CANNABINOIDS BLOCK RELEASE OF SEROTONIN FROM PLATELETS INDUCED BY PLASMA FROM MIGRAINE PATIENTS
Int J Clin Pharm. Res V (4) 243-246 (1985)
Volfe Z., Dvilansky A., Nathan I.
Blood Research, Faculty of Health Sciences, Soroka Medical Center, Ben-Gurion University of the Negev, P.O. Box 151, Beer-Sheva 84101, Israel.
Summary: The effects were assessed of delta-1-THC* (the psychoactive component of cannabis) and CBD and DMHP-CBD (the non-psychomimetic components of marijuana derivatives) on 14C labelled serotonin release from normal platelets, when incubated with patient's plasma obtained during migraine attack. A statistically significant inhibitory effect (p>0.005) of 14C serotonin release was found at 10-5M, 10-6M, 10-7M delta-1-THC concentrations. Plasma of migraine patients obtained in attack-free periods revealed no significant inhibitory effect on 14C serotonin release from normal platelets using the same delta-1-THC concentration. CBD and DMHP-CBD had no significant effect on 14C serotonin release from normal platelets when tested either at migraine-free period plasma or plasma obtained during migraine attack.
(*Nomenclature for THC is sometimes different in other countries. delta-1-THC is the same as delta-9-THC.)
Several mechanisms are involved in the relationship of platelets to migraine attacks. The first relates to the platelet itself and is associated with hyperaggregation of platelets (1-5) and their activation (6). On the other hand, a plasmatic factor has been reported to induce aggregation of normal human platelets and release serotonin (7-12). Previous reports on the beneficial effect of cannabinoids in migraine (13) raises the possibility that delta-1-3, 4-trans tetrahydrocannabinol (delta-1-THC), the active psychoactive components of the crude extract of marijuana, may be beneficial (14, 15). It is a fact that cannabis has an analgesic effect (16) decreases intraocular pressure (17), has a vasodilatory effect in bronchial asthma (18) and prevents vomiting (19). These various effects of cannabinoids and the effect of delta-1-THC on preventing release of rat brain serotonin induced by reserpin (20) and its effect on platelets in vivo (21, 22) and aggregation of platelets in vitro (23) raised the possibility that it might affect the previously described plasmatic factor in migraine patients responsible for 14C serotonin release of normal platelets (8). Therefore, we assessed that in vitro effect of three marijuana derivatives: delta-1-THC, the psychoactive component of cannabis (14) and cannabidiol (CBD) which has no psychomimetic effect (24). The effect of both drugs might discern the biological specificity of the marijuana derivatives. Also (6-hydroxydimethylheptyl) (DMHP-CBD) a homologue of cannabidiol which increases cannabinoid-activity five hundred-fold was also investigated (25).
Material and methods
Plasma was obtained from patients, being followed at the Neurology Clinic of the Ben-Gurion University Medical Center, and diagnosed according to a standard clinical definition of migraine (26). Patients refrained from taking drugs ten days prior to blood donation. Blood samples were obtained (in plastic tubes --- 3.8% sodium citrate 1:10 volume) once during an attack-free period and once during a migraine attack. Simultaneously, samples were obtained from normal controls of the same age and sex and platelet rich plasma was prepared and frozen at -72 degrees C. Plasma samples were incubated at 37 degrees C for ten minutes with the cannabinoids delta-1-THC, CBD and DMHP-CBD. The concentrations of cannabinoids varied from 10 -7M to 10 -3M. Ethanol 70% was used as control because it is used as the solvent for the cannabinoids. It did not affect the serotonin release during the ten minutes' incubation in comparison with normal saline. 14C labelled serotonin release was determined from normal donor's platelets blood group 0 Rh-, who refrained from taking medications for ten days. The assessment of 14C serotonin release was made with plasma of migraine patients during an attack, and an attack-free period and of normal plasma controls according to Hirshman and Schulman (27). Radioactivity was determined using a liquid Scintillation spectrometer TriCard 3255 Packard. The results were calculated in percentages, considering the total radioactivity of 14C serotonin uptake by the platelets tested as 100% value. Statistical evaluation was done using the Student's t-test.
Normal plasma incubated with delta-1THC at the range of concentrations 10 -7M to 10 -3M revealed significant increases of 14serotonin release from normal platelets only at 10 -4M and 10 -3M delta-1-THC of 106+ 1.9%, 117.9+ 2.3% respectively (p<0.05). The other two cannabinoid derivatives CBD and DMHP-CBD had no effect on 14C serotonin release from normal platelets when incubated with normal plasma, and tested at the same range of drug concentrations. Table I documents the effect of delta-1-THC, CBD, and DMHP-CBD on 14C labelled serotonin release from normal platelets when incubated with the migraine patient's plasma obtained during a migraine attack. There is a statistically inhibitory effect of 14C serotonin release (p<0.005) at 10 -5M, 10 -6M, 10 -7M delta-1-THC concentrations. It should be noted that delta-1-THC added at the same concentrations to plasma of migraine patients obtained in an attack-free period revealed no significant inhibitory effect on 14C serotonin release compared with normal platelets.
The other two cannabinoid derivatives CBD and DMHP-CBD had no significant inhibitory effect on 14C serotonin release from normal platelets, when tested either with migraine-free period plasma or plasma obtained during a migraine attack. These two derivatives were tested at the same concentrations as described in Table I.
Table I Inhibition of 14C serotonin release from normal platelets. Effect of delta-1-THC, CBD, DMHP-CBD on plasma of migraine patients obtained during migraine attack (mean + s.e. %).
Drug Concentration THC CBD DMHP-CBD
10 -5M 84.10 + 2.8 107.1 + 3.7 105 + 3.5
10 -6M 86.8 + 2.3 106.6 + 3.7 106 + 3.6
10 -7M 87.8 + 2.5 103.99 + 3.4 108 + 3.5
Plasmatic factor present in migraine patients' plasma was reported to release serotonin in vitro from normal platelets (7, 8). Serotonin release induced by this factor occurred in 60-85% of the patients and is presumed to be a fatty acid (9), prostaglandin (10) or some immunological factor related to decrease in complement (11, 12). Previous reports concerning delta-1-THC, the active component in marijuana derivative (14, 28), documented increased serotonin in rats' brains and prevented release of serotonin induced by reserpine (20). The present studies documented significant inhibition of 14C serotonin release from normal platelets in 10 -7M to 10 -5M delta-1-THC concentrations, when incubated with plasma from migraine patients ( Table I). It should mention that these concentrations induce a psychosomatic effect in marijuana smokers and stabilize red blood cells against lysis (29). It is not clear yet how cannabinoids affect migraine. Is it due to their analgesic effect (16), vasoconstrictor effect (30) or preventive effect on migraine (13)? The two other non psychomimetic components of marijuana derivatives CBD and DMHP-CBD did not show inhibition activity of 14C serotonin release from normal platelets induced by migraine plasma. It was shown that the psychoactive component of cannabis delta-1-THC did inhibit 14C serotonin release from platelets and it might give a clue to the effect of cannabinoids in vivo in respect of migraine attacks and their inhibition.
1. Hilton B.P., Cumings J.N. An assessment of platelet aggregation induced by 5HT. J. Clin. Path., 24, 250, 1971 2. Couch J.R., Hassanein R.S. Platelet aggregability in migraine and relation of aggregability to clinical aspects of migraine. Neurol., 26, 348, 1976.
3. Hanington E. Migraine, a blood disorder. Lancet, 1, 501, 1978.
4. Hanington E., Jones RJ., Amess J.A.L. Wachowica. Migraine, a platelet disorder. Lancet2, 720, 1981.
5. Gawel M.J., Burkett M., Rose F.C. The platelet release reaction during migraine attacks. Headache, 19, 323, 1979.
6. Manotti C., Manzoni G.C., Moretti G., Poti R., Tagliafern A. Platelet function in patients with migraine. Haematologica, 68, 775, 1983.
7. Anthony M., Hinterberger H., Lance J.W. The possible relationship of serotonin to the migraine syndrome. Headache, 2, 29, 1969.
8. Dvilansky A., Rishpon S., Nathan I., Zolotov Z., Korczyn A. The release of 5HT by plasma from patients during and between migraine attacks. Pain, 2, 315, 1976.
9. Anthony M. Some aspects of clinical pharmacology of serotonin. Agents Actions, 5, 490, 1975.
10. Anthony M. Plasma free fatty acids and prostaglandin E in migraine and stress. Headache, 16, 58, 1975.
11. Lord G.D.A., Duckworth J.W., Charlesworth J.A. Complement activation in migraine. Lancet, 1, 781, 1977.
12. Dalesio D.J. Use of platelet agonists in treatment of migraine. Headache, 16, 129, 1977.
13. Mikuriya T.H. Marijuana in medicine: Past, present and future, Calif. Med., 110, 34-40, 1969
14. Mechoulam R. Marijuana chemistry. Science, 168, 1159, 1970.
15. Mechoulam R., Gaoni Y. A total synthesis of delta-tetrahydrocannabinol, the active constituent of hashish. J. Amer. Chem. Soc., 87, 3273, 1965.
16. Kozersky S., Dewey W.L., Harris L.S. Antipyretic analgesic and anti-inflammatory effects of delta-9-THC in the rat. Europ. J. Pharmacol., 24, 1, 1973.
17. Hepler R.S., Frank J.M. Marijuana smoking and intraocular pressure. JAMA, 217, 1392, 1971.
18. Tashkin D.P., Shapiro B.J., Frank J.M. Acute effects of smoked marijuana and oral delta-9-THC on specific airway conductance in asthmatic subjects. Amer. Rev. Resp. Dis., 109, 420, 1974.
19. Sallan S.E., Cronin C., Zelen M., Zinberg N.E. Antiemetics in patients receiving chemotherapy for cancer. A randomized comparison of delta-9-THC land prochlorperazine. New Engl. J. Med., 302, 135, 1980.
20. Sofia R.D., Dixit B.N., Barry H. The effect of delta-9-THC on serotonin metabolism in the rat brain. Life Sciences, 10, 425, 1971.
21. King A.B., Cowen D.L. Effect of intravenous injection of marijuana. JAMA, 210, 724, 1969.
22. Pechet L., King A.B., Pechet G.S. The effect of intravenous marijuana on coagulation on platelet and white cell count. Fed. Proc., 29, 441, 1970.
23. Levi R., Friedlander M., Dvilansky A., Livne A. Effect of hashish component delta-1-THC on the lultrastructure of human platelets. Isr. J. Med. Sci., 2, 401, 1975.
24. Neumeyer J.L., Shagoway R.A. Chemistry and pharmacology of marijuana. J. Pharmacol. Sci., 60, 1433, 1971.
25. Loev B. Bender P.E., Dowals F. Cannabinoids structure-activity studies related to 1.2 dimethylheptyl derivates. J. Med. Chem., 16, 1200, 1973.
26. Procacci P. A survey of modern concepts of pain. In: Vinken P.J., Bruyn G.W. eds. "Handbook of clinical neuroloty," North Holland, Amsterdam, 1968, pp. 140-143.
27. Hirshman R.Y., Shulman N.R. The use of platelet serotonin as sensitive method for detecting antiplatelet factor in patients with thrombocytopenic purpura. Bri J. Haemat., 24, 793, 1973.
28. Mechoulam R. Drugs made from cannabis. Harefuah, 3, 378, 1976.
29. Rax A., Schur A., Livne A. The interaction of hashish component with human erythrocytes. Bioch. Biophys. Acta, 274, 269, 1972.
30. Adams M.D., Earnhardt J.T., Dewey W.L., Harris L.S. Vasoconstrictor actions of delta-8 and delta-9-THC in the ralt. J. Pharmacol.l Exp. Therap., 196, 649, 1976.
URL: http://www.mapinc.org/drugnews/v01.n1160.a02.html Newshawk: Amanda Pubdate: Thu, 28 Jun 2001 Source: WorldNetDaily (US Web) Copyright: 2001WorldNetDaily.com, Inc. Contact: firstname.lastname@example.org Website: http://www.worldnetdaily.com/ Details: http://www.mapinc.org/media/655 Author: Doug Casey
PARENTS AS DRUG PUSHERS
Looking back at Columbine and other school shootings around the nation, it's easy to get caught up in the frenzy for government control of guns, the Net, and the content of video games and movies. The envisioned controls are, however, not only stupid and counterproductive, but they also don't address the more basic question: Why has there been a spate of killings in U.S. schools over the past few years?
Without doubt, part of the answer lies in the sorry condition of government education, generally. But I suspect it's more than bad schools. And has next to nothing to do with guns, the Net, or video games.
There's plenty of reason to believe drugs are to blame. But not relatively benign illegal substances like marijuana. I'm talking about the extremely popular, and potentially very dangerous, class of psychiatric drugs called SSRIs, Selective Serotonin Reuptake Inhibitors.
Pusher parents SSRIs work by regulating the speed with which the neurotransmitter serotonin, which conducts messages between neurons, is used by the brain. Serotonin helps people to keep calm and act less impulsively; one reason men are more prone to impulsive violence than women is that the male brain has fewer serotonin receptors. People who are deficient in serotonin are more prone to depression, fits of violence, and suicide. In essence, SSRIs ( of which Prozac is the best known brand ) make you feel good by causing the brain to use up its supplies of serotonin more quickly; unfortunately, however, it doesn't help the brain create more. So when serotonin supplies become critically depleted, the SSRI user can snap unpredictably.
Interestingly, just before the massacre, Eric Harris was turned down for the Marine Corps because he was on an SSRI, the powerful antidepressant, Luvox ( fluvoxamine ). Alas, Eric was denied the possibility of venting his anger in a "controlled" setting, such as the Balkans or some other godforsaken quagmire, and resorted to working out his problems at school.
Less than one week after his rejection by the Marines, following manic, sleepless nights of pipe-bomb preparation, Eric and buddy Dylan Klebold launched their homemade version of a NATO assault, murdering 12 classmates and one teacher before killing themselves. Since then, an undeservedly small amount of attention has been given to the package insert warnings on fluvoxamine, including:
"All effective antidepressants [including the SSRI, fluvoxamine] can transform depression into mania in predisposed individuals."
"The usual presentation of this switch is the sudden appearance of insomnia."
"All antidepressants should be used with caution because of the possibility of suicidal ideation." Studies have also found that fluvoxamine can increase the effect of caffeine, so much so that caffeine intoxication may result; Harris was a coffee drinker. Furthermore, mixing fluvoxamine with alcohol can cause extreme agitation; Harris was known to enjoy Jack Daniels whiskey.
Psychiatric-drug expert Dr. Peter Breggin states, "According to the manufacturer, Solvay, 4% of children and youth taking Luvox developed mania during short-term controlled clinical trials. Mania is a psychosis which can produce bizarre, grandiose, highly elaborated destructive plans. ..."
Luvox withdrawal? Plausibly, the dual-edged Luvox may have held Eric at bay for a while. But then, it may have unleashed him when he blamed it for his rejection from the Marines, then swore it off. Some of his friends told The New York Times they believed he might have tried to go off the anti-psychotic drug after that Marine rejection. Short half-life SSRIs, such as fluvoxamine, produce difficult and intense withdrawal symptoms. If fluvoxamine is suddenly stopped, symptoms quickly intensify and the patient experiences a relapse.
What did the autopsy find? After repeated denials that any drug residues were found in Eric Harris's body, ABC's Colorado affiliate KCNC reported on May 4, 1999, "[T]he coroner has released further toxicology reports on Eric Harris, one of the two dead suspects. Specialized testing shows levels of Luvox in Harris' blood in a therapeutic range." According to another report Harris had a lower mid-level therapeutic amount of Luvox in his blood. Did they think to measure his serotonin metabolites? In the spirit of Dealy Plaza, the autopsy report was sealed to the public.
Luvox is approved by the FDA ( I like to think those initials stand for Federal Death Authority, because they kill more people in a year than the Defense Department does in a typical decade ) for treatment of obsessive-compulsive disorder, a.k.a. Bipolar Affective Disorder, in which there are swings between a "high," agitated mood and depression. It is in the same family as the SSRI Prozac and is often prescribed to people who are both depressed and have obsessive thoughts.
Drugs as an answer Why do people become depressed, with all the nasty side effects that accompany depression?
I'm of the opinion that, while having an adequate amount of the right nutrients and neurotransmitters can help one think more clearly and rationally, the root cause for most depression is simply bad ethics and/or a conflict between one's actions and one's values. Unresolved conflicts perpetuate mental turmoil. The Age of Prozac has made it possible for antidepressant drugs to become substitutes for counseling, therapy, cleaning up one's act, and genuine conflict resolution.
Prozac, Luvox and similar drugs give parents an excuse to shirk the need for attentiveness, guidance and supervision because they think some antidepressants will "listen" for them and absolve them of responsibility. In other words, SSRIs and other antidepressants "solve" your problems pretty much the way alcohol does, by making an examination of the root cause seem unnecessary.
Ironically, the first generation to grow up with drugs, the Boomers, have learned neither to use them wisely nor to teach their children to separate the "dumb" drug ones from the "smart" ones. Given the widespread use of drugs as solutions, as well as the general state of the culture and politics, I'm forced to conclude that more Columbines are in the pipeline.
Bad medicine The fact that psychiatric drugs are widely advocated for children and adolescents ( Ritalin comes to mind first ) reflects the utter corruption of not only America's educational system, but echoes what's wrong with our whole medical system.
What is now usually referred to as "conventional" medicine was not conventional until just this century. Its protocol grew out of the battlefield ( remember the opening scenes of "Dances With Wolves"? ) where emergency procedures were developed for acute trauma; this is where conventional medicine shines. When it comes to prevention, conventional medicine is more problematical. When it comes to how the mind works, conventional medicine, in the form of psychiatry, is still in the Dark Ages, using the equivalents of leeches and boiled toad skins. There's a reason Hannibal Lecter in "Silence of the Lambs" was portrayed as a psychiatrist. Educational philosophy is little better, and getting worse; the school system is increasingly indistinguishable from the prison system.
Using psychiatric drugs in the classroom is tantamount to asking Hannibal Lecter to be your babysitter.
If you want intelligent policy in any area ( whether education, medicine or politics ) you have to understand how ideas relate to actions; you have to understand that accepting responsibility for one's actions is the basis of civilization. In this regard, drugs do not help. Perversely, and surprisingly to most people, the really dangerous drugs aren't the illegal ones used for recreational purposes, they're the so-called therapeutic ones that can result in their recipients unpredictably "going postal." The fact things like Ritalin, Halcion, Prozac, Valium, Luvox and a hundred others are prescribed and legal means nothing except that there are a lot of people walking around like pressure cookers waiting to blow.
Coincidental with the educational system's transformation into an ersatz penal system, it's not surprising we have seen the rise of the therapeutic state, which acts as a combination father, mother, doctor and clergyman. A great deal of crime is increasingly attributed to "insanity" ( to wit: Andrea Yates, charged with systematically drowning her five children in a bathtub ) and treated/punished in asylums rather than prisons, much in the manner of the Soviet Union. In fact, during the Clinton administration, lobbyists pushed for inclusion of mental illness as a diagnosable and treatable disease also to be covered by federal largess.
Soon everyone will be able to play Woody Allen with a ( taxpayer-funded ) weekly visit to their shrink. Once that happens, legions more will cloud their minds in a haze of psychiatric drugs, primed for a violent explosion. Soma, the government's solution to dissidents in Aldous Huxley's "Brave New World" is not at all far-fetched in 21st century America.
Drugs for kids The overdiagnosis of mental diseases such as Attention Deficit Disorder has reached epidemic proportion, with some schools reporting 30 percent of the kids using Ritalin ( methylphenidate ), a drug closely related to methamphetamine, as a supposed remedy. The smart kids palm their Ritalin, and deal it to older kids who like the rush. Like so many psychiatric conditions, however, ADD has never actually been proven to even exist, and the criteria for diagnosis are so general that virtually anyone would qualify for a prescription.
Meanwhile, as the government fights its insane war on recreational drugs, cycling millions of otherwise innocent people through its prison system, it subsidizes millions of doses of Ritalin daily, turning a whole generation of kids into real junkies. It's completely insane giving a powerful psychiatric drug to kids while their personalities - indeed, their actual brains - are still forming.
But surely there must be a reason for all this? Would schools pass out all these drugs unless they were really needed? You can make the argument that kids today are more fidgety than in the past because they eat more sugar and get less exercise than they used to, but that's no excuse to put them on a powerful psychiatric drug - at least not before trying a better diet and more physical activity. Drug companies like to sell drugs, of course, but I suspect the real driving force behind what's going on is a desire on the part of most teachers, and some parents, to "harmonize" and homogenize the most creative kids. Smart, active, creative kids are notoriously hard to handle, especially when confronted with the typically dumb, reactive, and robotic public-school teacher. They're also a threat to the egalitarian system that sets up "special" ( handicapped ) kids as the standard, and drags everyone else down to the level of quadriplegics.
Creative kids are always troublesome to a system that bores them and parents that are too busy to be real parents. Pumping them full of Ritalin is society's way of telling kids to slow down.
It's fairly predictable a lot of these kids will graduate to Prozac. Longer-term consequences are less predictable, but I can't see any good ones. Among them will be more of the ultra-violence recently seen in U.S. schools.
A better approach What's a parent ( or an individual ) to do? First, realize that many illnesses are diagnoses of convenience, and that often, when there actually is a problem, the underlying problem may simply be a nutritional deficiency. There is some evidence that many ADD symptoms are caused by biochemical imbalances which could be greatly alleviated by supplementation with a natural cholinergic agonist, like DMAE ( dimethylaminoethanol ). In addition to helping with hyperactivity and attention problems, when legitimate, DMAE can increase memory and elevate mood. It can also provide a feeling of mild stimulation, and increase intelligence. DMAE may possibly extend mean lifespan by helping stabilize cell membranes, which degrade with age. And unlike psychiatric drugs, it's extremely cheap.
On the SSRI front ( the initials, again, stand for Selective Serotonin Reuptake Inhibitor ), the herbal extract 5-HTP ( 5-hydroxytryptophan ) has been shown to be as effective as Luvox, in direct comparison, but without the side effects. A direct precursor to the neurotransmitter serotonin, which is now accepted as the principle neurotransmitter involved in preventing depression, natural 5-HTP can help to maintain or restore serotonin levels to the level of a young adult. You are far less likely to have buffering problems, and far less likely to slip into depression. 5-HTP has been used successfully with adolescents without the zany side effects of the SSRIs, especially Luvox.
You might want to seek out a doctor who is not only expert in conventional medicine, but who also responds rationally to the evidence for alternative solutions, and who believes that ideas ( or their lack ) have consequences.
A solution It's strange, even surreal: Drugs in the schools actually are a huge problem - but they're not the drugs everyone imagines, nor are they coming from the sources most would suspect. It's scary, but there are lots of scary things going on in the United States today. What should you do? You should take your kids out of the local school, if at all possible, and engage in a program of home-schooling.
It's hard to believe that most parents automatically and brainlessly entrust their most valuable single asset, their children, to a bunch of government employees for education. My experience with most public-school teachers is that they'd have a hard time getting a job anywhere else, with the possible exception of the Post Office, or something low-level in the fast-food industry. They are generally not dedicated professionals; they're union members who almost certainly don't share your values.
What about the socialization that schools are supposed to provide for the kids? That's nonsense. Kids don't need to be incarcerated with the cast from "Lord of the Flies," including an unknown number of Eric Harris clones, supervised by moronic union workers, in order to make friends. School today is a place where they'll learn little except bad habits. And it's going to become ever more dangerous, no matter how many metal detectors they put in the hallways, as long as the trends I've discussed above remain in motion.