Methadone And Morphine in Depression

Irl Extein, M.D.,1 David Pickar, M.D.,2 Mark S. Gold, M.D.,3 Philip W. Gold, M.D.,4 A. L. C. Pottash, M.D.,1 Donald R. Sweeney M.D., Ph.D., 1 Richard J. Ross, M.D., Ph.D.,4 Robert Rebard, M.D.,5 David Martin, B.A.,3 and Frederick K. Goodwin, M.D.4

  1. Fair Oaks Hospital, Summit, New Jersey.
  2. Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
  3. Psychiatric Diagnostic Laboratories of America, Summit, New Jersey.
  4. Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, Maryland.
  5. Department of Reproductive Medicine, University of California


There has been much interest in recent years in the possible role of endogenous opioid peptides (endorphins) in depression (1). The high concentrates of opioid receptors and endorphins in limbic and hypothalamic regions, and their interaction with noradrenergic and dopaminergic systems, suggests involvement of endorphin systems in depression, as do certain clinical observations. These include anecdotal reports from the prepsychotropic era of the efficacy of opiates in depression, the appearance in some detoxified opiate addicts of depression responsive to opiates and antidepressants (2), and reports of improvement in some depressed patients following beta-endorphin (3). These observations, as well as the euphoric, analgesic, and calming effect of opiates, suggest that decreased functional activity in endorphin systems may be involved in the pathophysiology of depression.

In order to test this endorphin hypothesis of depression and to explore the possible efficacy of opiates in depression, the investigators administered single doses of methadone and morphine to depressed patients. Clinical and neuroendocrine responses were measured.

All subjects gave written informed consent to participate. The first experiment was an open investigation in 10 patients with major depressive disorder by Research Diagnostic Criteria (4) (9 unipolar, 1 bipolar; 5 male, 5 female; mean age = 44 ± 5). The control group was comprised of two normal volunteers and four inpatients with personality disorders (2 male, 4 female; mean age = 33 ± 8). Patients with recent neuroleptic use were excluded, and patients received no medication except flurazepam for at least 1 wk prior to the study. After an overnight fast, subjects were at bedrest for placement of an indwelling venous catheter through which 5 mg of morphine were infused at 9:00 a.m. Samples of blood were obtained via the catheter before, and 30, 60, 90, 120, and 180 min after, morphine infusion for assay of serum prolactin (PRL) in duplicate by radioimmunoassay (5). Each subject filled out an adjective checklist self-rating scale before the infusion and at the time of each blood drawing.

The second experiment was a double-blind, placebo-controlled investigation in six inpatients with major depressive disorder by Research Diagnostic Criteria (4) (2 unipolar, 4 bipolar; 2 male, 4 female; mean age =48 ± 4). None of the patients received any active medication for at least 2 wk prior to the study. Patients were at bedrest after an overnight fast for placement of an indwelling venous catheter through which 5 mg of methadone or saline placebo were infused at 9:30 a.m. Samples of blood were obtained in four of the patients via the catheter 60, 30, and 0 min before, and 15, 30, 60, 120, and 180 min after, the infusion for assay of plasma PRL and cortisol by radioimmunoassay and competitive protein binding, respectively. Clinical assessment was performed by Brief Psychiatric Rating Scale (BPRS) and NIMH self-rating scales before, and 15, 30, 60, 120, and 180 min after, infusion.

FIGURE 1. Effects of 5 mg intravenous morphine on self-rated mood in patients with major depressive disorder and controls.

FIGURE 2. Effects of 5 mg intravenous morphine of serum prolactin in patients with major depressive disorder and controls.

In the first experiment, morphine infusion produced only small nonsignificant antidepressant and antianxiety effects in both the depressed and control groups (see Figure 1). Baseline PRL (mean in ng/ml ± SEM) of 10.5 ± 1.9 for depressed patients and 9.0 ± 1.4 for controls did not differ. D PRL (peak minus baseline) of 7.2 ± 2.7 in the depressed patients was lower than that of 31.9 ± 9.5 in controls (p<0.01 by two-tailed t-test; see Figure 2).

In the second experiment, all six patients correctly distinguished the active methadone from the inactive saline infusion. Three of the six reported themselves "better" two the "same," and one "worse" 30 min after methadone infusion, whereas all six patients reported themselves the "same" 30 min after saline infusion. The methadone infusion produced little change according to BPRS and self-rating scales (see (Figure ). Methadone, but not placebo, produced large increases in plasma PRL (see Figure 4). Serum cortisol 180 min after saline infusion was significantly lower than cortisol 180 min after saline infusion (p<0.01; see Figure 5).

The well-documented increase in serum PRL produced in normals by opiates and endorphins is thought to be mediated in part by inhibitory opiate receptors on dopaminergic neurons (5-9). The blunted PRL response to morphine in depressed patients may be related to subtle changes in baseline PRL secretion or diurnal pattern and may reflect changes in endorphin, dopamine, serotonin, or other neuronal systems. This blunted response is consistent with an opiate receptor deficit, or presence of excess of an endogenous opioid antagonist, in major depressive disorder. The elevation of PRL in depressed patients after 5 mg of methadone, which is about twice as potent as morphine, suggests that depressed patients are not refractory to the neurodendocrine effects of opiates but may require a higher dose to achieve the same effect as in normals. The decrease in plasma cortisol following methadone is interesting in view of the known hypercortisol secretion in depression. Since ACTH and beta- endorphin have a common precursor (1), methadone may exert a feedback inhibition on ACTH and cortisol secretion.

FIGURE 3. Behavioural effects of 5 mg intravenous methadone and placebo in patients with major depressive disorder.

FIGURE 4. Effects of 5 mg intravenous methadone and placebo on plasma prolactin in patients with major depressive disorder.

FIGURE 5. Effects of 5 mg intravenous methadone and placebo on plasma cortisol I patients with major depressive disorder.

Despite the lack of clear clinical antidepressant effects of single doses of opioids, the neuroendocrine results reported here suggest dysfunction in central endorphin systems in depression. The results support the need for further investigation of these neuroendocrine findings as well as possible antidepressant effects of opioids, endorphins, and analogues in depression and other psychiatric disorders (1-3,5,7,9,10).


  1. Snyder, S. H. The opiate receptor and morphine-like peptides in the brain. Am. J. Psychiatry, 135:645-652, 1978.
  2. Gold, M. S., Pottash, A. L. C., Sweendy, D. R., et al Rapid opiate detoxification: Clinical evidence of antidepressant and antipanic effects of opiates. Am. J. Psychiatry, 136:982-983, 1979.
  3. Kline, N. S., Li, C. H., Lehmann, H. E., et al. Beta-endorphin induced changes in schizophrenic and depressed patients. Arch. Gen. Psychiatry, 34:1111-1113, 1977.
  4. Spitzer, R. L., Endicott, J., and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Arch. Gen. Psychiatry, 35:773-782, 1978
  5. Gold, M. s., Donabedian, R. K., Dillard, M., et al. Antipsychotic effect of opiate agonists. Lancet, ii:398-399, 1977.
  6. Ferland, L., Fuxe, K., Eneroth, P., et al. Effects of methionine-enkephalin on prolactin release and catecholamine levels and turnover in the median eminence. Eur. J. Pharmacol, 43:89-90, 1977
  7. Gold, M. S., Redmond, D. E., Jr., Donabedian, R. K., et al. Increase in serum prolactin by exogenous and endogenous opiates: Evidence for anti-dopamine and antipsychotic effects. Am. J. Psychiatry, 135:1415-1416, 1978
  8. Tolis, G., Dent, R., and Guyda, H. Opiates, prolactin, and the dopamine receptor. J. Clin. Endocrinol. Metab., 47:200-203, 1978
  9. Graffenried, B. V., Pozo, E. D., Roubicek, J., et al. Effects of the synthetic endephalin analogue FK33-824 in man. Nature, 272:729-730, 1978.
  10. Extein, I., Goodwin, F. K., Lewy, A. J., et al. Behavioural and biochemical effect of FK33-824, a parenterally and orally active enkephalin analogue. In: Usdin, E., Bunney, W. E., Jr., and Kline, N. S. (eds), Endorphins in Mental Health Research. London and Basingstoke: The Macmillan Press, Ltd., 1979, pp. 279-292.

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