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Kava lactones (kava pyrones, 5-12%): chief components include (+)-kavain, dihydrokavain (marindinine), (+)-methysticin, dihydromethysticin, yangonine, desmethoxyyangonin

Chalcones: including flavokavin A and B

KAVA-KAVA EFFECTS

The kava pyrones in the drug have centrally muscle-relaxing, anticonvulsive and antispasmodic effects. The herb also contains hypnotic/sedative, analgesic and psychotropic properties contributing to its use for anxiety and insomnia.

The centrally muscle-relaxing, analgesic and anticonvulsive action of the kava pyrones, kavain, dihydrokavain, dihydromethysticin and (+/-) kavain (synthetic kava pyrone) is attributed to the interaction with ion channels. The interaction consists of fast and specific inhibition of voltagedependent sodium channels and reduction of currents through voltage-activated sodium and calcium channels (Friese, 1998; Gleitz, 1995; Gleitz, 1996; Schirrmacher, 1999). The paralysis effect of Kava on neuromuscular transmission and muscle contractility is similar to that of local anesthetics (Jameison, 1989; Singh, 1983). The lipid soluble extract (kava resin) decreases spontaneous motility and motor control (Jamieson, 1989).

The analgesic action of kavain, dihydrokavain, methysticin and dihydromethysticin is due to antinociceptive activities. Nalaxone (opiate antagonist) is ineffective in reversing the antinociceptive activities, thus indicating the analgesia produced from the compounds occurs via non-opiate pathways (Jameison, 1990; Jameison, 1989).

The lipid soluble components of kava do not interact with benzodiazepine binding sites, but do seem to potentiate the activity of GABA-A in the brain center for sedative effects (Davies, 1992; Jussofie, 1994). The psychotropic properties of Kava have been demonstrated by the inhibition of norepinephrine uptake by kavain, dihydromethysticin and the racemate (+/-) kavain (Seitz, 1997). One study did find that desmethoxyyangonin, methysticin, yangonin, dihydromethysticin, kihydrokavain and kavain reversibly inhibit MAO-B (Uebelhack, 1998). An increase of dopamine and serotonin by activation of neurons results in central nervous system effects (Fachinfo Antares 120(R), 1996).

A recent study investigated the antithrombotic activity of kava pyrones. Kavain exerts antithrombotic action on human platelets through the inhibition of cyclooxygenase (COX) as a primary target. This suppresses the generation of thromboxane (TXA2), which normally induces aggregation of platelets and exocytosis of ATP by its binding on TXA2 receptors (Gleitz, 1997).

KAVA-KAVA CLINICAL TRIALS

A randomized, double-blind, placebo-controlled study was conducted with 101 outpatients suffering from anxiety of non-psychotic origin who met DSM-IH-R criteria. Improvements in anxiety were seen after week 8 with a standardized Kava Kava extract (70% kava-pyrone). The study continued over a 25-week period with significant improvement based upon the Hamilton Anxiety Scale (HAMA), somatic and psychic anxiety, Clinical Global Impression, Self-Report Symptom Inventory and Adjective Mood Scale (Volz, 1997).

The anxiolytic effect of a special kava extract (70 mg of kava pyrones three times daily) was compared to two benzodiazepine preparations (oxazepam 15mg/day, bromazepam). The multi-center, double-blind study involved 172 patients. There was a therapeutically relevant reduction in the severity of anxiety according to the HAMA scale in all three groups. There wasn’t a statistically significant difference between the three types of treatment in terms of reducing anxiety (Woelk, 1993).

A standardized Kava extract give’n 100 mg three times daily was compared to placebo in a randomized, double-blind study. The study included 58 patients with anxiety syndromes not caused by mental disorders. The HAMA overall score of anxiety symptoms revealed significant reduction in the Kava treatment group compared to placebo after 1 week of therapy. After 4 weeks of therapy, an even greater reduction in anxiety symptoms was seen with the Kava treatment group, with no adverse reactions (Lehmann, 1996).

KAVA-KAVA DESCRIPTION
Medicinal Parts: The medicinal parts are the peeled, dried, cut rhizome, which has normally been freed from the roots, and the fresh rhizome with the roots.

Flower and Fruit: The plant has numerous small flowers in spike-like inflorescences 3 to 9 cm long.

Leaves, Stem and Root: The plant is a 2 to 3 m high, erect dioecious bush. The leaves are very large, measuring 13 to 28 cm by 10 to 22 cm. They have a deeply cordate base and 9 to 13 main ribs that are slightly soft on the undersurface. The stipules are large. The plant has a massive, 2 to 10 kg, branched and very juicy rhizome with many roots. They are blackish-gray on the outside and whitish on the inside. The fracture is mealy and somewhat splintery. The central portion is porous with irregularly twisted thin woody bundles, separated by broad medullary rays, forming meshes beneath the bark.

Characteristics: The taste is pungent and numbing, and the odor is reminiscent of lilac.

Habitat: The plant is indigenous to the South Sea Islands and is mainly cultivated there.

Production: Kava Kava rhizome consists of the dried rhizomes of Piper methysticum.

Other Names: Ava, Ava Pepper, Intoxicating Pepper, Kawa, Kawa Pepper, Tonga, Kew

Thanks to the “Prozac (fluoxetine) revolution” of the 1980s and 1990s, a majority of people in America know someone who has used antidepressants. Over 34 million people in the United States have been issued prescriptions for Prozac (fluoxetine) or another selective serotonin reuptake inhibitor (SSRI). In other words, one American in ten has used

antidepressants and studies have estimated that one in six people will have a major depressive episode in their lives (Figure 1.2).

The term “depressive” does not just signify a simple feeling of sadness, but can also refer to any mental disorder with symptoms of moodiness and melancholy — anxiety or eating disorders, for example. Depression is no longer a disease that is shameful or that must be kept hidden. Depression is also no longer as debilitating as it was in the early twentieth century, before the development of antidepressant drugs. Still, the costs of depression to society in terms of lost work, treatment, and other associated expenses have been estimated to be in excess of $30 billion per year. Even with all the progress in antidepressant research, there is an even bigger push to find more antidepressants that work faster and better since rates of depression appear to be growing every year.

But how can a chemical change a person’s outlook on life? If the root of depression is caused by a problem in a person’s life, is it right to take a pill rather than confront the problem? Or is depression something organic, a brain imbalance that can only be cured by taking antidepressants? Are antidepressants, in essence, changing a person’s personality? Furthermore, how well do they work (all hype aside)?

Antidepressants became a media obsession in the early 1990s largely following the publication of Prozac Nation, Elizabeth Wurtzel’s memoir of adolescent depression and its unexpected “cure” by a new kind of antidepressant called fluoxetine, better known as Prozac. Listening to Prozac (fluoxetine), psychiatrist Peter Kramer’s best-selling book, continued the drug’s run of publicity with its descriptions

of formerly depressed patients becoming social, focused, and successful professionals. But on the trail of Listening to Prozac’s success are many other books, which protest that Prozac (fluoxetine) and other antidepressants from the same family (selective serotonin reuptake inhibitors) do not deserve the reputation that the media has given them. Furthermore, other researchers have published findings that refute the effectiveness of selective serotonin reuptake inhibitors (SSRIs) as compared to older antidepressants, straight talk therapy, or even herbal mood-boosters such as St. John’s wort. One study even claims that SSRIs are no better than placebo (the sugar pill used as a control in clinical studies) and might, in fact, be making patients worse.

Source: Antidepressants (Drugs The Straight Facts).

A strong connection exists between apathy and mental disorders. Apathy is one of the hallmark symptoms of schizophrenia. Many people with schizophrenia express little interest in the events surrounding them. Apathy can also occur in depression and depressive disorders. For example, people who are depressed and have  major depressive disorder or  dysthymic disorder often feel numb to events occurring around them, and do not derive pleasure from experiences that they once found enjoyable.

The World Health Organization (WHO) defines health as an optimal state of being that maximizes one’s potential for physical, mental, emotional and spiritual growth. It does not confine health to physical parameters or measures. Passion, interest and action are needed for optimal mental and emotional health. Persons who are apathetic would seem to fall short of the WHO definition
of health.

All people may experience periods of apathy. Disappointment and dejection are elements of life, and apathy is a normal way for humans to cope with such  stresses— to be able to “shrug off” disappointments enables people to move forward and try other activities and achieve new goals. When the stresses pass, the apparent apathy also disappears. A period of apathy can also be viewed as a normal and transient phase through which many adolescents pass.

It is important to note, however, that long-term apathy and detachment are not normal.

How to Treatment

Transient apathy can be overcome. Friends and professionals may be able to assist individuals to develop an interest in their surroundings. Attitude is important. Persons who desire to overcome apathy have much higher odds of succeeding than do persons lacking a positive attitude.

Other than support, no specific treatment is needed for apathy associated with adolescence, unless other, more troubling disorders are also present.

The treatment of more persistent apathy (in a depressive disorder, for example), or the apathy that is characteristic of schizophrenia, may respond to treatment for the primary disorder.

DEPRESSION. For depressive disorders, a number of antidepressants may be effective, including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). The tricyclic antidepressants include  amitriptyline (Elavil), imipramine (Tofranil), and  nortriptyline (Aventyl, Pamelor). MAOIs include  tranylcypromine (Parnate) and  phenelzine (Nardil). The most commonly prescribed SSRIs are  fluoxetine (Prozac),  sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa).

SCHIZOPHRENIA. For schizophrenia, the primary goal is to treat the more prominent symptoms (positive symptoms) of the disorder, such as the thought disorder and  hallucinations that patients experience. Atypical antipsychotics are newer medications introduced in the 1990s that have been found to be effective for the treatment of schizophrenia. These medications include clozapine (Clozaril),  risperidone (Risperdal),  quetiapine (Seroquel),  ziprasidone (Geodon), and  olanzapine (Zyprexa). These newer drugs are more effective in treating the  negative symptoms of schizophrenia (such as apathy) and have fewer side effects than the older antipsychotics. Most atypical antipsychotics, however, do have weight gain as a side effect; and patients taking clozapine must have their blood monitored periodically for signs of agranulocytosis, or a drop in the number of white blood cells.

Resources

BOOKS

Gelder, Michael, Richard Mayou, and Philip Cowen. Shorter Oxford Textbook of Psychiatry. 4th ed. New York, Oxford University Press, 2001.

Wilson, Josephine F. Biological Foundations of Human Behavior . New York, Harcourt, 2002.

PERIODICALS
Adams, K. B. “Depressive symptoms, depletion, or developmental change? Withdrawal, apathy, and lack of vigor in the Geriatric Depression Scale.” Gerontologist 41, no. 6 (2001): 768-777.

Carota A., F. Staub, and J. Bogousslavsky. “Emotions, behaviours and mood changes in stroke.” Current Opinions in Neurology 15, no. 1, (2002): 57-69.

Kalechstein, A. D., T. F. Newton, and A. H. Leavengood. “Apathy syndrome in cocaine dependence.” Psychiatry Resident 109, no. 1 (2002): 97-100.

Landes, A. M., S. D. Sperry, M. E. Strauss, and D. S. Geldmacher. “Apathy in Alzheimer’s disease.” Journal of the American Geriatric Society 49, no. 12 (2001): 1700-1707.

Ramirez, S. M., H. Glover, C. Ohlde, R. Mercer, P. Goodnick, C. Hamlin, and M. I. Perez-Rivera. “Relationship of numbing to alexithymia, apathy, and depression.” Psychological Reports 88, no. 1, (2001): 189-200.

Starkstein, S. E., G. Petracca, E. Chemerinski, and J. Kremer. “Syndromic validity of apathy in Alzheimer’s disease.” American Journal of Psychiatry 158, no. 6 (2001): 872-877.

ORGANIZATIONS

American Psychiatric Association. 1400 K Street NW, Washington, DC 20005. Telephone: (888) 357-7924. FAX: (202) 682-6850.

American Psychological Association. 750 First Street NW, Washington, DC, 20002-4242. Phone: (800) 374-2721 or (202) 336-5500, Web site: <http://www.apa.org/>.

L. Fleming Fallon, Jr., M.D., Dr.P.H.

Studies in the elderly have been carefully reviewed by Soldatos and his colleagues. Some deterioration in the soundness of sleep has been detected but the amount of rebound insomnia following zopiclone (somnosan, ximovan) discontinuation is relatively weak. Although one would certainly expect rebound in a hypnotic with a half-life of around 5 h, the frequency and severity of such rebound seems definitely less than those observed with comparative benzodiazepines such as triazolam and temazepam.

Longer-term studies have been designed to detect withdrawal as well as rebound phenomena. A large scale study in France recorded any reactions to stopping zopiclone (somnosan, ximovan) after it had been taken for up to 12 months. Over a thousand patients took part, most of whom stopped abruptly. In only 1.3% of the overall population was there substantial evidence of any withdrawal. The symptoms comprised anxiety, irritability, malaise and perceptual changes, which are characteristic of a sedativetype withdrawal reaction. Two parallel studies evaluated the withdrawal following long-term zopiclone (somnosan, ximovan) and long-term zolpidem. Thirty eight percent of those who withdrew from zopiclone (somnosan, ximovan) had apparent symptoms, but these were also found in 27% of those who continued. Most of the withdrawal symptoms related to sleep complaints. Excluding these, no treatment-emergent increase in withdrawal symptoms was found.

An evaluation has beenmade of the utility of zopiclone (somnosan, ximovan) substitution in facilitating the withdrawal of flunitrazepam. Twenty-four volunteers with insomnia and a history of long-termbenzodiazepine hypnotic usewere assessedwith both subjective and objective measures during a 5-week substitution with zopiclone (somnosan, ximovan) and subsequent withdrawal or continuation on flunitrazepam. Withdrawal from flunitrazepam was accompanied aworsening of sleep quality, both subjectively and objectively. No such deterioration was seen in the zopiclone (somnosan, ximovan) - substituted groups.

Lemoine and Ohayon completed a much larger scale study. Over 1000 patients being treated with a hypnotic were allocated to one of three treatments: gradual substitutionwith zopiclone (somnosan, ximovan); immediate substitutionwith zopiclone (somnosan, ximovan); remained on their benzodiazepine. The gradual and abrupt substitution group had improved sleep during this initial phase; the abrupt substitution group did best. During withdrawal, the last group (benzodiazepine-using) fared worst and more resumed their medication. The PSG withdrawal effects of zopiclone (somnosan, ximovan) (7.5 mg), zolpidem (10 mg) and triazolam (0.25 mg) as compared with placebo were studied in 38 healthy subjects over 4 weeks. Slight, non-signi?cant rebound effects on sleep continuity were detected after withdrawal of zopiclone (somnosan, ximovan) and zolpidem. Total sleep time and sleep efficiency were lower the first night after cessation of triazolam.

A very detailed review of zopiclone (somnosan, ximovan) noted its proven efficacy and good tolerability.With respect to withdrawal, clinical trials showed no evidence for significant rebound insomnia. The risk of withdrawal reactions was very low, although dependency and abuse have been reported.

Post-marketing surveillance and pharmacovigilance data contain few convincing cases of withdrawal from zopiclone (somnosan, ximovan). Most consist of rebound insomnia, but there are a few instances of withdrawal convulsions following high-dose dependence. A reviewof 25 zopiclone (somnosan, ximovan) discontinuation studies found rebound effects andwithdrawal symptoms to be minimal.

Lorazepam [Ativan, Temesta] Uses. This antianxiety drug is also known for its sedative properties and is used to promote sleep and to fight convulsions. The substance is given to treat status epilepticus, a dangerous condition in which people have one epileptic seizure after another, back-to-back. It can reduce and sometimes even eliminate vomiting from cancer chemotherapy.  Lorazepam has been used to treat LSD and methamphetamine overdose and has been a standard medicine to help alcoholics through the alcohol withdrawal syndrome. Recreational sedative users report euphoria from lorazepam. When given experimentally in combination with other drugs, it has helped reduce depression. In contrast, experimentation using motion picture excerpts to evoke particular emotions found that lorazepam may reduce happy feelings and increase unhappy ones. One study found that lorazepam worked as well as alprazolam for treating panic attacks, and a case report tells of success in treating mania. Lorazepam has been used to cure both catatonia (in which people are frozen in place) and akathisia (compulsive moving around). Patients being prepared for surgery receive the drug to calm them and to cloud their memory of the event.

Lorazepam is 5 times stronger than diazepam and 15 times stronger than oxazepam, and one experiment showed that lorazepam is 370 to 783 times stronger than meprobamate in producing some effects, ranging from degraded performance in tests to amount of liking for one drug or the other.

Relatively little research seems to be done on whether members of different races respond differently to the same drug. This type of uncommon study has been done with lorazepam. The work found that although doses lasted about as long in young Americans as in young Japanese, a dose lasted about 20% longer in elderly Japanese than in elderly Americans—and a dose lasted about 20% longer in elderly Americans than in young Americans, so the difference became quite noticeable in Japanese subjects. (“American” and “Japanese” are nationalities, not races, but the research  description stated that the issue of racial effect was being investigated; so those nationality labels were intended to have racial connotations.)

Lorazepam [Ativan, Temesta] Drawbacks. Partial amnesia is a typical effect of the substance, and after using it for several days, people may have trouble gaining new memories. Investigators have also found that the drug interferes with detecting whether information is correct, while simultaneously reducing a person’s awareness of memory trouble. Occasionally lorazepam temporarily stops respiration, and people suffering from serious breathing trouble should avoid the substance. The same goes for persons with acute narrow-angle glaucoma. The drug can reduce body temperature and, depending on circumstances in experiments, either raise or lower heart rate and blood pressure.

Researchers find that the substance interferes with recognizing common items shown in distorted pictures; such trouble is considered evidence of the brain suffering from weakened ability to understand what the eyes see. A case report notes that lorazepam may impede movements of the mouth and face. The drug somewhat garbles speech. Because of adverse impact on mental clarity and physical performance, people are advised to avoid operating dangerous machinery (such as cars) for at least 48 hours after using lorazepam. Driving tests have shown the drug to reduce vehicle control skill while increasing risk-taking. Other tests demonstrate worsened attention, slower reaction time, and delay in reasoning out the solution to a problem. An experiment demonstrated that users may be unaware of how much the drug is interfering with their abilities. Dizziness and weakness may occur. Typically a dose has greater impact on the elderly, and all persons risk falling down until the drug wears off. A case report notes that lorazepam can eliminate a person’s interest in sexual activity. An unusual case report tells of someone who was hearing noises in an ear, and the noises became musical hallucinations of popular songs when the person began taking lorazepam. More typically, however, the drug is able to stop auditory hallucinations. Other case reports tell of visual hallucinations after taking the compound, and that response was also observed in 3 children among 112 who were given the drug. Although lorazepam is used to reduce anxiety, case reports and formal experimentation show that the substance can increase aggressiveness (perhaps because people are less afraid to do things). A schizophrenic who received the drug lost enough inhibitions to start acting out violent impulses, and similar reports exist. In formal experimentation volunteers receiving lorazepam became more aggressive but did not realize they were angrier than other persons in the experiment.

Lorazepam [Ativan, Temesta]  Abuse Factors. Various psychological tests measure how much a drug appeals to someone. Among persons who already have a history of drug abuse (a population prone to like drugs much more than nonusers do), some results indicate lorazepam has about the same addictive potential as diazepam or meprobamate; some results simply show lorazepam to have an unspecified amount of appeal; and in one experiment abusers found the drug about as attractive as a placebo (indicating low addictive potential). Rats begin exhibiting tolerance to lorazepam after several days of dosing. If a person takes lorazepam enough to develop dependence on it, suddenly quitting the drug can produce a withdrawal syndrome. If drug use has been heavy the withdrawal can include confusion, depression, perspiration, cramps, tremors, vomiting, mania, and convulsions. Lighter use can produce lighter withdrawal such as insomnia and generally feeling out of sorts. Symptoms can be avoided altogether if a person gradually takes smaller and smaller doses rather than stopping abruptly.

Lorazepam [Ativan, Temesta]  Drug Interactions. Lorazepam generally makes people more susceptible to effects of alcohol. If a person taking lorazepam simultaneously ingests other  depressants (alcohol, barbiturates, opiates) the total depressant effects deepen. Although we might expect stimulants to counteract lorazepam’s actions, research has found that cocaine can boost some of them, with sleepiness becoming particularly greater. Thus cocaine users receiving lorazepam for medical treatment may require lower doses than normal.

Lorazepam [Ativan, Temesta] and Cancer. Mice and rat studies have not yielded evidence that lorazepam causes cancer.

Lorazepam [Ativan, Temesta]  and Pregnancy. In mice lorazepam increases incidence of eyelid malformation and cleft palate. Mice having fetal exposure to lorazepam exhibit lasting neurochemistry abnormalities, and rats with fetal exposure demonstrate brain difficulty. Extrapolating from rat test results, two researchers concluded that fetal exposure to the drug may result in male offspring having more anxiety than normal and females having less than normal. Pregnant rabbits receiving lorazepam in an experiment produced more birth defects than usual. Persuasive  evidence indicates that the drug passes from a pregnant woman into the fetus. The drug is not recommended for pregnant women unless the need is dire. Analysts examining thousands of medical records concluded that lorazepam does not necessarily cause birth defects but found that the drug may be involved with a deformity blocking an infant’s anal opening. Fetal exposure to lorazepam is suspected of slowing development of infants’ abilities to move and think. Case reports say that infants can have withdrawal symptoms if the mother used the drug during pregnancy, symptoms accompanied by abnormal muscle tone and trouble with eating. Nursing mothers are told to avoid lorazepam, as infants might be drugged from the amount of lorazepam that passes into milk.

Additional scientific information may be found in:

1. Bond, A., and M. Lader. “Differential Effects of Oxazepam and Lorazepam on Aggressive Responding.” Psychopharmacology 95 (1988): 369–73.
2. Funderburk, F.R., et al. “Relative Abuse Liability of Lorazepam and Diazepam: An Evaluation in ‘Recreational’ Drug Users.” Drug and Alcohol Dependence 22 (1988): 215–22.
3. “Lorazepam.” In Therapeutic Drugs, C. Dollery. 2d ed. New York: Churchill Livingstone, 1999. L98–L100.
4. O’Hanlon, J.F., et al. “Anxiolytics’ Effects on the Actual Driving Performance of Patients and Healthy Volunteers in a Standardized Test. An Integration of Three Studies.” Neuropsychobiology 31 (1995): 81–88.
5. Schweizer, E., et al. “Lorazepam vs. Alprazolam in the Treatment of Panic Disorder.” Pharmacopsychiatry 23 (1990): 90–93.
6. Shader, R.I., et al. “Sedative Effects and Impaired Learning and Recall after Single Oral Doses of Lorazepam.” Clinical Pharmacology and Therapeutics 39 (1986): 526–29.

Phenobarbital (Somnosan, Donnatal, Phenobarb, Luminal) Uses. This is one of the more familiar pharmaceuticals. For about a century it has been used as an anticonvulsant and was prescribed as a tranquilizer and as a migraine remedy, although all those functions are being superseded by more modern drugs. Phenobarbital is also given to treat cyclic vomiting in children and hyperbilirubinemia (a type of jaundice) in infants. The drug is used against epilepsy and against seizures with other causes, such as fever. The substance has cross-tolerance with alcohol and is given temporarily to help relieve withdrawal symptoms from opiates or alcohol. Despite acceptance of phenobarbital for that purpose, scientific proof is lacking for its usefulness in alcohol withdrawal.

Phenobarbital played a walk-on role in the history of drug manufacturing when it was discovered as a contaminant in a batch of the antibiotic sulfathiazole. After that 1941 discovery the U.S. Food and Drug Administration created the system of manufacturing controls that has made the terms “purity” and “American pharmaceuticals” synonymous.

Phenobarbital (Somnosan, Donnatal, Phenobarb, Luminal) Drawbacks. Experimental use of the drug to treat cerebral malaria in juveniles was disastrous. The treatment halved the seizure rate but doubled the death rate, a rate that climbed even higher when diazepam was administered in combination. Some medical personnel have noted that patients taking phenobarbital tend to become more bellicose and uncooperative. A medical curiosity noted as late as the 1960s was that persons could be pronounced dead from a phenobarbital overdose and later be discovered alive.

In some research children receiving the drug for seizures show long-lasting reduction in IQ scores and in scores of other cognitive tests, but different research finds normal results after children have received the drug daily for years. Phenobarbital is known to alter adrenal and thyroid mechanisms. Persons suffering from a body chemistry disorder called porphyria are supposed to avoid the drug. Skin rashes and sores have been attributed to phenobarbital. Scientists suspect the drug causes liver damage in dogs, but an experiment testing a group of dogs for over six months was unable to confirm that suspicion.

Phenobarbital (Somnosan, Donnatal, Phenobarb, Luminal) Abuse factors. Characteristics are the same as for barbiturate class depressants in general.

Phenobarbital (Somnosan, Donnatal, Phenobarb, Luminal) Drug Interactions. Birth control pills might not work properly while a woman is taking phenobarbital. The drug may interfere with medicines designed to reduce blood clotting. Phenobarbital lowers blood levels of an antischizophrenia medicine called clozapine and thereby affects proper dosage. Persons taking phenobarbital in a task performance test typed more slowly but more accurately, catching and fixing more errors than when a placebo was used. Taking alcohol at the same time increased both speed and errors, but typists believed they were working as well as ever and were unaware of their worsening inaccuracy. From results in variations of the experiment the researchers concluded that alcohol boosts some effects of phenobarbital.

Phenobarbital (Somnosan, Donnatal, Phenobarb, Luminal) and Cancer. In some mice experiments the drug promotes liver tumors, but complexities in the results have deterred researchers from making conclusions about the drug’s ability to do the same in humans. Scientists do find that persons using the drug have higher rates of liver and lung cancer, but a causeeffect relationship has not been demonstrated. In contrast, cigarette smokers who use the drug have lower bladder cancer rates than nonsmokers; as a partial explanation, researchers suspect the drug may reduce the amount of chemicals in tobacco smoke that cause bladder cancer.

Phenobarbital (Somnosan, Donnatal, Phenobarb, Luminal) and Pregnancy. In animal experiments birth defects caused by phenobarbital are described as “profound and prominent.” For example, pregnant mice dosed with phenobarbital produce offspring with retarded muscle development, and pregnant rats receiving the drug produce offspring with heart defects. Debate exists about whether phenobarbital causes human birth defects. Medical records in 151 human pregnancies from the 1970s into the 1990s gave no indication that phenobarbital alone causes malformations, a conclusion supported by another study of 178 pregnancies. In Europe phenobarbital has been classified as safe for using during pregnancy.

Yet a review of almost 20,000 pregnancies found that 4.6% of children born to women who used phenobarbital during early pregnancy had birth defects, almost twice the rate suffered by children from women who used no drugs. An international examination of almost 1,000 birth outcomes in Asia and Europe put the rate of all defects (serious or not) associated with phenobarbital at 5%. Investigations have associated phenobarbital with heart defects, facial deformities, urinary tract malformations, and incomplete development of fingers or toes. One study found that about 20% of pregnant epileptic women taking the drug gave birth to children with serious birth defects, a finding consistent with still more studies. One study compared pregnant epileptic women who used phenobarbital with those who did not and revealed that women using the drug had infants with smaller head size. As children from the phenobarbital group grew older, they had shorter attention spans and more trouble with spelling and math.

Worse deformities have been seen when phenobarbital is used in combination with some other drugs than when used alone. A review of epilepsy medicines published in 1997 said malformations from phenobarbital are no more likely than from carbamazepine, phenytoin, or valproic acid—yet those latter three substances have been found to cause birth defects. A 1994 analysis of outcomes in several hundred pregnancies concluded that birth defects were more likely from phenobarbital than from carbamazepine or phenytoin. Phenobarbital and other epilepsy drugs may reduce vitamin K levels in a fetus, a reduction that can promote bleeding and cause disfiguring birth defects. Some researchers think that pregnant women using such drugs should ingest extra vitamin K.

Researchers believe that pregnant rats receiving phenobarbital seem to produce male offspring with “feminized behavior” and female offspring with masculine behavior. A group of humans who were prenatally exposed to phenobarbital showed higher rates of homosexual, cross-gender, and transsexual behavior when compared to a matched group that had no prenatal exposure to phenobarbital.

After phenobarbital is given to pregnant rats, their mature progeny act more nervous and uneasy than mature progeny from rats not exposed to the drug during pregnancy and also exhibit defects in reproductive ability. Mice exposed to the drug during fetal development and soon after birth show improper functioning of the hippocampus (a part of the brain affecting memory), and their brains weigh less than normal. Tests of thinking ability in adult humans whose mothers used phenobarbital and phenytoin while pregnant reveal deficiency in perceiving differences among geometrical figures. Other research has found that such adults generally have normal intelligence but are far likelier to have learning difficulties than adults who did not have prenatal exposure to the phenobarbital-phenytoin combination. Two studies have found verbal intelligence scores to be below expectations in men whose mothers took phenobarbital while pregnant, and another study found psychological maturation to be slowed in about 20% of children whose mothers received phenobarbital while pregnant. The director of a National Institutes of Health research center reported contrary findings in which offspring performed better if their mothers had used phenobarbital while pregnant, but analysts have noted methodological aspects in that study that weaken its findings.

The drug is sometimes given to pregnant women having premature labor, to reduce the hazard of infants developing bleeding inside the skull. One follow-through study found that infants born to pregnant women receiving such therapy had better nervous system development than children from mothers who did not receive such therapy, measured both in organic and cognitive factors. Another study measuring two such populations found the phenobarbital children to have lower mental development.

If a pregnant woman uses phenobarbital her infant can be born dependent on the drug; neonatal withdrawal is characterized by peevishness, vomiting, and poor muscle tone. Typically a nursing woman’s milk will contain about 45% of the phenobarbital level found in her blood. Breast-feeding by mothers who use phenobarbital is considered marginally acceptable, but infants should be watched for untoward effects.

Combination products. Arco-Lase Plus combines phenobarbital, hyoscyamine sulfate, and atropine sulfate. The product is a remedy for digestive complaints ranging from bloat and cramps to nausea, diarrhea, and ulcers. Arco-Lase Plus can impair vision and is not recommended for persons with glaucoma. The substance increases heart rate and reduces saliva production. The combination product should be avoided by persons suffering from enlarged prostate.

Donnatal combines phenobarbital, hyoscyamine sulfate, atropine sulfate, and scopolamine hydrobromide. The combination product is a treatment for assorted bowel complaints and duodenal ulcers. Normally Donnatal is considered inappropriate for persons with glaucoma or with gastrointestinal or urinary obstruction. The substance may decrease alertness, so a person taking Donnatal should not run dangerous machinery.

Additional scientific information may be found in:

1. Joyce, C.R., et al. “Potentiation by Phenobarbitone of Effects of Ethyl Alcohol on Human Behaviour.” Journal of Mental Science 105 (1959): 51–60.
2. Lerman-Sagie, T., and P. Lerman. “Phenobarbital Still Has a Role in Epilepsy Treatment.” Journal of Child Neurology 14 (1999): 820–21.
3. “Phenobarbital.” In Therapeutic Drugs, ed. C. Dollery. 2d ed. New York: Churchill Livingstone, 1999. P83–P85.
4. Poindexter, A.R. “Phenobarbital, Propranolol, and Aggression.” Journal of Neuropsychiatry and Clinical Neurosciences 12 (2000): 413.
5. Reinisch, J.M., et al. “In Utero Exposure to Phenobarbital and Intelligence Deficits in Adult Men.” Journal of the American Medical Association 274 (1995): 1518–25.
6. Rodgers, J.E., and M.A. Crouch. “Phenobarbital for Alcohol Withdrawal Syndrome.” American Journal of Health-System Pharmacy 56 (1999): 175–78.

Zolpidem [Ambien, Stilnoct, Stilnox] Uses. Zolpidem became available for medical purposes in the United States during the 1990s, after already being used in Europe. The substance can be used to relax people shortly before they undergo surgery. Zolpidem promotes sleep and has both sedative and  anticonvulsant properties. Generally insomnia patients are not supposed to take the drug for much more than a week. They are also not supposed to take the drug until they are ready for sleep; the substance is fast acting, and a person could doze off while in the middle of doing something. Elderly nursing home residents have been known to fall after taking zolpidem. People may forget things they do while under the drug’s influence; a U.S. Army test found that the amnesia can be prevented if the drug flumazenil is taken soon enough after a zolpidem dose (flumazenil is used to counteract benzodiazepine depressants).

Scientific studies of zolpidem generally find no hangover drug effects, but people should be careful about what they do after waking up from a dose until they know they are functioning normally. No problem in that regard surfaced when the drug was tested on French military pilots and ground crews to determine if zolpidem could improve rest during prolonged military activity, nor did Swiss researchers find any reduction in performance if athletes used zolpidem to get a good night’s sleep before a sporting competition. Not everyone, of course, has the same vigor as those populations. Experimenters running the French military test concluded that the drug is suitable for active military duty, and the substance also has U.S. Air Force approval for aircrew use.

The drug has been used to counteract jet lag, allowing travelers to compensate for changes in their sleep/wake cycles and to function effectively while crossing many time zones. During a simulation of such conditions for long distance troop transport the U.S. Army found that zolpidem worked for promoting sleep but had no advantage over triazolam. Another U.S. Army experiment tested human performance during at least 38 hours of continual wakefulness, with ambiguous results about whether short naps induced by zolpidem would be useful in combat circumstances. French researchers found the drug to be useful for improving quality of sleep in low air pressures found at high altitude (4,000 meters or 13,123 feet) while producing no breathing difficulty, a finding relevant not only to mountaineers but to aviators and astronauts.

Many insomnia medicines produce a rebound effect, meaning that the insomnia comes back worse than ever for a few days after people stop taking the medication. Rebound is seldom observed with zolpidem, however. An experiment with the drug produced temporary improvement in Parkinson’s disease symptoms, and zolpidem has helped clear up catatonia. A case report tells of the drug being given to treat anorexia nervosa, a condition in which thin people do not eat much because they imagine they are overweight, but results were unsatisfactory.

Animal experiments show that various chemicals related to zolpidem relieve pain, reduce inflammation and body temperature, and protect against gastric ulcers. Chemically these substances differ from barbiturates and benzodiazepines, but have effects similar to them and operate in some ways similar to benzodiazepines. Monkeys responded in ways indicating that zolpidem shares similarities with benzodiazepines but few or none with barbiturates. Despite those resemblances to benzodiazepines, rats trained to distinguish differences in drug effects acted as if zolpidem was unlike the benzodiazepine chlordiazepoxide. Various other differences have been documented. To take one example, caffeine typically counteracts some benzodiazepine actions, but counteraction does not necessarily happen when caffeine is administered with zolpidem. In animal experimentation chemicals related to zolpidem can produce sedation at doses low enough to avoid unwanted effects that occur with benzodiazepine sedation. Substances like zolpidem are generally believed to accomplish some of the same therapeutic actions as benzodiazepines, with less abuse potential.

Zolpidem [Ambien, Stilnoct, Stilnox] Drawbacks. Caution is recommended if a depressed person takes zolpidem, as the drug can deepen despondency and even promote suicidal thinking. Less serious occasional unwanted effects include dry mouth, headache, hiccups, nausea, and diarrhea. Hallucinations and other psychotic reactions (ranging from delirium to euphoria) are even less common but documented nonetheless.

Zolpidem [Ambien, Stilnoct, Stilnox] Abuse Factors. Drug abusers report mental pleasure from zolpidem and say that higher doses feel similar to diazepam. Human experience indicates that tolerance does not occur with zolpidem, although two or three disputed case reports exist. Typically, animals who have been dosed with zolpidem for months show no tolerance, dependence, or withdrawal symptoms. Diligent experimenters, however, have been able to produce dependence and withdrawal in baboons. Those effects have seldom been observed in humans, but case reports exist. Someone took 30 to 40 times the normal daily medical dosage on his own accord for months and developed dependence. This person showed enough cross-tolerance with clorazepate dipotassium that this chemical could help control withdrawal symptoms caused by zolpidem dependence, indicating that zolpidem shares some characteristics with benzodiazepine class depressants. Other reports tell of zolpidem dependence developing in individuals who had a history of drug abuse. Two clinical studies giving the drug to persons for four weeks also produced dependence. Normally dependence is light enough to cause only mild discomfort upon stopping the drug, but withdrawal seizures are known among persons who have taken huge doses of zolpidem for months. However, zolpidem’s abuse liability is low enough that the substance is believed to have special potential for treating ailments in persons prone to drug abuse. Drug interactions. The antifungus drug ketoconazole lengthens and increases zolpidem effects. The tuberculosis drug rifampin shortens and decreases zolpidem effects.

Zolpidem [Ambien, Stilnoct, Stilnox] and Cancer. Standard laboratory tests have not indicated that zolpidem causes cancer. In studies using many times the recommended human dose, no evidence emerged of the drug causing cancer in mice. Rats receiving such high doses developed tumors with no more frequency than rats receiving no dose at all.

Zolpidem [Ambien, Stilnoct, Stilnox] and Pregnancy. Offspring from pregnant rats and rabbits receiving several times the maximum human therapeutic dosage showed no obvious birth defects, although there were indications of delayed fetal bone development. Standard advice for women is to be cautious about using zolpidem during pregnancy. Although tests have shown only minute quantities of zolpidem to pass into a mother’s milk (less than 0.02% of a dose taken by a mother), the effect on infants is unknown.
Additional scientific information may be found in:

1. Boyle, J.A. “Look Again at Information on Zolpidem Tartrate.” American Journal of Hospital Pharmacy 51 (1994): 1354, 1356–57.
2. Fleming, J., et al. “Comparison of the Residual Effects and Efficacy of Short Term Zolpidem, Flurazepam and Placebo in Patients with Chronic Insomnia.” Clinical Drug Investigation 9 (1995): 303–13.
3. Hoehns, J.D., and P.J. Perry. “Zolpidem: Nonbenzodiazepine Hypnotic for Treatment of Insomnia.” Clinical Pharmacy 12 (1993): 814–28.
4. Lobo, B.L., and W.L. Greene. “Zolpidem: Distinct from Triazolam?” Annals of Pharmacotherapy 31 (1997): 625–32.
5. Rush, C.R. “Behavioral Pharmacology of Zolpidem Relative to Benzodiazepines: A Review.” Pharmacology, Biochemistry, and Behavior 61 (1998): 253–69.
6. Toner, L.C., et al. “Central Nervous System Side Effects Associated with Zolpidem Treatment.” Clinical Neuropharmacology 23 (2000): 54–58.
7. “Zolpidem for Insomnia.” Medical Letter on Drugs and Therapeutics 35 (1993): 35–36.

As might be expected with drugs that promote sleep, benzodiazepines can worsen reaction time, vigilance, and thinking abilities and therefore should be used cautiously if a person is operating dangerous machinery such as an automobile.  Problems may also develop for persons who are already unsteady on their feet, such as elderly persons prone to falling. The substances can also cause memory trouble, typically difficulty in recalling recent experiences. Headache, peevishness, confusion, and tremors may occur. In unusual cases rageful outbursts may occur. These are “paradoxical reactions,” meaning they are the opposite of what would be expected from the drug. Expressions of rage possibly emerge because the drug reduces anxiety in a person who is angry about something, and less anxiety can lead to less inhibition against doing something.

Over a 12-year span a practitioner observed patients taking benzodiazepines to treat serious sleep problems such as night terrors and sleepwalking. The practitioner found that 2% of this population (not 2% of all patients but just those using benzodiazepines against these sleep disorders) occasionally abused them,27 and this population base included persons with a previous
history of drug abuse; thus we can expect benzodiazepine abuse to be even lower in a general population. Among persons treated for drug abuse, benzodiazepines are among the least-abused substances. Experiments giving free access to benzodiazepines to persons undergoing treatment for drug abuse revealed little interest in those compounds.28 This class of depressants can be
highly popular among special populations, however. One study noted that 30% of alcoholics were using benzodiazepines.29 When benzodiazepines were given to rats in experiments, the animals’ consumption of alcohol increased,30 suggesting that human benzodiazepine usage might increase alcohol’s appeal. Although benzodiazepines are administered to treat alcohol withdrawal, combining the two substances recreationally is a dangerous mix that can prove fatal.

Different benzodiazepines have differing attractiveness to abusers. Measured by amount of misuse, claims made by misusers about drug effects, mental and physical effects verified in scientific experiments, and impressions reported by medical caregivers, diazepam is considered to have one of the greatest potentials for abuse. Alprazolam and lorazepam have similar, but lower, risk. Halazepam and oxazepam seem to be among the least risky for abuse.

Tolerance to some benzodiazepine effects can develop (many details are in this book’s alphabetical section). Dependence can also emerge, with a withdrawal syndrome similar to those of alcohol and barbiturates. Often the syndrome may be avoided by gradual reduction of dosage.

Small studies have found that women who use benzodiazepines during  pregnancy produce infants who are smaller than normal.31 Children in one of these studies32 rapidly caught up in some growth perimeters, but at the age of 18 months head size still remained smaller than normal. Facial deformities were common. The children had persistent trouble with muscle control. Similar
findings in another small study33 included mental retardation, but still another study34 noted that such children also had heavy fetal exposure to alcohol, exposure that is known to produce mental retardation. Thus the actual role of benzodiazepines was unclear.

Some of these reports did not track outcomes past infancy. Research tracking children up to four years of age found that early problems attributed to benzodiazepines cleared up in most of them.35 When teachers were asked to evaluate schoolchildren who had fetal exposure, the instructors found no difference between them and classmates.

Researchers who investigated the outcome of thousands of pregnancies found no evidence that benzodiazepines cause cleft palate. A large study involving hundreds of pregnancies found birth defects to be no more likely among women who used benzodiazepines than among women who did not use them; and even when malformations occurred, no particular kind of birth defect tended to appear in benzodiazepine offspring.38 Drugs that cause fetal harm generally cause particular types of damage; lack of a particular type with benzodiazepines suggests that the drug was not the cause of observed malformations. Some investigators believe they have detected a particular birth defect pattern, but such findings have been questioned.39 As the twenty-first century began, a research team reported evidence that benzodiazepines may damage fetal brain development.40 Science has not yet rendered a verdict on the safety of benzodiazepines during pregnancy. Infants with fetal exposure can be born dependent on this type of drug. It passes into breast milk, but the amount from lower-dosage levels probably has no effect on nursing infants.

Some drugs of benzodiazepine class: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam.