prison inmates and has been removed from several prison formularies.[8,32] One report describes abuse of quetiapine to potentiate the effect of buprenorphine/naloxone (Suboxone).[33]

Olanzapine (Zyprexa)

Three reports describe olanzapine abuse for sedation and similar effects. A 53-year-old woman took up to 40 mg/day and "couldn't control the use of olanzapine."[34] A 48-year-old woman taking 50 mg/day experienced nervousness, insomnia, and unbearable anxiety when she attempted to stop.[35] A 25-year-old man took 40 mg at a time "for a buzz" and combined olanzapine with alcohol or benzodiazepines to produce euphoria. He reported observing another person intravenously injecting dissolved olanzapine.[36]


Case reports suggest that antidepressants with stimulating or sedating properties may be abused. Antidepressants with anticholinergic or dopaminergic effects may particularly pose risks.

Tranylcypromine (Parnate). Eighteen cases of abuse involving high doses to produce stimulant effects have been reported with tranylcypromine, a monoamine oxidase inhibitor.[37] Abuse is related to the amphetamine-like structure of the drug; other monoamine oxidase inhibitors not sharing this structure have not demonstrated abuse potential. Delirium has occurred following abrupt cessation of large doses.[38]

Tricyclics. Tricyclic antidepressants (TCAs), particularly those with sedating and anticholinergic effects have abuse potential. Multiple reports describe the abuse of large doses of amitriptyline (Elavil) to produce euphoria, relaxation, giddiness, and contentment. Dothiepin has similarly been abused in Europe.[39–42] Cohen[43] cautioned about prescribing TCAs after finding that 25% of patients in a methadone program were abusing amitriptyline "with the purpose of achieving euphoria."

Among patients attending a drug treatment center and not prescribed TCAs, 19% had TCAs or metabolites in their urine and admitted TCA abuse to produce euphoria and pleasant auditory/visual hallucinations.[42] Paitents abusing narcotics may try to take advantage of the synergistic interaction between opiates and TCAs to enhance or prolong the effect of opiates.[44]

Bupropion (Wellbutrin). Oral abuse of bupropion is unlikely, but abuse does occur by nasal insufflation. The effects have been described as similar to cocaine, but weaker.[45,46] At least three incidents of seizures following nasal insufflation have occurred.[47–49] A report described several occurrences of intranasal bupropion abuse by inmates and of their knowledge of abuse outside prison. One inmate described intranasal bupropion as "overwhelmingly addictive" with a "cocaine-like feel and taste,"[50] and another individual admitted continuing to abuse bupropion after learning about snorting it in jail.[51] Nasal insufflation bypasses first-pass metabolism, resulting in more rapid, higher plasma concentrations than with oral intake. Structurally, bupropion resembles amphetamines and endogenous monoamines, inhibits dopamine and norepinephrine reuptake, and potentiates dopaminergic neurotransmission.[52]

Other Antidepressants. Reports have indicated that high doses of fluoxetine (Prozac) have been taken for amphetamine-like effects. One found that fluoxetine taken with 80 mg with two beers produced increased energy, mood elevation, and jitteriness, but was unlike "speed" because the individual also felt "numb and calm." Taking up to a "handful" of medication resulted in amphetamine-like effects and insomnia, whereas taking as much as 280 mg/day led to tolerance, dependence, and then withdrawal following discontinuation.[53,54] Combining fluoxetine with 3,4-methylenedioxy-methamphetamine (MDMA, commonly known as ecstasy), and fluoxetine with sertraline (Zoloft) has been reported to result in a prolonged effect of the ectsasy.[55]

Another report detailed excessive use of venlafaxine (Effexor), with the individual averaging 2100 mg/day, with doses of up to 3750 mg/day, that resulted in amphetamine-like effects. He was hospitalized for detoxification and had significant withdrawal symptoms. He later resumed abuse.[56]


Anticonvulsants generally have not demonstrated significant abuse potential, except for pregabalin and gabapentin. Abuse of pregabalin (a Schedule V drug) is already recognized and is not discussed here. With approximately 20 cases of gabapentin addiction having been described in Europe,[57] there is significant evidence of gabapentin (Neurontin) abuse because of its ability to illicitly potentiate the effect of buprenorphine/naloxone.[33] A 42-year-old cocaine user substituted gabapentin for cocaine, reporting relaxation and feeling "laid back."[58] Inmates have admitted snorting gabapentin powder for an effect similar to cocaine and the drug has been removed from several prison formularies.[8,59]

Several cases of withdrawal from gabapentin have occurred with symptoms including elevated vital signs, confusion, agitation, diaphoresis, and seizures, and some cases have been similar to alcohol or benzodiazepine withdrawal.[60–66] Catatonia also has been reported after gabapentin discontinuation; this is notable because catatonia may occur during benzodiazepine withdrawal.[67] Gabapentin may reduce cocaine craving and may decrease withdrawal symptoms during methadone-assisted opioid detoxification.[68,69]

Carbamazepine may decrease alcohol craving, and divalproex has been shown to reduce alcohol withdrawal symptoms more consistently than benzodiazepines.[70] Although these properties suggest potential for abuse, none has been reported.

Skeletal Muscle Relaxants

Many skeletal muscle relaxants possess sedative properties that may result in their abuse. Carisoprodol abuse was discussed above. Skeletal muscle relaxants may be used as primary drugs of abuse or in conjunction with other depressive substances affecting the central nervous system.[71]

Cyclobenzaprine (Flexeril) is structurally similar to amitriptyline and has sedating and anticholinergic effects. DAWN reported an 87% increase in cyclobenzaprine-related ED visits, from 6183 in 2004 to 11,151 in 2011.[7] Orphenadrine (Norflex) has been abused in high doses to produce mood enhancement and pleasant disperceptions.[72] Tizanidine (Zanaflex), a centrally acting α2-adrenergic agent, may be abused to produce significant drowsiness and may be useful in the treatment of opioid and alcohol withdrawal.[73]

Baclofen (Lioresal), a GABAB receptor agonist, may cause excessive sedation or ataxia in doses of ≥80 mg/day. Baclofen is closely related structurally to γ-hydroxybutyrate, a drug abused for its euphoric, sedative, and amnestic properties, and better known as a "date rape drug." In one report, a group of adolescents took 3 to 30 20-mg baclofen tablets during a party that resulted in 14 of the adolescents being hospitalized and nine requiring intubation.[74] Baclofen may be used to treat γ-hydroxybutyrate and alcohol withdrawal and has been proposed as a treatment for alcohol dependence, although the drug may be more substitutive than anticraving.[75,76] Withdrawal may occur with the cessation of large doses.[77]


Abuse of certain antiemetics in large doses may produce psychotropic effects. Dimenhydrinate (equimolar amounts of diphenhydramine and 8-chlorotheophylline), is reported to be abused by drug users for its effects of euphoria and hallucinations, whereas psychiatric patients abuse it for its anxiolytic and anticholinergic effects.[78] There also have been reports of abuse by adolescents. Dimenhydrinate is an H1 receptor antagonist that additionally interacts with acetylcholine, serotonin, norepinephrine, opioid, and adenosine receptors.[75] There has been concern regarding its risk for dependence, even in certain patients taking therapeutic doses.[79,80]

Cyclizine (Bonine), an antihistamine used to treat nausea, has been taken intravenously in large doses with methadone, resulting in intense stimulation, hallucinations, and sometimes aggressive behavior and seizures.[81] Cyclizine abuse has occurred among teenagers and patients undergoing cancer treatment.[82,83] Promethazine, a histamine (H1), muscarinic (M1), and dopamine (D2) antagonist used as an antiemetic and perioperative sedative, has been abused in conjunction with opioids in several settings.[84] Significant abuse of cough syrup containing codeine and promethazine occurs in teenagers and college students to produce euphoric effects and self-medication/coping.[85]