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The treatment of heroin addicts with dextromethorphan: a double-blind comparison of dextromethorphan with chlorpromazine
Abstract: According to the hypothesis that the development of physical dependence on and tolerance to opiates depends on the inhibition by opiates of L-asparaginase and L-glutaminase activities in the brain, and the blockade by opiates of the aspartatergic/glutamatergic receptors especially NMDA, four female and fourty-four male heroin addicts were included in a double-blind clinical trial. Four mg chlorpromazine (CPZ) was administered every hour and 10 mg diazepam (DIA) every 6 hours to a group consisting of two female and nineteen male inpatients. The remaining subjects received 15 mg non-opioid antitussive dextromethorphan (DM) instead of CPZ. The withdrawn addicts were controlled twice a day and yawning, lacrimation, rhinorrhoea, perspiration, goose flesh, muscle tremor, dilated pupils, anorexia, joint and muscle aches, restlessness, insomnia, emesis, diarrhea, craving and rejection of smoking as abstinence syndrome signs were observed and rated on a scale of 1, 2 and 3 points according to their intensity. All signs, except perspiration and emesis, were significantly less intense in the group given DM + DIA than CPZ + DIA. The other plus points included the immediate stop of craving and the early onset of smoking in DM + DIA group. The results are considered to be supporting evidence for the hypothesis emphasizing the blockade of NMDA receptors by opiates in opiate addiction. Furthermore, the decrease caused by non-opioid NMDA antagonists in the responsiveness of NMDA receptors appears very promising for the treatment of opiate addicts.
The combination of tizanidine markedly improves the treatment with dextromethorphan of heroin addicted outpatients.
Abstract: According to the hypothesis implying that the main mechanism underlying opiate addiction is the blockade by opiates of NMDA receptor functions and subsequent upregulation and supersensitivity of the receptors, noncompetitive NMDA receptor blocker dextromethorphan (DM) has been successfully used in the heroin addict treatment. As the stimulation of NMDA receptors modulates the release of neurotransmitters and hormones such as NE, D, ACh, GH, LH, LSH, ACTH etc., all of which have been found responsible for the manifestation of abstinence syndrome signs including craving and neuronal death by excessive stimulation of NMDA receptors, the incomplete blockade of the NMDA receptors minimizes the intensity of the abstinence syndrome and provides the downregulation of the receptors. In the present study, tizanidine (TIZ), which inhibits the release of endogenous excitatory aminoacids by the agonistic activity on alpha 2-adrenoreceptors, was combined with DM to obtain further benefits. Forty-four male and three female heroin addicts were the subjects of the study. Their daily mean heroin intake was about 2.28 g street heroin. The main duration of heroin use was approximately 3.4 years. Two to three hours after abrupt withdrawal, the outpatients were given 15 mg DM every hour, 25 or 50 mg chlorpromazine (CPZ) + 4 mg TIZ every six hours and 10 mg diazepam + 10 mg hyoscine N-butyl Br + 250 mg dipyrone every six hours three hours following CPZ. The addicts were controlled twice a day. Yawning, rhinorrhea, perspiration, piloerection, restlessness, insomnia, emesis, diarrhea, craving, rejection of smoking and pupils were observed and/or questioned. Two of the 47 outpatients took heroin on the first days.(ABSTRACT TRUNCATED AT 250 WORDS)
Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats
Abstract: Combined oral administration of morphine sulfate (MS) and the over-the-counter antitussive drug and N-methyl-d-aspartate receptor antagonist dextromethorphan (DM) prevented the development of tolerance to the antinociceptive effects of MS (15, 24, or 32 mg/kg) in rats. This combined oral treatment regimen also attenuated signs of naloxone-precipitated physical dependence on morphine in the same rats. A wide range of ratios of MS to DM (2:1, 1:1, and 1:2) were effective for preventing the development of morphine tolerance and dependence. In addition, we provide evidence that under certain circumstances DM increases the acute antinociceptive effects of MS. All of these results indicate that oral treatment that combines DM with opiate analgesics may be a powerful approach for simultaneously preventing opiate tolerance and dependence and enhancing analgesia in humans.
Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance
Abstract: N-Methyl- d-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.
Dextromethorphan attenuates and reverses analgesic tolerance to morphine
Abstract: Tolerance to the antinociceptive (analgesic) effect of morphine, a mu-opioid agonist, was developed in male CD-1 mice as assessed by a shift to the right of the analgesic (tail-flick) dose-response curves and an increase in the ED50 values. Administration of dextromethorphan at 30 mg/kg s.c., but not saline, 30 min prior to an escalating 3 times per day (t.i.d.) morphine dosing schedule prevented a 5-fold increase in the morphine ED50 value observed on treatment day 4. Concurrent administration of dextromethorphan at 12 mg/kg/24 h by s.c. infusion prevented the 6-fold increase in the morphine ED50 value that was observed in control mice that received morphine at 30 mg/kg/24 h by s.c. infusion. Implantation of two 25 mg morphine pellets resulted in a 10-fold increase in the morphine ED50 value on treatment day 4. Administration of dextromethorphan at 30 mg/kg s.c. t.i.d., but not saline, resulted in a reversal of morphine tolerance with the almost complete return of the morphine ED50 value to the control (opioid naive) value. These results demonstrate that dextromethorphan, an NMDA receptor antagonist can modulate morphine (mu-receptor)-mediated tolerance.
Dextromethorphan as a potential rapid-acting antidepressant
Abstract: Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA–to–NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.
An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan
Abstract: It was previously hypothesized that dextromethorphan (DM) and dextrorphan (DX) may possess antidepressant properties, including rapid and conventional onsets of action and utility in treatment-refractory depression, based on pharmacodynamic similarities to ketamine. These similarities included sigma-1 (σ1) agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and μ receptor potentiation. Here, six specific hypotheses are developed in light of additional mechanisms and evidence. Comparable potencies to ketamine for DM and DX are detailed for σ1 (DX > DM > ketamine), NMDA PCP site (DX > ketamine > DM), and muscarinic (DX > ketamine >>>> DM) receptors, 5HTT (DM > DX ≫ ketamine), and NMDA antagonist potentiation of μ receptor stimulation (DM > ketamine). Rapid acting antidepressant properties of DM include NMDA high-affinity site, NMDR-2A, and functional NMDR-2B receptor antagonism, σ1 stimulation, putative mTOR activation (by σ1 stimulation, μ potentiation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ1 stimulation, μ potentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ1 and mTOR signaling. Those for dextrorphan include NMDA high-affinity site and NMDR-2A antagonism, σ1 stimulation, putative mTOR activation (by σ1 stimulation and ß adrenoreceptor stimulation), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ1 stimulation, ß stimulation, and μ antagonism), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ1 and mTOR signaling. Conventional antidepressant properties for dextromethorphan and dextrorphan include 5HTT and norepinephrine transporter inhibition, σ1 stimulation, NMDA and PCP antagonism, and possible serotonin 5HT1b/d receptor stimulation. Additional properties for dextromethorphan include possible presynaptic α2 adrenoreceptor antagonism or postsynaptic α2 stimulation and, for dextrorphan, ß stimulation and possible muscarinic and μ antagonism. Treatment-refractory depression properties include increased serotonin and norepinephrine availability, PCP, NMDR-2B, presynaptic alpha-2 antagonism, and the multiplicity of other antidepressant receptor mechanisms. Suggestions for clinical trials are provided for oral high-dose dextromethorphan and Nuedexta (dextromethorphan combined with quinidine to block metabolism to dextrorphan, thereby increasing dextromethorphan plasma concentrations). Suggestions include exclusionary criteria, oral dosing, observation periods, dose–response approaches, and safety and tolerability are considered. Although oral dextromethorphan may be somewhat more likely to show efficacy through complementary antidepressant mechanisms of dextrorphan, a clinical trial will be more logistically complex than one of Nuedexta due to high doses and plasma level variability. Clinical trials may increase our therapeutic armamentarium and our pharmacological understanding of treatment-refractory depression and antidepressant onset of action.
For me, my spiritual path began with my first psychedelic trip, which totally changed my frame of view on life and the universe. So I use psychedelics periodically to help keep me on that path or just for fun, and I just try to live being present in the moment. I try to notice the beauty in those moments, and I try to surround myself with like-minded people, and do things with my time that mean something to me. As a result, most things in life usually make sense to me, and I live most of my time being happy and content.
