International Journal of Neuroscience

Gillman, Mark A.

doi: 10.3109/00207459408985985pmid: 7960459

Gillman, Mark A.; Lichtigfeld, Frederick J.

doi: 10.3109/00207459408985986pmid: 7960469

We show that psychotropic analgesic nitrous oxide is a partial opioid agonist since it fulfills all the following criteria to be classified as an opioid: 1) its effects are antagonised by various opioid antagonists including stereospecific naloxone antagonism; 2) it is cross tolerant with morphine; 3) its effects are potentiated by enkephalinase inhibition; 4) it provokes the release of endogenous opioid; 5) it interferes at low concentrations with specific opioid ligand binding at radio-receptor assay. Like the prototype opioid morphine it acts directly and indirectly at opioid receptors. PAN, although considered an exogenous inorganic molecule was also the first gas to be shown to have a direct role in influencing neurotransmission. We also describe some of the relationships that exist between nitrous oxide and its close relative, the endogenous gas nitric oxide. We describe the use of PAN as a safe, effective tool for investigating and treating the endogenous opioid system in man.

Daynes, Guy; Gillman, Mark A.

doi: 10.3109/00207459408985987pmid: 7960461

We investigated the anti-craving effect of psychotropic analgesic nitrous oxide (PAN) in both an urban and rural community. Our results show that PAN, effectively eliminates or reduces craving in both cohorts in 98% of cases reporting craving. This positive effect is extremely rapid occurring within 40 minutes in patients withdrawing from alcohol, cannabis and nicotine. Although the concept of craving has been dogged by confusion and misunderstanding the idea is of practical importance because there appears to be a link between craving and relapse in patients who have a problem with substance abuse. The anti-craving effect of PAN may, therefore, be useful in preventing relapses in patients who abuse alcohol, nicotine and cannabis. Because PAN is an opioid it would seem that craving may be mediated by an underactivity of the endogenous opioid system. This work also confirms the safety and rapidity of the PAN therapy for treating addictive withdrawal states produced by alcohol, nicotine and cannabis. These findings confirm the usefulness of PAN as an investigative, diagnostic and therapeutic tool of the endogenous opioid system in man.

Lichtigfeld, Frederick J.; Gillman, Mark A.

doi: 10.3109/00207459408985988pmid: 7960465

We relate the extremely rapid and lasting beneficial effects of psychotropic analgesic nitrous oxide (PAN) on the alcohol withdrawal state (AWS) to the underlying neurotransmitter system disturbances and clinical findings. PAN is an opioid and its main therapeutic effects are produced by stimulating the underactive endogenous opioid system (EOS) found in the AWS. In common with other opioids, PAN also acts on other neurotransmitter systems. While controlling the cholinergic and adrenergic overactivity and the concomitant stress state, through its opioid agonism, it simultaneously stimulates the underactive serotinergic and GABA-ergic systems found in the AWS. PAN also ameliorates disturbances in corticotropin-releasing factor (CRF) dopaminergic, glutaminergic and second messenger function. This unique combination of stimulation and inhibition enables a single 20 minute administration of PAN to rapidly restore the patients' homeostatic balance with lasting effect, and almost no other medication requirements during the entire detoxification period. Unlike other currently available therapies this is achieved without sedation.

Ojutkangas, Reijo; Gillman, Mark A.

doi: 10.3109/00207459408985989pmid: 7960466

In a retrospective study of 500 patients we present evidence that psychotropic analgesic nitrous oxide (PAN) can be used safely and successfully as an out-patient treatment for the AWS in the vast majority of cases. A feature of the PAN therapy is the rapidity of recovery of patients within 60 minutes; which is in stark contrast to that found when traditional benzodiazepine medication regimens are used. Our work confirms earlier findings confined to in-patients. Importantly, the requirements for addictive sedative medications is also dramatically reduced, greatly diminishing the dangers of secondary addiction. In a small number of cases PAN can be used to treat alcohol craving, which may prevent relapses through its positive effects on reducing craving. The promising, rapid anti-craving effects of PAN would seem to require further investigation to establish when it is likely to be of benefit in preventing relapse. In order to maximize the benefit of the PAN treatment to both patient and physician it is essential for the physician to undergo a short hands-on training course.

Lecore, Angela

doi: 10.3109/00207459408985990pmid: 7960467

There is a clear indication for the use of psychotropic analgesic nitrous oxide in conjunction with psychotherapy in the treatment of patients where excessive anxiety is a major component of the symptomatology and especially in patients unresponsive to traditional psychotherapy. Although only a relatively small sample was studied over a short time period, the beneficial results in the majority of patients were clear. Patient acceptability was high. The treatment is extremely safe and produced accelerated behavioral change with stability and integration maintained after 4 weeks. However, the administration of psychotropic analgesic nitrous oxide is extremely technique sensitive and therefore requires supervised on-hands training with the correct fail-safe equipment to maximise the benefit of the therapy for both physician and patient.

Ardila, Alfredo; Rosselli, Monica

doi: 10.3109/00207459408985991pmid: 7960468

Twenty-one patients with right hemisphere damage were studied (11 men, 10 women; average age equals; 41.33; range equals; 19–65). Patients were divided in two groups: pre-Rolandic (six patients) and retro-Rolandic (15 patients) right hemisphere damage. A special reading test was given to each patient. The observed errors included: literal errors (substitutions, additions, and omissions of letters), substitutions of syllables and pseudowords for meaningful words, left hemispatial neglect, confabulation, splitting of words, verbal errors (substitutions, additions, and omission of words), grouping of letters belonging to two different words, misuse of punctuation marks, and errors in following lines. It was proposed that spatial alexia is characterized by: (1) some difficulties in the recognition of the spatial orientation in letters; (2) left hemispatial neglect; (3) tendency to “complete” the sense of words and sentences; (4) inability to follow lines when reading texts, and sequentially explore the spatial distribution of the written material; and (5) grouping and fragmentation of words, most likely as a consequence of the inability to interpret the relative value of spaces between letters correctly.

Gerrard, John W.; Richardson, J. Steven; Donat, Jeffrey

doi: 10.3109/00207459408985992pmid: 7960470

Three cases are reported of patients who had episodic movement disorders triggered by foods or components of the diet. In the first patient, the movement consisted of shaking the head from side to side that was triggered by milk and a number of other foods. In the second patient, the movement consisted of a repeated shrugging of the shoulders that was triggered by egg and coffee. In the third, the movement consisted of rhythmic contractions of the arms and legs that were triggered by aspartame. The first patient agreed to participate in a study in which she drank 250 ml of skim milk, an amount sufficient to trigger head shaking, after pretreatment with drugs known to alter neurotransmission across β-adrenergic, dopaminergic, GABAergic or purinergic synapses. At the doses used, propranolol and diazepam had no effect on the milk evoked movement disorder. Levodopa (plus carbidopa) blocked the reaction to milk. Haloperidol, salbutamol and theophylline by themselves triggered a reaction similar to that evoked by milk. These observations suggest that, in susceptible individuals, foods can trigger movement disorders through an action on dopamine and other neurotransmitter pathways in the brain. A videotape of the reactions of the first two patients is available.

Sandyk, Reuven; Awerbuch, Gavin I.

doi: 10.3109/00207459408985993pmid: 7960471

Calcification is a known morphological feature of the pineal gland. The mechanisms underlying the development of pineal calcification (PC) are elusive although there is experimental evidence that calcification may be a marker of the past secretory activity of the gland and/or of degeneration. The increased incidence of PC with aging suggests that it may reflect cerebral degenerative changes as well. In a recent Editorial in this Journal it was proposed that the pineal gland is implicated in the pathogenesis of multiple sclerosis (MS). Cerebral atrophy, which can be demonstrated on CT scan, is a common feature of MS resulting from demyelination and gliosis. If PC is a marker of a cerebral degenerative process, then one would expect a higher incidence of calcification of the gland in patients with cerebral atrophy compared to those without cerebral atrophy. To test this hypothesis, we studied the incidence of PC on CT scan in a cohort of 48 MS patients, 21 of whom had cerebral atrophy. For the purpose of comparison, we also assessed the incidence of choroid plexus calcification (CPC) in relation to cerebral atrophy. PC was found in 42 patients (87.5%) and its incidence in patients with cerebral atrophy was significantly higher compared to the incidence in patients without cerebral atrophy (100% vs. 77.7%; p <. 025). In contrast, CPC was unrelated to cerebral atrophy or to PC thus supporting the notion of a specific association between the pineal gland and the pathogenesis of MS. As PC may also be a marker of the secretory activity of the gland and since the pineal gland functions as an immunomodulator, it is proposed that the high incidence of PC in MS may reflect an adaptive process by the pineal gland to correct the immunodysregulation associated with the disease.

Sandyk, Reuven; Awerbuch, Gavin I.

doi: 10.3109/00207459408985994pmid: 7960472

We have reported recently that nocturnal melatonin levels are reduced in a subgroup of patients with multiple sclerosis (MS). We have also noted in these patients a high incidence of hypercholesterolemia and propose that this may be linked to dysfunction of the pineal gland since pinealectomy in rats was reported to be associated with elevation of blood cholesterol levels. To test this hypothesis, we studied the relationship between nocturnal plasma melatonin levels and serum cholesterol levels in a cohort of 24 MS patients (4 men; 20 women; mean age: 40.2 years SD equals; 9.5) who were admitted to an inpatient neurologic clinic for acute exacerbation of symptoms. For the purpose of comparison we also evaluated in these patients the association between melatonin levels and serum triglyceride (TG) levels. As predicted, we found a significantly higher serum cholesterol level in 10 patients who had low nocturnal plasma melatonin levels (mean: 17.1 pg/ml ± 5.9) compared to 14 patients in whom melatonin levels were in the normal range (mean: 42.9 pg/ml ± 10.6) (mean cholesterol equals; 241.5 mg/dl ± 50.8 vs. 183.7 mg/dl ± 27.2; p <. 001). In contrast, serum TG levels did not differ significantly between the groups. As serum cholesterol levels were statistically unrelated to TG levels, these findings suggest a specific association between pineal melatonin and cholesterol metabolism. If confirmed in future research, these findings suggest that the pineal gland may exert a cholesterol reducing effect and that melatonin could be used therapeutically in the treatment of hypercholesterolemia.