Help For Satsvarupa And Others With Anxiety And Migraine

Here is some data on what can help this kind of suffering, it appears SDG is in Stockton ? with one of you guys ? I'm living close by in merced.

I recommend valerian (reduces stress considerably) and ganja, maybe moving to maui ( i lived there for 15 years ) and relax on the beach and under a waterall , the environment there is very soothing.

Cannabis for Migraine Treatment: The Once and Future Prescription
By Ethan B. Russo, M. D.
Published in Pain, v 76 1998, p 3-8. Reprinted by permission

Abstract: Cannabis, or marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was highly esteemed as a headache remedy by the most prominent physicians of the age between 1874 and 1942, remaining part of the Western pharmacopoeia for this indication even into the mid twentieth century. Current ethnobotanical and anecdotal references continue to refer to its efficacy for this malady, while biochemical studies of THC and anandamide have provided a scientific basis for such treatment.

The author believes that controlled clinical trials of Cannabis for acute migraine treatment are warranted.

Introduction:

One of the basic tenets of medical history is that remedies fall in and out of favor. Once supplanted, most pharmaceuticals fail to re-attain a position of prominence. Very few are popular for many decades. Not many physicians today are aware of the prominence that Cannabis drugs once held in medical practice. Problems with quality control and an association with perceived dangerous effects sounded the death knell for Cannabis as a recognized Western therapy. Other medicines that are far more potentially damaging than Cannabis remain in our pharmocopeias because of recognized medical indications: opiates for pain control, amphetamines for narcolepsy and attention deficit hyperactivity disorder, etc. Thalidomide, which was banned due to its role in birth defects, may be effecting a therapeutic revival. Even the lowly leech is once again the object of serious medical investigation. This study will examine the history of Cannabis use for one indication, that of headache treatment, its scientific rationale, and possible future as an alternative therapeutic agent.

Historical and Ethnobotanical Usage of Cannabis in Migraine Treatment:

Headaches have likely afflicted man throughout history. Archeological records substantiate an ancient association between man and the plant genus Cannabis, plant family, Cannabaceae. Its botanical origin has been debated to be as far east as China, but most experts suspect it to be in Central Asia, possibly in the Pamir Plains (Camp, 1936). Some botanists have maintained Cannabis as monotypic genus, while others (Schultes et al., 1974) have provided convincing documentation of three Cannabis species: sativa, indica, and ruderalis. All contain the psychoactive chemical delta-9- tetrahydrocannabinol (THC) in varying degree.

Use of Cannabis fibers to make hemp has been documented as early as 4000 BC by Carbon-14 dating (Li, 1974), and that use has been maintained continuously up to the present day. Its seed grain was an ancient human foodstuff, which may have lead to an early recognition of its medicinal use. The first records of the latter seem to be in the Pên-tsao Ching, a traditional herbal written down in the first two centuries AD, but said to be based on the oral traditions passed down from the Emperor Shên-nung in the third millenium BC. The text noted that the plant fruits "if taken in excess will produce hallucinations (literally "seeing devils")(Li, 1974).

The Zend-Avesta, the holy book of Zoroastrianism, which survives only in fragments, dating from around 600 BC in Persia, alludes to the use of Banga in a medical context, and it is identified as hemp by the translator (Darmesteter, 1895).

The classical Greek literature also documents knowledge of the inebriating actions of Cannabis. Herodotus, circa 450 BC, described how the Scythians set up tents, heated stones and threw Cannabis seeds or flowering tops upon them to create a vapor, and "the Scythians, delighted, shout for joy." The Greek physicians Dioscorides and Galen expounded on medical indications, mainly gastrointestinal (Brunner, 1977).

The Atharva Veda of India, dated to between 1400 and 2000 BC, referred to a sacred grass, bhang, and medicinal references to Cannabis were cited by Susrata in the sixth to seventh centuries AD (Chopra and Chopra, 1957) and included indication for its use for headache (Dwarakanath, 1965). O'Shaughnessy introduced the medical use of Cannabis indica, or "Indian hemp," to the West in 1839 (Walton, 1938; Mikuriya, 1969). His treatise on the subject supported the utility of an extract in patients suffering from rabies, cholera, tetanus, and infantile convulsions.

Throughout the latter half of the nineteenth century, many prominent physicians in Europe and North America advocated the use of extracts of Cannabis indica for the symptomatic and preventive treatment of headache.

Proponents included Weir Mitchell in 1874, E.J. Waring in 1874, Hobart Hare in 1887, Sir William Gowers in 1888, J.R. Reynolds in 1890, J.B. Mattison in 1891, et al., (Walton, 1938; Mikuriya, 1969). Cannabis was included in the mainstream pharmacopeias in Britain and America for this indication. As late as 1915, Sir William Osler, the acknowledged father of modern medicine, stated of migraine treatment (Osler, 1915), "Cannabis indica is probably the most satisfactory remedy. Seguin recommended a prolonged course." This statement supports its use for both acute and prophylactic treatment of migraine.

In 1916, in a quotation attributed to Dr. Dixon, Professor of Pharmacology, Kings' College, and the University of Cambridge (Ratnam, 1916), reference is specifically made to the therapeutic effects of smoked Cannabis for headache treatment. He stated, "In cases where immediate effect is desired, the drug should be smoked, the fumes being drawn through water. In fits of depression, mental fatigue, nervous headache, feelings of fatigue disappear and the subject is able to continue his work refreshed and soothed."

In the years that followed, Cannabis came to be perceived as a drug of abuse, smoked by certain classes of people as "marijuana" or "marihuana." Nevertheless, it retained adherents for a variety of medical indications, throughout the early decades of the twentieth century. In 1938 Robert Walton published a comprehensive review of Cannabis, with botanical, historical, chemical and political discussions (Walton, 1938). After discussing the abuse issue, he stated his belief that the political action that had rendered marijuana illegal in the U.S.A. in 1937 (and which the American Medical Association vigorously opposed), should not serve to prohibit further medical use and scientific investigation of Cannabis' possible applications. Walton referred to twelve major authorities on its efficacy for migraine, and only one detractor.

In 1941, Cannabis preparations were dropped from the United States Pharmacopeia (U.S.P.), but the following year, the editor of the Journal of the American Medical Association still advocated oral preparations of Cannabis in treatment of menstrual (catamenial) migraine (Fishbein, 1942). This practitioner seemed to prefer Cannabis to ergotamine tartrate, which remains in the migraine armamentarium, some fifty-five years later. Thus, Cannabis was touted in eight consecutive decades in the mainstream Western medical literature as a, or the, primary treatment for migraine. As late as 1957, despite governmental controls in that country, Cannabis drugs retained a role in the indigenous medicine of India (Chopra and Chopra, 1957), and other countries.

In the 1960's marijuana moved to center stage of Western consciousness, and attained a degree of notoriety sufficient to render medical usage inconceivable to most. Medical research has resumed only recently, spurred on by anecdotal reports of patients who serendipitously discovered its benefits on their maladies.

Modern Research Developments on Cannabis:

In 1974, the first of several studies appeared examining issues of pain relief with Cannabis (Noyes and Baram, 1974). This article examined five case studies of patients who volitionally experimented with the substance to treat painful conditions. Three had chronic headaches, and found relief by smoking Cannabis that was comparable, or superior to ergotamine tartrate and aspirin.

One subsequent study of Cannabis pertained to pain tolerance in an experimental protocol (Milstein et al., 1975). A statistically significant increase in pain threshold was observed after smoking Cannabis in naïve (8% increase) and experienced subjects (16% increase). Another trial involved oral THC in cancer patients (Noyes et al., 1975a). They observed a trend toward pain relief with escalating doses significant to the P<0.001 level. The peak effect occurred at three hours with doses of 10 and 15 mg., but not until five hours after ingestion of 20 mg. Subsequently, the analgesic effect of THC was compared to codeine (Noyes et al 1975b). In essence, 10 mg. of oral THC vs. 60 mg. of codeine, and 20 mg. of THC vs. 120 mg. of codeine relieved the subjective pain burden of patients by similar decrements. The effects of 10 mg. of THC were well tolerated, but at 20 mg., sedation, and psychic disturbances bothered many of the elderly Cannabis-naïve subjects.

In the 1980's more comprehensive data on pharmacological effects of Cannabis and its derivative, THC became available. In 1983, research with varying potencies of smoked Cannabis demonstrated some correlation between serum THC levels and subjective "high" (Chiang and Barnett, 1983). Additionally, experimental subjects were able to distinguish the potency of the various samples with accuracy.

In a forensic review (Mason et al., 1985), the issue of marijuana's effect on driving was addressed, and it was indicated that isolated reports of adverse outcomes secondary to impairment by Cannabis as a sole inebriant were rare. The authors concluded that there was no suitable correlation between plasma or blood levels of THC and the degree of apparent impairment a human might exhibit.

In 1986 the journal Pharmacological Reviews devoted an entire issue to Cannabis and cannabinoids. In "Cellular Effects of Cannabinoids" (Martin, 1986), the author noted their analgesic properties, but reported that the mode of action was not blocked by naloxone, and seemed to work independently of opioid mechanisms. Another article examined pharmacokinetics (Agurell et al., 1986). Many facets were presented, including their findings that smoking a standard marijuana cigarette destroyed 30% of available THC.

The final article of the issue was entitled "Health Aspects of Cannabis" (Hollister, 1986). Pertinent points made included dose delivery efficiency of THC by inhalation of 10% in marijuana-naïve vs. 23% in experienced smokers. Oral bioavailability for THC was only about 6%, and onset of effects was not seen for 30-120 minutes.

Smoking of massive Cannabis doses daily for a prolonged period produced lower intraocular pressure, serum testosterone levels, and airway narrowing, but no chromosomal aberrations, or impairment of immune responses were noted (Cohen, 1976). Other "marijuana myths" were unsupported by careful review of the literature. While aggravation of pre-existing psychotic conditions by marijuana use was documented, no cause and effect relationship was noted.

Similarly, chronic use studies in Jamaica (Comitas et al., 1976), revealed no deficits in worker motivation or production. Two studies of brain computerized tomography (CT scan) refuted prior claims of heavy use producing cerebral atrophy (Co et al, 1977; Kuehnle et al., 1977). With respect to behavior, Hollister refuted the tenet that depicted Cannabis as a contributor to violent and aggressive behavior. Concerning addiction, he noted minimal withdrawal symptoms of nausea, vomiting, diarrhea, and tremors in some experimental subjects after very heavy chronic usage. Such effects were brief and self-limited.

The next year, an article entitled "Marijuana and Migraine" (El-Mallakh, 1987), presented three cases in which abrupt
cessation of frequent, prolonged, daily marijuana smoking were followed by migraine attacks. One patient noted subsequent remission of headaches with episodic marijuana use, while conventional drugs successfully treated the others. The author hypothesized that THC's peripheral vasoconstrictive actions in rats, or its action to minimize serotonin release from the platelets of human migraineurs (Volfe et al., 1985), might explain its actions.

In 1988 action was initiated through the DEA to reclassify marijuana to Schedule 2, potentially making it available for prescription to patients. The DEA administrative law judge, Francis Young, reviewed a tremendous amount of testimony from patients, scientists, and politicians in rendering his ruling. Although a medical indication of marijuana for migraine was not considered, its use was approved as an anti-emetic, an anti-spasticity drug in multiple sclerosis and paraplegia, while its utilization in glaucoma was considered reasonable. He stated, "By any measure of rational analysis marijuana can be safely used within a supervised routine of medical care."

In 1992, a study examined subjective preferences of experimental subjects smoking Cannabis, or ingesting oral THC (Chait and Zacny, 1992). Ten subjects in two trials preferred smoking active Cannabis over placebo, while ten of eleven preferred oral THC to placebo. These results call into serious question the plausibility of true blinding with placebo preparations in prospective therapeutic drug studies of marijuana, especially when smoked.

A more profound understanding of Cannabis, THC, and their actions in the brain has occurred with the discovery of an endogenous cannabinoid in the human brain, arachidonylethano-lamide, named anandamide, from the Sanskrit word ananda, or "bliss" (Devane et al., 1992). This ligand inhibits cyclic AMP in its target cells, which are widespread throughout the brain, but demonstrate a predilection for areas involved with nociception (Herkenham, 1993). The exact physiological role of anandamide is unclear, but preliminary tests of its behavioral effects reveal actions similar to those of THC (Fride and Mechoulam, 1993).

Additional research sheds light on possible mechanisms of therapeutic action of the cannabinoids on migraine. An inhibitory effect of anandamide and other cannabinoid agonists on rat serotonin type 3 (5-HT3) receptors was demonstrated (Fan, 1995). This receptor has been implicated as a mediator of emetic and pain responses. In 1996, a study in rats demonstrated antinociceptive effects of delta-9-THC and other cannabinoids in the periaqueductal gray matter (Lichtman et al., 1996). The PAG has been frequently cited as a likely anatomic area for migraine generation (Goadsby and Gundlach, 1991).

The understanding that Cannabis and THC effect their actions through natural cerebral biochemical processes has intensified the public debate on medical benefits of marijuana. In 1993, a book entitled Marihuana: The Forbidden Medicine (Grinspoon and Bakalar, 1993) examined a variety of claims for ailments treated by marijuana, and included an entire section on migraine. One clinical vignette discussed at length the medical odyssey of a migraineur through failures with standard pharmaceuticals, and ultimate preference for small doses of smoked marijuana for symptom control.

The editor of the British Medical Journal (Smith, 1995) recently wrote an editorial espousing moderation in the drug war. The Journal of the American Medical Association published a supportive commentary in 1995 (Grinspoon, 1995). The author rated the respiratory risks potent medical marijuana as low, and pointed out the contradiction of the Schedule 2 status of synthetic THC, dronabinol, while its natural source, marijuana remained a Schedule 1 product, and thus unavailable for legal use to patients who might prefer its easier dose titration. Grinspoon raised as a theoretical possibility the synergistic effects of the whole plant and its components as compared to pure THC.

The American Journal of Public Health issued its plea (AJPH, 1996), to allow access to medical marijuana as an Investigational New Drug (IND). The Australian government (Hall et al., 1995) recently compiled a recent exhaustive review of sequelae of Cannabis use. In the summary, it states: Acute Effects: anxiety, dysphoria, panic and paranoia, especially in naïve users; cognitive impairment, especially of attention and memory, for the duration of intoxication; psychomotor impairment, and probably an increased risk of accident if an intoxicated person attempts to drive a motor vehicle, or operate machinery; an increased risk of experiencing psychotic symptoms among those who are vulnerable because of personal or family history of psychosis; an increased risk of low birth weight babies if cannabis is used during pregnancy. In a current review of over 65,000 patient records in an HMO (Sidney et al., 1997), little effect of smoked Cannabis was seen on morbidity and mortality of non-AIDS patients.

Surely, not all in the medical establishment are convinced of the relative safety or benefit of Cannabis for medical usage. In a recent review (Voth and Schwartz, 1997) the authors concluded, "The evidence does not support the reclassification of crude marijuana as a prescribable medicine." However, their study was far from comprehensive, confining itself to the clinical issues of nausea, appetite stimulation, glaucoma, and spasticity.

Methodologically, it was flawed in that only the medical literature from 1975-1996 was screened, an era during which it was quite difficult to initiate research seeking to support medical indications for Cannabis. These authors did not examine migraine as an indication for Cannabis usage, nor did they review the extensive literature of the past. The debate on the subject of "medical marijuana" has extended to the World Wide Web, and includes myriad postings with anecdotal attestations of efficacy for a variety of indications.

Various investigators have examined the roles of different smoke delivery systems (Gieringer, 1996). From these studies, it is clear that vaporization of marijuana makes it possible to deliver even high doses of THC to the lungs of a prospective patient far below the flash point of the Cannabis leaf, eliminating a fair amount of smoke containing tar and other possible carcinogens. However, the marijuana joint was about as effective as any examined smoking device, including waterpipes, in providing a favorable ratio of THC to tar and other by-products of smoking. A standardized smoking procedure for use of Cannabis in medical research has been developed (Foltin et al., 1988).

Suppository preparations of Cannabis have been used to advantage in the past, and may be an acceptable form of administration for the migraineur, although dose titration would be less available.

Discussion:

Despite the development of serotonin 1D-agonist medications, migraine remains a serious public health issue. An estimated 23 million Americans suffer severe migraine. Of these, 25% have four or more episodes per month, and 35% have one to three severe headaches each month (Stewart et al., 1992). In economic terms, the impact of migraine is enormous: an estimated 14% of females, and 8% of males missed a portion of, or an entire day of work or school in one month (Linet et al., 1989). Migraine has been estimated to account for an economic impact of $1.2 to $17.2 billion annually in the U.S.A. in terms of lost productivity (Lipton et al., 1993). In 1990 studies were published outlining the biochemical basis of migraine treatment in serotonin receptor pharmacology (Peroutka, 1990). It was this research that led to the development of the first drugs active on serotonin receptor subtypes, sumatriptan, and ondansetron.

However, despite the justifiable success of sumatriptan in treating acute migraine, problems remain. Although rapidly active subcutaneously, its oral absorption is relatively slow, and often unreliable in the migraineur. Sumatriptan and its analogues are ineffective when administered in the "aura phase" of classic migraine (Ferrari and Saxena, 1995). Additionally, headache recurrence after "triptan" 5-HT1D agonist agents is a not infrequent occurrence. Unfortunately, repetitive dosing, and development of agents with longer half-lives does not seem to avert the issue (Ferrari and Saxena, 1995).

Another curiosity in the development of sumatriptan is its relative inability to pass the blood-brain barrier. Once more, the development of newer agents with improved central nervous system penetration has not necessarily improved efficacy, but does increase the likelihood of side effects, such as chest and throat tightness, numbness, tingling, anxiety, etc. (Ferrari and Saxena, 1995; Mathew, 1997).

Ultimately disappointing, none of the triptan drugs seems to exert any benefit on the frequency of migraine incidence, unlike dihydroergotamine, which has degree of prophylactic benefit.

Thus, it is the author's contention that this group of agents, though impressive, may represent somewhat of a "therapeutic dead end." Especially considering the large percentages of migraineurs who either fail to respond to the triptans, or can not tolerate them, there seems to be definite need for alternative treatment agents.

The author believes that the issue of medical marijuana, and its possible role in migraine treatment deserves proper scientific examination, both biochemically and clinically.

Results of controlled clinical trials may be valuable for migraineurs and professionals who treat them because there is a strong need for additional medications that will effectively this condition in its acute state. At this time, the best available medication, injected sumatriptan (Imitrex) has been ineffective in up to 30% of patients, or has produced undesirable side effects for up to 66% when administered subcutaneously (Mathew, 1997). The available evidence seems to suggest that smoked Cannabis would be a far safer alternative than butorphanol nasal spray (Stadol-NS), which, heretofore, has been an unscheduled drug approved in the U.S.A. for migraine treatment despite its addictive potential and unfavorable side effect profile (Fisher and Glass, 1997).

Conclusions:

1) Cannabis, whether ingested, or smoked, has a long history of reportedly safe and effective use in the treatment and prophylaxis of migraine.

2) Cannabis has a mild but definite analgesic effect in its own right.

3) Cannabis seems to affect nociceptive processes in the brain, and may interact with serotonergic and other pathways implicated in migraine.

4) Cannabis is reportedly an effective anti-emetic, a useful property in migraine treatment.

5) Cannabis, even when abused, has mild addiction potential, and seems to be safe in moderate doses, particularly under the supervision of a physician.

6) Cannabis' primary problem as a medicine lies in its possible pulmonary effects, which seem to be minimal in occasional, intermittent use.

7) Cannabis when inhaled, is rapidly active, obviates the need for gastrointestinal absorption (impaired markedly in migraine), and may be titrated to the medical requirement of the patient for symptomatic relief.

8) Cannabis delivered by pyrolysis in the form a marijuana cigarette, or "joint," presents the hypothetical potential for quick, effective parenteral treatment of acute migraine.

In closing, a quotation seems pertinent (Schultes, 1973):

"There can be no doubt that a plant that has been in partnership with humanity since the beginnings of agricultural efforts, that has served man in so many ways, and that, under the searchlight of modern chemical study, has yielded many new and interesting compounds will continue to be a part of man's economy. It would be a luxury that we could ill afford if we allowed prejudices, resulting from the abuse of Cannabis, to deter scientists from learning as much as possible about this ancient and mysterious plant."

Ethan Russo, M.D.
Clinical Child and Adult Neurologist
Clinical Assistant Professor of Medicine, University of Washington
Adjunct Associate Professor of Pharmacy, University of Montana
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"The earliest allusion to bhang's mind-altering influence is contained in the fourth book of the Vedas, the Atharvaveda ("Science of Charms"). Written some time between 2000 and 1400 B.C., the Atharvaveda (12:6.15) calls bhang one of the "five kingdoms of herbs... which release us from anxiety." But it is not until much later in India's history that bhang became a part of everyday life. By the tenth century A.D., for example, it was just beginning to be extolled as a indracanna, the "food of the gods". A fifteenth-century document refers to it as "light-hearted", "joyful", and "rejoices", and claims that among its virtues are "astringency", "heat", "speech-giving", "inspiration of mental powers", "excitability", and the capacity to "remove wind and phlegm"."

"By the sixteenth century A.D., it found its way into India's popular literature. The Dhurtasamagama, or "Rogue's Congress", a light farce written to amuse audiences, has two beggars come before an unscrupulous judge asking for a decision on a quarrel concerning a maiden at the bazaar. Before he will render his decision, however, the judge demands payment for his arbitration, In response to this demand, one of the beggars offers some bhang. The judge readily accepts and, tasting it, declares that "it produces a healthy appetite, sharpens the wits, and acts as an aphrodisiac".

"In the Rajvallabha, a seventeenth-century text dealing with drugs used in India, bhang is described as follows:

India's food is acid, produces infatuation, and destroys leprosy. It creates vital energy, increases mental powers and internal heat, corrects irregularities of the phlegmatic humor, and is an elixir vitae. It was originally produced like nectar from the ocean by churning it with Mount Mandara. Inasmuch as it is believed to give victory in the three worlds and to bring delight to the king of the gods (Siva), it was called vijaya (victorious). This desire-filling drug was believed to have been obtained by men on earth for the welfare of all people. To those who use it regularly, it begets joy and diminishes anxiety."

[G.A. Grierson, "On References to the Hemp Plant Occurring in Sanskrit and Hindi Literature", in Indian Hemp Drugs Commission Report (Simla, India: 1893-4), 3: 247-8.]

"The Atharva Veda of India mentions a sacred grass for anxiety, bhang, which remains a modern term for cannabis. Medical references to cannabis date to Susruta in the sixth to seventh centuries BCE. Dwarakanath ( 1965 ), described a series of Ayurvedic and Arabic traditional preparations containing the herb indicated for migraine, neuralgic and visceral pains. "

CANNABIS AND PAIN MANAGEMENT

The following article is an edited composite of a Policy Paper on Cannabis in Pain Treatment presented to the American Academy of Pain Management by Dr Ethan Russo, MD

Effective treatment of acute, chronic and intractable pain is a critically important public health concern in the world today. Despite a vast array of analgesic medicines including anti-inflammatory and opioid analgesics, countless patients continue to suffer the burden of unrelieved pain. Opiate addiction, and the recent OxyContin controversy underline the importance of newer effective and safe alternatives.

For over a century, international commissions have studied the issue of cannabis, and virtually uniformly recommended its decriminalization and provision for medical applications, specifically including the treatment of pain.

Cannabis has been employed as an analgesic for thousands of years, and was utilized in this country as well, particularly for neuropathic pain, prior to its effective removal from the American market 65 years ago. Historical cannabis supporters have included such physicians and scientists as Galen, Dioscorides, Parkinson, Linnaeus, Gowers, Weir Mitchell, Osler, Solomon Snyder, and many others. Cannabis remains a frequently employed ethno-botanical agent in pain management among indigenous peoples of the world.

Modern research on endogenous cannabinoids and the cannabinoid receptor system has demonstrated a scientific basis for the efficacy of synthetic and phytocannabinoids in pain management based on serotonergic, dopaminergic, Substance P, and glutamatergic mechanisms, interactions with the endogenous opioid system, as well as antioxidant and anti-inflammatory effects. These mechanisms have been demonstrated in both central and peripheral systems. Adjunctive effects of cannabis and cannabinoids on depression, anxiety, spasticity, tremor, nausea and anorexia also contribute to treatment benefits in chronic pain patients. Whole cannabis and its extracts provide an entourage of cannabinoids, terpenoids, and flavonoids that combine to create a synergy of benefits in holistic treatment of chronic and intractable pain.

Systematic examination of the toxicology and side effect profile of cannabis and cannabinoids on long-term cognitive, other nervous system, endocrine, hematological, and immunological function demonstrate little documentation of significant detrimental effects, and suggest a safety margin well within that of most prescription medicines. The sole area of demonstrable concern surrounds chronic pulmonary issues attendant with smoked cannabis. These problems are possibly avoidable with harm reduction techniques such as vaporization, and are totally so with alternative delivery methods such as sublingual or nebulized cannabis-based medicine extracts. Fears of cannabis-induced psychosis, addiction, and cognitive impairment and deterioration have been largely exaggerated.

Oral synthetic THC ( Marinol ), a synthetically derived THC dissolved in sesame oil, was developed by Unimed Pharmaceuticals. It is available in capsules of 2.5, 5 and 10 mg and is marketed in the USA, Canada, Australia, and some areas in Europe, and has proven quite disappointing as a pain management tool. Cannabis proper, and a variety of synthetic agents are in various stages of clinical investigation. Development and FDA approval of synthetic cannabinoids will require many years. In contrast, cannabis-based medicine extracts have proven safe and effective in a large variety of pain conditions, and are expected to attain governmental regulatory approval in the UK, Western Europe and Canada within a very short time.

The History of Cannabis in Pain Management

Traditional knowledge of cannabis in China may span 5000 years, dating to the legendary emperor, Shen-Nung. Julien ( 1849 ) wrote of the physician Hoa-tho in the early 2nd century and his use of a cannabis extract in anesthesia for major surgical procedures.

The Atharva Veda of India ( dating to between 1400 and 2000 BCE ) mentions a sacred grass for anxiety, bhang, which remains a modern term for cannabis. Medical references to cannabis date to Susruta in the sixth to seventh centuries BCE. Dwarakanath ( 1965 ), described a series of Ayurvedic and Arabic traditional preparations containing the herb indicated for migraine, neuralgic and visceral pains.

Similar proof of the medicinal use of cannabis exists in records and artifacts from ancient Egypt, Assyria, Israel/Palestine/Judea, and the Greek and Roman Empires.

In common use throughout the Medieval world and Renaissance Europe, the medical use of cannabis, or "Indian hemp" was reintroduced to the West by O'Shaughnessy ( 1838-1840 ). His treatise on the subject dealt with the apparent utility of a plant extract administered to patients suffering from rabies, cholera, tetanus, infantile convulsions, but also a series of painful rheumatological conditions. Of particular note, even patients that succumbed to their illnesses were greatly relieved by cannabis with convincing palliative benefits.

Shortly thereafter in England, Clendinning ( 1843 ) described his results of treatment of 18 patients: 3 with headaches, one with abdominal pain secondary to tumor, one with pain secondary to a laceration, two with rheumatic joint pain, and one with gout. In each case, the tincture of Indian hemp provided relief, even in cases of morphine withdrawal symptoms.

In Ireland, Donovan ( 1845 ) extensively described his own extensive trials with small doses of cannabis resin, mainly in patients with various types of neuropathic and musculoskeletal pain. Effects were almost uniformly impressive, with few side effects. He also described the benefits of local application of hemp leaf oil on hemorrhoids and neuralgic pains.

Over the next decades, numerous authorities recognized cannabis as helpful for painful conditions. Sir John Russell Reynolds was eventually to become Queen Victoria's personal physician. He successfully treated her dysmenorrhea with a cannabis extract throughout her adult life ( Reynolds 1868 ) and used it extensively to treat migraine and neuropathic pain.

Hobart Hare ( 1887 ): I have found the efficient dose of a pure extract of hemp to be as powerful in relieving pain as the corresponding dose of the same preparation of opium... During the time that this remarkable drug is relieving pain a very curious psychical condition sometimes manifests itself; namely, that the diminution of the pain seems to be due to its fading away in the distance, so that the pain becomes less and less, just as the pain in a delicate ear would grow less and less as a beaten drum was carried farther and farther out of the range of hearing.

In the French literature, See ( 1890 ) submitted a detailed report on use of cannabis in the treatment of various disorders producing gastric and intestinal pain, and found it preferable in efficacy and side effects to opiates and bismuth.

Suckling ( 1891 ) noted the ability of cannabis to allow migraine sufferers to return to work.

An American drug handbook stated the following: ( Lilly, 1898 ) "Antispasmodic, analgesic, anesthetic, narcotic, aphrodisiac. Specially recommended in spasmodic and painful affections."

Hare ( 1922 ) still advocated use of cannabis noting "For the relief of pain, particularly that depending on nerve disturbance, hemp is very valuable."

An editor of the Journal of the American Medical Association, as late as 1930 noted the ability of cannabis to achieve a labor with pain burden substantially reduced or eliminated, followed by a tranquil sleep ( Anonymous 1930 ) without sequelae.

Despite its political disenfranchisement, Fishbein ( 1942 ) still advocated oral preparations of cannabis in treatment of menstrual ( catamenial ) migraine.

Cannabis remained in the British armamentarium somewhat longer, and was extolled above opiates and barbiturates in the treatment of the pain of hospitalized patients with duodenal ulcers ( Douthwaite, 1947 ).

In Tashkent in the 1930's, cannabis or nasha was employed medicinally, despite Soviet prohibition ( Benet 1975 ) for headache and pain of defloration. In Southeast Asia, cannabis remains useful ( Martin 1975 ). Everywhere it is considered to be of analgesic value, comparable to the opium derivatives. Moreover, it can be added to any relaxant to reinforce its action. Cooked leaves, which have been dried in the sun, are used in quantities of several grams per bowl of water. This decoction helps especially to combat migraines and stiffness.

In a book about medicinal plants of India ( Dastur, 1962 ) Charas [hashish] --- is a valuable narcotic, especially in cases where opium cannot be administered; it is of great value in malarial and periodical headaches, migraine, acute mania, whooping cough, cough of phthisis, asthma, anaemia of brain, nervous vomiting, tetanus, convulsion, insanity, delirium, dysuria, and nervous exhaustion; it is also used as an anaesthetic in dysmenorrhea, as an appetizer and aphrodisiac, as an anodyne in itching of eczema, neuralgia, severe pains of various kinds of corns, etc.

In Colombia the analgesic effects of a cannabis tincture were lauded ( Partridge 1975 ) "the knowledge that cannabis can be used for treatment of pain is widespread." Rubin documented extensive usage of cannabis in Jamaica for a variety of conditions ( Rubin, 1976; Rubin and Comitas, 1972 ), including headache.

In Brazil, Hutchinson ( 1975 ) "Such an infusion [of leaves] is taken to relieve rheumatism, "female troubles", colic and other common complaints. For toothache, marijuana is frequently packed into and around the aching tooth and left for a period of time, during which it supposedly performs an analgesic function".

Cannabis and Cannabinoids as Medicine.

Cannabis Proper Cannabis is traditionally employed therapeutically by smoking or ingestion. Grotenhermen has produced an excellent summary of "Practical Hints" ( Grotenhermen, 2002 ), as have Brazis and Matthre ( 1997 ) and Russo ( 2002 ).

Dosing of therapeutic cannabis must be titrated to the patient's need. In general, 5 mg of THC content represents a threshold dose for noticeable effects in the average adult ( Grotenhermen 2002 ). Whereas tolerance to cardiovascular effects ( tachycardia ) and psychoactive effects ( "high" ) are achieved after some days to weeks of chronic usage, observed clinical and "anecdotal" reports support retention of analgesic efficacy over the long term. Occasionally, upwards dose titration is necessary, as is true for any agent.

Allergies to cannabis are rare, although some may experience rhinitis symptoms, particularly when exposed to the smoke of the unrefined product. People employing cannabis therapeutically must be warned of the usual caveats assigned to any potentially sedative drug: due care with operation of machinery, motor vehicles, etc., which are analogous to the industry warnings for Marinol® ( synthetic THC ).

Acute over-dosages of cannabis are self-limited, and most frequently consist of panic reactions. These are uniquely sensitive to reassurance ( "talking down" ) and are quite unusual once a patient becomes familiar with the drug. Cannabis has a unique distinction of safety over four millennia of analgesic usage: No deaths due to direct toxicity of cannabis have ever been documented in the medical literature.

Some cannabis-drug interactions are apparent, but are few in number. Additive sedative effects with other agents, including alcohol, may be observed. Similarly however, additive or synergistic anti-emetic and analgesic benefits may accrue when combining dopamine agonist neuroleptics and cannabis ( Carta, Gessa, and Nava 1999 ). Cannabis may accelerate metabolism of theophylline, while slowing that of barbiturates. Anticholinergic-induced tachycardia may be accentuated by cannabis, while this effect is countered by beta-blockers ( Grotenhermen 2002 ). Indomethacin seems to reduce slightly the psychoactive and tachycardic effects of cannabis ( Perez-Reyes et al. 1991 ). As discussed above, synergistic analgesic benefits may accrue with concomitant usage of cannabis and opioids ( Cichewicz et al. 1999; Hare 1887 ). CBD is a powerful inhibitor of cytochrome P450 isozymes 3A4, 2C19, and 2D6 ( Bornheim et al. 1994; Bornheim and Grillo 1998 ) indicating the need for caution in cannabis patients taking that component in conjunction with fentanyl, sildenafil ( Viagra® ), tricyclic antidepressants and anti-arrhythmic drugs.

Crude cannabis contains most of its THC in the form of delta-9-THC acids that must be decarboxylated by heating to be activated. This occurs automatically when cannabis is smoked, whereas cannabis that is employed orally should be heated to 200-210šC. for 5 minutes prior to ingestion ( Brenneisen 1984 ).

Contrary to disseminated propaganda in the USA, average cannabis potency has varied little over the last 3 decades ( ElSohly et al. 2000; Mikuriya and Aldrich 1988 ). It is true that the maximum potency has increased through applied genetics, cultivation and harvesting techniques. This goal is achieved through production of clonal cultivation of the preferred female plants and maximization of the yield of unsterilized flowering tops known as sinsemilla ( Spanish for "without seed" ). In this manner a concentration of glandular trichomes where THC and therapeutic terpenoids are produced is effected. Resultant yields of THC may exceed 20% by weight. This is potentially advantageous, particularly when smoked, because a therapeutic dosage of THC is obtained with fewer inhalations, thereby decreasing lung exposure to tars and carcinogens. As noted by Professor Wayne Hall ( Lords 1998 ).

Indeed, it is conceivable that increased potency may have little or no adverse effect if users are able to titrate their dose to achieve the desired state of intoxication. If users do titrate their dose, the use of more potent cannabis products would reduce the amount of cannabis material that was smoked, thereby marginally reducing the respiratory risks of cannabis smoking.

A considerable concentration of THC, other cannabinoids and terpenoids may also be achieved through some simple processing of crude dried cannabis. Techniques for sieving or washing of cannabis to isolate the trichomes to produce hashish are well described ( Clarke 1998; Rosenthal, Gieringer, and Mikuriya 1997 ), and may produce potential yields of 40-60% THC. Clarke demonstrates a simple method of rolling the resultant powdery material into a joint of pure hashish, termed "smoking the snake" ( Clarke 1998 ), providing a relatively pure product for inhalation.

Cultivation techniques are beyond the scope of this review, but emphasis should focus on potent medicinal strains, scrupulous organic cultivation of female plants, clonal selection and augmentation, and appropriate processing with a high degree of quality control throughout the process. It deserves emphasis that clinical cannabis patients benefit from consistent quality and dosing. This is extremely difficult to achieve on a practical basis, unless cloned cannabis strains or standardized extracts are employed. Additionally, although cannabis is often touted as relatively "pest-free," it is subject to predation by a number of insects, bacteria, viruses, fungi, etc. ( McPartland, Clarke and Watson 2000 ).

Cannabis strains in the USA are THC predominant, almost uniformly devoid of CBD content ( Gieringer 1999 ). While this may be appropriate for certain medical conditions, patients with concomitant muscle spasm, anxiety, seizure disorders, or susceptibility to psychoactive effects may not achieve optimal results.

The labor required to manage cannabis genetics, culture, maintenance of "organic" technique without contamination, processing and quality control are likely beyond the ken and capabilities of most patients, particularly those with chronic pain.

It remains the case that smoked cannabis is a crude delivery system with some inherent respiratory risk. This fact, taken with the inability to develop smoked cannabis into an FDA-approved medicine in the USA, makes the development of alternative rapid-delivery cannabis-based systems mandatory.

Oral Use of Cannabis

A variety of issues attend oral cannabis administration. The most important concerns bioavailability. Oral absorption of cannabinoids is slow and erratic at best, often requiring 30-120 minutes. In HIV positive or chemotherapy patients and in acute migraine, nausea and emesis may preclude oral usage altogether. Additionally, oral THC is subject to the "first pass effect" of hepatic metabolism yielding 11-hydroxy-THC, considerably more psychoactive than THC itself. Thus, some patients become 3too high2 even on low doses of medicine, such as 2.5 mg of THC as dronabinol.

Advantages of oral usage are its avoidance of lung exposure in those who are immunosuppressed or have impaired pulmonary function, and its prolonged half-life. This may be of advantage for nocturnal complaints where sedation is less of an issue.

Grotenhermen suggests dose titration beginning with the equivalent of 2.5 mg of oral THC bid with increases as needed and tolerated ( Grotenhermen 2002 ). Most painful clinical conditions require tid dosing of cannabis.

THC, CBD and terpenoids are all highly lipophilic. Gastrointestinal absorption is markedly enhanced by inclusion of lipids in the cooked preparations. Therapeutic tincture extraction in alcohol is also possible.

Smoked Cannabis

Techniques of smoking cannabis are legion. Pharmacodynamically, smoking would be an ideal method of application of clinical cannabis, but for the attendant pulmonary issues. Clinical effects are noted within seconds to minutes after smoking. Inhalation avoids the first pass effect that hampers oral use, and allows effective dosage titration. When symptoms return, repeat dosage is achieved quickly and easily. Overdosage is frequently avoidable.

Traditional smoking techniques in the USA make prolonged holding of a marijuana "toke" de rigueur. From a dose-response standpoint, this is unnecessary. Inhaled THC is well absorbed after a very brief interval, and subjective high and serum THC levels do not increase beyond a maximum 10-second inhalation. Furthermore, prolonged breath holding under pressure increases the potential for hypoxia or pneumothorax.

Contamination of herbal cannabis by pesticides, herbicides, and bacterial or fungal agents is possible, and may represent a threat to the smoker, especially immunosuppressed patients. Scrupulous cultivation techniques avoid some of these issues. McPartland recommends pasteurization of herbal cannabis by heating in an oven of 150C. for 5 minutes ( McPartland 2001 ).

Waterpipes and bongs are popular techniques for cooling smoke. While they may reduce particulate matter as well, THC content and pharmaceutical efficiency also seem to be compromised. Surprisingly, the unfiltered "joint" seems to represent the most efficient means for conventional smoking, although use of hashish in a pipe ( without tobacco ) was not examined.

Vaporizers for Cannabis Administration

Vaporization of herbal cannabis may allow delivery of THC and terpenoid components below the flash point of the leaf, thereby reducing exposure to smoke, tar and carcinogens. The technology has been hampered in its development by paraphernalia laws. Initial investigations of available devices had disappointing results, but further studies have demonstrated promising benefits on avoidance of carcinogenic components from smoking ( Gieringer 2001 ). Research continues.

Sublingual Tincture of Cannabis

This method of administration is under investigation by GW Pharmaceuticals in the United Kingdom employing combinations of specific strains of cannabis that are rich in THC or CBD. Terpenoids and other minor components that are important to therapeutic effects of cannabis are retained. Dose-metered sublingual sprays are currently in Phase 2 and 3 clinical trials for a variety of indications. Initial results indicate good bioavailability and excellent patient tolerance and clinical effects. Painful conditions have been of particular note in this research.

Aerosol THC Preparations

Cannabis has a long history of use in asthma, even as a smoked preparation. A pure THC aerosol has been attempted numerous times in the past. Physical and delivery issues have been challenging, but more interestingly, pure THC seems to have an irritating and even bronchoconstrictive effect when employed in isolation ( Tashkin et al. 1977 ). Some authors believe that anti-inflammatory effects of concomitant terpenoid and flavonoid administration are necessary for full effects and tolerance in pursuit of the pulmonary route. Further research is underway by GW Pharmaceuticals, Inhale Therapeutic Systems, and possibly others.

Marinol ( dronabinol, synthetic THC )

Marinol is a synthetically derived THC dissolved in sesame oil, developed by Unimed Pharmaceuticals. It is available in capsules of 2.5, 5 and 10 mg and is marketed in the USA, Canada, Australia, and some areas in Europe. Until 1999, Marinol was a Schedule II drug in the USA with close scrutiny to its usage, which was restricted to indications of AIDS-associated anorexia and cancer chemotherapy. After safety studies revealed a low potential for abuse or diversion, dronabinol was "down-scheduled" to Schedule III in 1999, allowing refill prescriptions for up to 6 months, and its "off-label" administration for any indication. Clinicians have utilized Marinol to only a limited degree. Its bioavailability is only 25-30% of an equivalent smoked dose of THC ( Association 1997 ). Additional problems include the first pass effect of hepatic metabolism, which results in the production of a more psychoactive metabolite 11-hydroxy-THC, and its considerable cost, which may exceed US $600 per month for the lowest dosage of 2.5 mg tid. Considerable anecdotal data supports preference by patients of smoked cannabis over dronabinol.

Nabilone

Nabilone is a synthetic cannabinoid said to be pharmacologically similar to THC, but more potent, less apt to produce euphoria, and possessing lower "abuse potential" ( Association 1997 ). It is produced by Eli Lilly Company as Cesamet and is available in the UK, Canada, Australia and certain countries in Europe as an agent for nausea in chemotherapy. Some scattered reports have noted benefit on spasticity in MS, and effects on dyskinesias.

A group in the UK assessed analgesic effects of nabilone in patients including some with neuropathic pain ( Notcutt, Price, and Chapman 1997 ). Side effects of drowsiness and dysphoria were troubling. Several patients claimed improved pain relief and fewer side effects with smoked cannabis and preferred it to this legal alternative. Nabilone's cost was also estimated to be 10 times higher than cannabis even at black market rates.

Future Directions and Needs

Future directions for research on cannabis and cannabinoids will be primarily determined by political factors. Studies with smoked cannabis in the USA will continue under constraints imposed by NIDA: limited access to low potency smoked marijuana with rigorous oversight. Such studies may have limited applicability to the actual potential of true medical-grade cannabis or cannabis-based medicine extracts.

Herbal cannabis as a smoked medicine will never fulfill FDA guidelines to become a prescription medicine. Such a process requires absolute standardization of constituents, rigorous quality control, bacteriological purity, safety, reliability, reproducibility, and uniform dose titration. In contrast cannabis-based medicine extracts, whether employed sublingually or via aerosol, can easily meet this burden and will likely achieve market approval in Europe and Canada within months.

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DR. RUSSO'S FINDINGS AND POLICY RECOMMENDATIONS

1 ) Cannabis has a long and documented history in the treatment of neuropathic, musculoskeletal, spasmodic, and inflammatory pain conditions. Cannabis has a historical role as a palliative agent in terminal patients

2 ) Additional adjunctive antidepressant and anti-anxiety properties of cannabis, as well as its anti-spasticity, and appetite stimulatory effects offer important therapeutic value in pain management patients.

3 ) Modern pharmacological and receptor studies of cannabis and cannabinoids support therapeutic claims.

4 ) Cannabinoids represent an important parallel system to the endogenous opioid system of pain modulation, and administration of cannabinoids can effectively synergize opioid responses while mitigating side effects. Cannabinoids show unique promise in treatment of neuropathic pain.

5 ) Historically, governmental commissions have almost uniformly recommended allowance or provision of cannabis for medical indications including pain.

6 ) Financial investment in research into cannabis and cannabinoid strategies for pain management are deserving of support by medical and governmental organizations.

7 ) Current research supports the contention that no single agent will ever possess the spectrum of synergistic activity of whole cannabis.

8 ) Alternative delivery systems for whole cannabis and especially its standardized extracts represent the logical methods for administering this medicine to pain patients.

9 ) These practical and effective methods of cannabis administration ( sublingual and inhaled CBME ) in painful conditions are available now in other countries with imminent licensure. Government agencies should expedite efforts to provide comparable access to rapid onset alternative methods of delivery of standardized cannabis-based medicine extracts to deserving patients, or, alternatively until their approval, re-open the Compassionate Use IND, with the availability of potent, well manicured sterilized cannabis. I believe that the USA should provide expedited access to cannabis-based medicine extracts and appropriate synthetic cannabinoids by patients with pain conditions, or, re-open the Compassionate Use Investigational New Drug ( IND ) program to provide potent, well-manicured medicinal-grade cannabis to chronic pain patients.

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