Gamma-Hydroxybutyrate and MDMA: The First Sociabilising MoleculesThe sociabilisers are a novel class of molecules, whose properties were discovered by the author, and which could revolutionise the treatment of diverse psychopathoogies. In these psychopatho- logies I am including the high level of undesirable intra-specific aggression found in the human species. Man has been unable to control his unwanted base-line paranoia and intra-specific aggressivity even with such a powerful ideology such as Christianity. The sociabilisers promise to reach, at last, such a control of these highly undesirable behaviours. The future of mankind is in enhancing sociability, first by sociabilising molecules, then through a new science (not yet in existence) called Neuromorphogenetics. The definitive enhancement of sociability in man is a desirable step for our descendants as this will promote cooperation between individuals instead of a totally useless and destructive intra-specific aggression. Man has suffered since his origin from his absurd intra-specific aggression, a heritage of his animal origin, of his present-day bestiality. Intra-specific aggression should be eradicated in order to make "human" beings really human beings and not sheer tallking and vociferous animals. The study of the Sociabilisers is the first step in this important direction. Christianity has failed to change the intra-specific aggression behaviour of man because this very primitive behaviour is deeply entrenched in the human CNS. Men (especially males and this applies equally to male scientists!) have a propensity to aggress each other and to establish a pecking- order, like all animals. But this primitive entropic behaviour is no longer in accordance with technological societies. In advanced technological societies we need highly sociable individuals.Where, for obvious reasons, Christianity has failed, Science will, probably, succeed! When intra-specific aggression will be only a foregone memory of the primitive Barbarians we are just now, then we can predict a bright future to our descendants. The discovery of the Sociabilisers is just, then, the beginning of a formidable behavioural revolution. One day wars and misery will be seen only as the consequences of a primitive faulty brain created by accident and not by a rational will. The first sociabiliser was invented in France, in 1961: Gamma-OH or gamma-hydroxy- butyrate. Gamma-OH was invented by my late friend Henri Laborit and his colleague, Wermuth when Laborit was thinking of creating a GABA analog which could penetrate through the blood-brain barrier. He talked about this with Wermuth and Wermuth came up with gamma- hydroxybutyric acid. At that time nobody knew that this discovery was potential gold for the study of human behaviour and intra-specific aggression. Three classes of sociabilisers have been now defined:
Since the discovery of Gamma-OH, in France, the French were unable to classify this molecule under anything known and so the classification of Gamma-OH has been rather erratic! It was, first, a hypnotic. Then it became a pre-anaesthetic and now, it became an anti-addictive medicine for alcoholism! It may or may not become also an anti-addictive medication against opiate intoxication, as shown in Italy. After about 15 years of studying this molecule I finally arrived at the conclusion that Gamma-OH was the first molecule in a serie of novel molecules to be correctly called the sociabilisers (Sociabilisants, en francais) because they act by enhancing sociability. Experimenting with both Gamma-OH and MDMA, on myself and volunteers, I soon discovered that these two molecules had subjectively indistinguishable actions on sociability though the sociabilising action of MDMA is first masked because of its serotonin releasing property which is subjectively quite similar to the effects of fluvoxamine (the first specific serotoninergic reuptake blocker which was successfully put on the market) on consciousness and behaviour. Gamma-OH and non-neurotoxic MDMA derivatives: A Revolution for Mankind - On the Road to Sociability Gamma-OH is a pure sociabiliser as its sociabilising effects are not hindered by other antagonistic actions such as enhancement of serotoninergic neurotransmission. Gamma-OH and MDMA have been both classified under the novel concept of Sociabilisers, together with the yet to be synthesised molecules sharing the properties of both Gamma-OH and MDMA which I already nickname "sociabilines". When human beings interact on increasingly friendly terms, natural base-line paranoia progressively disappears to be replaced by a feeling of intense pleasure, which is the result of social interaction.This is believed to involve oxytocine pathways in the brain and MDMA and Gamma-OH are both hypothesised to act, directly or indirectly, on oxytocin. In fact the effects of both MDMA and Gamma-OH mirror the behavioural effects of oxytocin and oxytocin has been demonstrated to have anti-depressant properties in Italy. The lower natural paranoia becomes, the more sociability intensifies. Theory demonstrates that such consciousness states as "love" or "mystical" states are only states of exceedingly low paranoia and of progressively intensified sociability. In fact,there seems to be a "circuit of paranoia"in the CNS which would generate both paranoia and sociability, depending on how it is activated. Hyperactivation of this system would generate paranoid states while hypoactivation would generate sociable states, from love to mystical states. It is thus hypothesised that depressing paranoia (naturally or pharmacologically) leads automatically to increased sociability (probably through oxytocinergic neuromediation, etc) while increasing paranoia (like with pentazocine, phenylisopropylamines, cannabinoids) leads to associability and some psychopathologies such as paranoid schizophrenia, etc. Modulating the sociability states of human beings can represent a powerful therapeuthics in depression and in the suppression of anxiety or suppression of the negative symptoms of schizophrenia and paranoid symptoms. For instance,depression arises when sociability is decreased: intensifying sociability will thus have a thymoanaleptic (anti-depressant) effect. This is demonstrated by the powerful thymoanaleptic properties of Gamma-OH. Unfortunately for depressed patients, and because of the imipraminomimetic dogma, the thymoanaleptic properties of Gamma-OH remained essentially crypto-thymoanaleptic properties until the author discovered the remarkable effects of gamma-hydroxybutyrate on depression! Concerning MDMA, anti-depressant effects of non-neurotoxic analogs are predicted. Why?Because the present-day SSRIs, which act by increasing the post-synaptic effects of serotonin, are, in fact, not thymoanaleptics, but thymoanaesthetics, meaning that they work by anaesthetising emotions! In fact, SSRIs are "mood-blunters", they blunt mood, an effect reminiscent of another purported "new" "anti-depressant": captopril. We have, recently, also found a natural mood thymoanaesthetic principle in a species os sage (salvia splendens) or the scarlet sage! This active principle is not yet identified but seems, theoretically, due to one or both remarkable compounds found in this sage: salviarin and splendidin, which are neo-clerodanes diterpens hypothesized to act as anti-insects, by disturbing the function of the tiny "brains" of insects. The blunting of mood is also a symptom of negative schizophrenia.So SSRIs are, in fact, "mind xylocaines" (xylocaine is an anaesthetic used for the suppression of pain,like in hemorhoids,for example)! Psychiatrists, not knowledgeable in introspective psychopharmacology, erroneously interpret the blunting of emotions induced by the SSRIs as a thymoanaleptic effect while it is, in fact, a thymoanasthetic effect!The French have invented the first authentic serotoninergic anti-depressant which is called Stablon or Tianeptine. Tianeptine has both anti-depressant and anxiolytic activity and has been used, successfully, in depressive individuals exposed priorly to MDMA. Tianeptine is a selective serotonin re-uptake enhancer(SSRE), which is just exactly the opposite of SSRIs! The reason why Stablon is a thymoanaleptic is, precisely, because, normally, serotonin decreases all form of reactivity in the central nervous system, mood included. Serotonin is a general behavioural reducer.Then, antagonising the effects of serotonin should, if properly targetted in the limbic system and its association with the pre-frontal cortex, give rise to a true anti-depressant effect with mood elevation instead of mood blunting. This is what is, precisely, observed with Tianeptine! Here is where MDMA becomes interesting as a prototypal molecule for novel anti-depressants of the new sociabilisers class. MDMA seems to act on serotoninergic receptors which decrease the effects of serotonin somewhere in the limbic system, thus giving rise to stimulation of sociability, like with Gamma-OH. Though some differences are observed between MDMA and GHB these differences are not important because MDMA is, in fact, a partial sociabilier, while GHB is a full sociabiliser even though MDMA might seem, to some, to be stronger than Gamma-OH. However, I have minutely dissected the effects of both, on myself, and I found that the subjective quality of enhancement of sociability per se with MDMA was absolutely similar to the enhancement of sociability with Gamma-OH. What makes a subjective difference, between both molecules, is that MDMA has additional SSRIs-mimetic psychotropic effects and low "hallucinogenic" effects reminiscent of psilocine (with an "e"! Psilocine is an alkaloid and, according to international law of nomenclature, the "e" should be added!). This combination of GHB effects, SSRIs-mimetic effects and low hallucinosis is the very essence of the MDMA experience. I have, recently, reclassified all the molecules formerly called "hallucinogenic" as "cogitatiogens" or "pensogens", from the Latin and the French, meaning: molecules which generate and increase, specifically, thought. Thus the cogitatiogenic effect of MDMA is quite an important psychotropic effect of this molecule, as a medicine.It is the specific mixture of increased thought, increased sociability with decreased anxiety and stress which is the basis of the therapeutical effect of MDMA. Coming back to Tianeptine, novel non-neurotoxic derivatives of MDMA will be found to have not only anti-depressant but also anxiolytic and anti-stress effects and we can safely assume that they will start, in concomittance with the development of Gamma-OH mimetics, a new psychopharmacological revolution. The fact that depression in priorly exposed MDMA individuals can be reversed with tianeptine is a very important fact which will, obviously, be noticed by all our readers. As increasing, globally, serotoninergic neurotransmission gives a net effect of blunting of affect it is logical (and demonstrated with Stablon) to expect that reducing serotonin action in some specific crucial loci will stimulate affect. Regarding this, an interesting observation has been made with the drug NAN-190 which increases tyrosine hydroxylase activity, nearly to GHB levels, by an action at 5-HT1a post-synaptic heteroreceptors. The net effect of this might mean that a reduction of serotoninergic neurotransmission could lead to an increase in dopaminergic neurotransmission. In fact the antagonistic links between dopamine and serotonin in the central nervous system has led me to the concept of the serotonin/balance hypothesis. This hypothesis predicts that MDMA sociabilising effects should be linked to both dopamine and serotonin. My present working hypothesis, as stated before, is that the sociabilisers exert a chain of neurochemical events leading to an increased oxytocinergic function. Sociabilisers will probably throw most SSRIs to the wastebasket once they are fully developed! How many lives could had been saved had the research on anti-depressants not stayed confined on the invention of imipraminomimetics only. The present working hypothesis on the mechanism of action of sociabilisers is that they depress paranoia, as we noticed, thus leading, as natural sociability, to a vast array of potentially useful therapeutic effects. From the effects of natural (non-pharmacological) sociability it can be predicted that full sociabilisers should have the following properties:
From my experience with Gamma-OH, I found that this remarkable molecule had most of the above mentioned properties (but, curiously, baclofen, which mimics Gamma-OH on many points, is not a sociabiliser, though it can elevate mood and potently stimulate sexuality in man while depressing sexuality in the mouse! Here are some properties of Gamma-OH:
We might expect many of those effects to be found, also, in newnon-neurotoxic analogs of MDMA. MDMA and GHB are, inextricably,linked and should NOT at all be studied as a separate group but as one group only. A substantial number of the imipraminomimetics are, in fact, thymoanaesthetics and not authentic thymoanaleptics: they "suppress" depression by inducing a deficit: blunting of affect, that is an anaesthesia of emotions. So, thymoanaesthetics cannot be classified as authentic anti-depressants but only as pseudo-antidepressants. Why is Gamma-OH so efficient in depression? Because depression can be defined as a deficit of pleasure, due to inhibition of social contacts. Some cultures are more depressogenic than others in this respect. For example, protestant cultures generate more psychopathologies than other cultures because of the extreme repression of emotions. They are thus psychotoxic and psychopathogenic. By stimulating the desire to interact with others, depression is automatically switched off under Gamma-OH! The psychopharmacology of Gamma-OH is still largely unknown but we should focus our attention, I think, on the psychopharmacology of what is called the "maternal instinct" in order to unravel the remarkable properties of this old but unknown molecule, as sociability seems a manifestation of maternal behaviours but expressed differently in adulthood. The development of Sociabilisers will, in my opinion, lead to a complete revolution in the therapy of many psychopathologies, including human intra-specific aggression (competition, war, etc). But why did we wait until now to discover the remarkable properties of a molecule invented 33 years ago? One reason is because Gamma-OH is a short acting medicine: its effects subside within 1 and a half to 2 hours and repeated doses during the day should be used in order to obtain an anti-depressant response. Another reason is that the imipramnomimetic dogma sterilised research and, as all dogma, completely blocked the research of authentic thymoanaleptics. Moreover and worse: due to the chronic lack of enthusiasm of most scientists in the fields of psychiatry and psychopharmacology and also due to the absence of serious research on human beings (isolated people, like Alexander Shulgin, still do introspective research), it took a great deal of time for this researcher to discover, at last, the concept of thymoanaesthesia and to understand that research in depression, for instance, was going nowhere because of a constant confusion concerning the logical nature of what authentic anti-depressants should be like. Conclusion: A Behavioural RevolutionThe men and the women of the Future will, out of necessity which has guided Evolution so far, be more sociable and devoid of intra-specific aggression.The development of MDMA non-neurotoxic analogs, together with the development of the sociabilisers, as a natural class of novel pharmaceutical agents, will radically modify our life and make it more happy and worthwhile, more effective globally. Sociabilisers hold a great promise:make true the teachings of Christ. Claude Rifat El-Sayed, Japan |