Δ9-Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors

Background and purpose:
It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage. In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB1) agonist, Δ9-tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil.
Experimental approach:
The effects of AM 404 (0.015–2x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1) and THC (0.05–2x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1), given 5x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmin after ischaemia, were measured from 1x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsh to 7 days in terms of electroencephalographic (EEG) total spectral power, spontaneous motor activity, memory function, rectal temperature and hippocampal CA1 neuronal count.
Key results:
Over the dose range tested, AM 404 (2x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1) and THC (1x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1) completely reversed the ischaemia-induced behavioural, EEG and histological damage. Only THC (1 and 2x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1) induced a decrease of body temperature. Pretreatment with the selective CB1 receptor antagonist, AM 251 (1x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1) and the opioid antagonist, naloxone (2x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1) reversed the protective effect induced by both AM 404 and THC while the TRPV1 vanilloid antagonist, capsazepine (0.01x2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorsmgx2009 Δ9 Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptorskg−1), was ineffective.
Conclusions and implications:
Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB1 and opioid receptors. Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies.

Are oral cannabinoids safe and effective in refractory neuropathic pain?

Although cannabinoids have anti-hyperalgesic e.ects in animal models of nerve injury, there are currently very few prospective trials of the efficacy of cannabinoids in neuropathic pain in humans. This open label prospective study investigated the safety, tolerability and analgesic benefit of oral delta-9-tetrahydrocannabinol (THC) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain. Spontaneous ongoing and paroxysmal pain, allodynia and paresthesias were assessed. The sensory and affective components of pain using the McGill pain questionnaire, quality of life, mood, anxiety and functionality were also evaluated. Seven patients suffered from side effects necessitating premature arrest of the drug in 5 of them. THC (mean dosage: 16.6±6.5 mg/day) did not induce any significant effects on ongoing and paroxysmal pain, allodynia, quality of life, anxiety/depression scores and functional impact of pain. These results do not support an overall benefit of THC in pain and quality of life in patients with refractory neuropathic pain.

Antinociceptive effect of cannabinoid agonist WIN 55,212–2 in rats with a spinal cord injury

Spinal cord injury (SCI) pain exhibits many symptoms associated with peripheral neuropathic pain, including increased tactile hypersensitivity. One novel approach to ameliorate SCI pain is the use of cannabinoid (CB) ligands. The current study evaluated the efficacy of the nonselective CB receptor agonist WIN 55,212–2 on tactile hypersensitivity in rats following a brief compression to the thoracic spinal cord. The withdrawal thresholds of the hind paws following SCI were significantly decreased, indicating tactile hypersensitivity. Systemic injection of WIN 55,212–2 increased withdrawal thresholds in a dose-dependent manner. Pretreatment with the CB1 receptor subtype-selective antagonist AM 251 completely abolished the antinociceptive effect of WIN 55,212–2 whereas pretreatment with the CB2 receptor subtype-selective antagonist AM 630 did not alter the antinociceptive effect of WIN 55,212–2. These data indicate that a CB1 selective agonist may be novel therapeutic treatment for clinical SCI pain.

Role of cannabinoids and endocannabinoids in cerebral ischemia

The human costs of stroke are very large and growing; it is the third largest cause of death in the United States and survivors are often faced with loss of ability to function independently. There is a large need for therapeutic approaches that act to protect neurons from the injury produced by ischemia and reperfusion. The goal of this review is to introduce and discuss the available data that endogenous cannabinoid signaling is altered during ischemia and that it contributes to the consequences of ischemia-induced injury. Overall, the available data suggest that inhibition of CB1 receptor activation together with increased CB2 receptor activation produces beneficial effects

Clinical investigation of delta-9-tetrahydrocannabinol (THC) as an alternative therapy for overactive bladders in spinal cord injury (SCI) patients.

We are presenting the preliminary results of a pilot study. THC was administered over a period of 6 weeks. In 15 patients with spastic spinal cord injury the effect of THC on the overactive bladder has been investigated. The effect of THC was compared with urodynamic and clinical parameters, first without any bladder medication and after 6 weeks medication with THC. There are no data of invasive investigation in literature up till now.
Patients and methods:
THC was administered for 6 weeks in two different groups orally as Dronabinol (Marinol®) in 9 patients and rectally as THC-Hemisuccinate suppositories (THC-HS-supp) in 6 patients in several individual dosages per day. An urodynamic investigation, urine analysis and urine bacteriology was performed at the beginning of the study (without any bladder medication and without any spasmolytic therapy) and in the end after 6 weeks treatment. On the last day of medication all patients have been administered either 10 mg Dronabilon or 10 mg THC-HS-supp 2 h before the urodynamic investigation (relating to the group they were in).
Investigated parameters: first desire to void (FDV), maximum cystometric capacity (MCC), intravesical pressure (IVP), bladder compliance (CPL), post void residual urine volume (RV), volume at first detrusor contraction (VFC).
Results:
The dronabinol group showed an increase of the CPL from mean 34.3 ml/cm H2O (9 – 100) to mean 52.2 ml/cm H2O (11 – 200). All other parameters have not been changed essentially.
The THC-HS-supp group showed a trend with increase of MCC from mean 227 ml (143 – 323) to mean 278 ml (121 – 322) (p value = 0.075), and an increase of the VFC from mean 191.3 ml (121 – 322) to mean 224.6 ml (96 – 407), CPL increased from mean 21.3 ml/cm H2O (6 – 60) to mean 40 ml/cm H2O (10 – 120) significantly
(p value = 0.028). All other parameters have not been changed essentially.
Conclusion:
These preliminary results indicate a reduction of the overactivity of the detrusor of the bladder especially in the THC-HS-supp group with potential therapeutic consequences. The different results between oral and rectal application may demonstrate their different bioavailability.

The treatment of spasticity with D9-tetrahydrocannabinol (D9-THC) in patients with spinal cord injury

Introduction:
Spasticity is a common complaint after traumatic SCI. 9–THC the main psychoactive cannabinoid of cannabis has been shown to have beneficial effects in the treatment of spasticity of different origin. The aim of the study was to assess the effectiveness and safety of 9–THC (Dronabinol, Marinol® capsules) and THC-hemisuccinate suppositories (THC-HS) for the treatment of spasticity in patients with SCI as a homogeneous population of patients. We are presenting the results of spasticity as partial results of a finished study with a wide spectrum of other investigations.

Methods:
Phase 1: open trial, six weeks treatment of 22 patients with Dronabinol (7 drop outs)
Phase 2: open trial, six weeks treatment of 8 patients with THC-HS (1 drop out)
Phase 3: randomized, double-blind, placebo controlled clinical trial with 13 patients (Marinol/placebo)
25 patients mean age 42.3 years with spasticity due to SCI (11 para- and 14 tetraplegics) were included. Mean time since injury was 13.4 years. Inclusion criteria for spasticity were minimum of 3 points on the Ashworth scale without therapy, negative urine drug screening, age > 18 years.
Spasticity was investigated using the modified Ashworth scale (MAS) after administration of 10 mg Dronabinol (Marinol®) or 10 mg THC-HS at day one and after one and six weeks treatment with an individual dose. Self-rating of spasticity was performed every day using a seven point scale from absent to unbearable.

Results:
Phase 1: Dronabinol (Marinol®) significantly decreased the mean spasticity sum score (± SD) (summed Ashworth scores divided by four) in 15 patients after a single dose of 10 mg (day 1) from 16.72 ± 7.60 to 7.75 ± 7.00 points (p<0.001) and after 6 weeks of treatment with an individual symptom oriented mean dose of 30 mg Dronabinol to 8.92 ± 7.14 points (p<0.05).
Phase 2: THC-HS significantly decreased the mean spasticity sum score (± SD) in 7 patients after a single dose of 10 mg (day 1) from 22.71 ± 11.68 to 9.86 ± 8.15 points (p<0,05) and after 6 weeks of treatment with an individual symptom oriented mean dose of 43 mg THC-HS to 9.21 ± 9.25 points (p<0.05).
The comparison of oral and rectal application in five patients showed no difference.
Phase 3: summed spasticity scores for the Dronabinol group (7.21 points) differed significantly from summed scores of the placebo group (12.10 points) as a treatment effect of Dronabinol during the entire 6 weeks (p=0.001).

Conclusion:
The results demonstrate a significant therapeutic effect of &#61508;9–THC (Dronabinol, Marinol ®) as well as THC-HS in patients with SCI. However the antispastic efficacy is significant the treatment often is limited by side effects.

Acknowledgement:
The research was supported by ElSohly Laboratories Inc., Oxford, Mississippi

Are oral cannabinoids safe and effective in refractory neuropathic pain?

Although cannabinoids have anti-hyperalgesic e.ects in animal models of nerve injury, there are currently very few prospective trials of the efficacy of cannabinoids in neuropathic pain in humans. This open label prospective study investigated the safety, tolerability and analgesic benefit of oral delta-9-tetrahydrocannabinol (THC) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain. Spontaneous ongoing and paroxysmal pain, allodynia and paresthesias were assessed. The sensory and affective components of pain using the McGill pain questionnaire, quality of life, mood, anxiety and functionality were also evaluated. Seven patients suffered from side effects necessitating premature arrest of the drug in 5 of them. THC (mean dosage: 16.6±6.5 mg/day) did not induce any significant effects on ongoing and paroxysmal pain, allodynia, quality of life, anxiety/depression scores and functional impact of pain. These results do not support an overall benefit of THC in pain and quality of life in patients with refractory neuropathic pain.

The Use of Cannabis as a Mood Stabilizer in Bipolar Disorder: Anecdotal Evidence and the Need for Clinical Research

The Use of Cannabis as a Mood Stabilizer in Bipolar Disorder: Anecdotal Evidence and the Need for Clinical Research
Lester Grinspoon, M.D. & James B. Bakalar
Published in Journal of Psychoactive Drugs, Volume 30 (2), April – June 1998, pp. 171-177.

Abstract-The authors present case histories indicating that a number ofpatients find cannabis (marihuana) useful in the treatment of their bipolardisorder. Some used it to treat mania, depression, or both. They stated thatit was more effective than conventional drugs, or helped relieve the sideeffects of those drugs. One woman found that cannabis curbed her manicrages; she and her husband have worked to make it legally available as amedicine. Others described the use of cannabis as a supplement to lithium(allowing reduced consumption) or for relief of lithium’s side effects.Another case illustrates the fact that medical cannabis users are in dangerof arrest, especially when children are encouraged to inform on parents bysome drug prevention programs. An analogy is drawn between the status ofcannabis today and that of lithium in the early 1950s, when its effect onmania had been discovered but there were no controlled studies. In the caseof cannabis, the law has made such studies almost impossible, and the onlyavailable evidence is anecdotal. The potential for cannabis as a treatmentfor bipolar disorder unfortunately cannot be fully explored in the presentsocial circumstances.
[EDITOR'S NOTE: The following article is based in part on materials thatappear in the revised and expanded edition of the authors' book, Marihuana,The Forbidden Medicine, republished in 1997 by Yale University Press, NewHaven and London. While the interviews have previously appeared in print,they provide a reference point for the authors' discussion of cannabis'potential role in the treatment of bipolar disorder as it appears in thistheme issue. In their revised and expanded book, Grinspoon and Bakalardiscuss a wide range of what they refer to as "Common Medical Uses" and"Less Common Medical Uses" for cannabis. The former include treatment forthe nausea and vomiting of cancer chemotherapy, glaucoma, epilepsy, themuscle spasms of multiple sclerosis, paraplegia and quadriplegia, the weightloss syndrome of AIDS, chronic pain, migraine, rheumatic diseases, pruritus,PMS, menstrual cramps and labor pains, depression and other mood disorders.The latter include treatment for asthma, insomnia, antimicrobial effects,topical anesthetic effects, antitumoral effects, dystonias, adult ADD,schizophrenia, systemic sclerosis, Crohn's disease, diabetic gastroparesis,pseudotumor cerebri, tinnitus, violence, PTSD, phantom limb pain, alcoholismand other addictions, terminal illness and aging.]

In bipolar or manic-depressive disorder, major depression alternates withuncontrollable elation, or mania. Symptoms of depression include loss ofinterest and pleasure in life, sadness, irrational guilt, inability toconcentrate, appetite loss, lethargy, and chronic fatigue. Manic symptomsinclude sleeplessness, tirelessness (until exhaustion leads to a breakdown),and recklessly gregarious and expansive behavior, which sometimes turns toirritability, rage and paranoid delusions. Bipolar disorder is treatedmainly with lithium salts and anticonvulsant drugs, which can have seriousside effects. Thirty percent to 40% of patients with bipolar disorder arenot consistently helped by or cannot tolerate standard medications. In thecourse of the authors’ studies of the medical uses of cannabis (Grinspoon &Bakalar 1997), a number of sufferers were discovered who believed marihuanato be more effective than conventional anti-manic drugs, or who used it torelieve the side effects of lithium.

Our first account was written by a 47-year-old woman:

I was born on Friday, October 13, 1950, a few months before my father hadhis first serious bout with manic depression. My mother said he was takingvaluable art objects they owned and throwing them down the trash chute intheir New York apartment building.

I enjoyed my youth with a great deal of abandon. How much of this would bemood disorder I could not tell you. As a single person I didn’t notice; Ijust rode the waves of emotional highs and lows and didn’t think much aboutit. I was an old pro at this by the time I was 19 and met my husband. It wasonly through my association with him that I came to terms with my moodproblems, although right before I met him I had checked myself in at amental health clinic complaining that I sometimes felt unable to concentrateon one thing at a time.

I think I was 22 years old when my troubles cropped up again. At one pointmy husband and I went to see a psychologist. We talked about my mood swingsand spells of nervousness, anger, and depression. The tiniest negative thinghappening would cause long-lasting rage, very hard to quell. We told thepsychologist of my father’s history, even longer and grislier by then. Hemust have been in every state mental institution along the East Coast. Mygrandmother, his mother, was wasting away by this time, losing her lifelongbattle with chronic depression. I don’t know much about her case except thatshe was chronically sad and starved herself to death after her husbandpassed away.

This man said my husband and I needed to lose weight; that was the extent ofhis advice. We did not see him much longer. By this time I was experiencingmost of the symptoms I have today, although they have strengthened year byyear. Sometimes I feel elated, exhilarated, with a great deal of energy. Itsounds great, but you can get to be feeling so good that you scare thepeople around you, believe me! This is accompanied by light sleeping andnocturnal habits. I tend to become angry or aggressive when it is notappropriate, or just talk too loud. I often have a low self-image or feelsad. I sometimes have a hard time getting up to work, a heaviness that keepsme from moving. I get racing thoughts that make concentration hard. I havestrong emotions that change rapidly. I tend to be physically clumsy. Idevelop unexplained skin rashes, and sometimes feel like I’m generatingelectricity and shooting it out my fingers and toes. My judgment is oftenpoor.

It was in my early twenties that I first used cannabis for my condition. Ihad been exposed to it several times, the first when I was quite young. Mymother had taken me to a mental health center after my initial signs oftrouble as a child. After a group therapy session there, some of the otherkids took me riding and gave me a joint. Nothing at all happened, and Iconcluded it must be a mild drug.

When I was exposed to it later, I would actually choose it over alcoholbecause it didn’t have such strong and negative effects on me. This is how Idiscovered that it was effective against most of my symptoms. Suppose I amin a fit of manic rage-the most destructive behavior of all. A few puffs ofthis herb and I can be calm. My husband and I have both noticed this; it isquite dramatic. One minute out of control in a mad rage over a meaninglessdetail, seemingly in need of a strait jacket, and somewhere, deep in mymind, asking myself why this is happening and why I can’t get a handle on myown emotions. Then, within a few minutes, the time it takes to smoke a fewpinches-why, I could even, after a round of apologies, laugh at myself!

But this herb is illegal and I have a strong desire to abide by the law. Myfather was having great success with a new drug, lithium carbonate. I saw myfather’s physician and he recommended that I try it. I took lithium for sixmonths and experienced several adverse side effects: shaking, skin rashes,and loss of control over my speech. But I would still be taking it if it hadworked for me as it did for my father. It literally restored his life. I hadgotten worse, if anything.

The combination of lithium side effects and increased manic depressivesymptoms drove me back to the use of cannabis. Some years later I tried togo without it again, this time because of increased social pressure againstillegal drug use. It was a very difficult time for my family. Whenever Istarted to become manic, my husband and son would get scared and cower,triggering rage and making matters worse. When depression struck it was ablack funk on our household. And I can tell you from the experience with myfather that this can really destroy a family. After a while the knowledgethat a little bit of marihuana would help me so much became irresistible. Atfirst I tried eating cannabis, but soon returned to smoking because I couldcontrol the dose better.

I don’t at all consider myself a drug abuser. I am doing what any rationalperson in my position would do. Cannabis does not cure my condition and overthe years it has probably continued to worsen. But with judicious use ofthis medicine my life is fine. I can control things with this drug thatseems so harmless compared to the others I’ve tried, including tranquilizersas well as lithium. I am constantly concerned that I will be cut off from mysupply of marihuana or caught with it in my possession. I feel my sanity maydepend on it. Cannabis lessens what is troubling me and returns me to a morenormal state. Often I do not experience a “high” at all, just a return tonormal.

This patient’s husband bears witness to the usefulness of cannabis:

I’ve been mates with my full-blown manic-depressive (M-D) wife for 26 years.Her father was the classic, well-studied and well-written-aboutmanic-depressive, and she’s the one who inherited it. She’s lovely, and asI’ve always truthfully told her, she has the perfect personality, blemishedonly by M-D.

I’ve always been smooth-sailing. Smoking marihuana only makes me sleepy. Inever use it. She requires it, or, I swear she’d be institutionalized justlike her father. There wouldn’t be any other way.

We’ve tried Marinol [dronabinol]. It works for her too, but to get the sameeffect as marihuana she must take 10 mg about six times a day, which costsabout $65 a day. What’s worse is that it takes forty-five minutes to engageand tapers off within two hours maximum. Timing of capsule ingestion must beexact or the symptoms can print through. Marihuana [smoked] lasts a littlelonger and is smoother, and, most importantly takes effect quickly.

What does marihuana do for my wife? It “recenters” her personality and herinteraction with the immediate family moves back into a normal range-nohighs, no lows, at least not the highs and lows that are abnormally extremeand that you can tell are from a crazy person with active M-D. Narcolepticdrugs really “zone” her out, like a temporary lobotomy in a medicine bottle.Marihuana never does that! It normalizes, that’s all. If there’s anoverdose, which is rare, it’s not dangerous and is very short.

Yesterday we went downtown (one and a half hour’s drive one way). However,going several hours without the medicine can be quite calamitous. The worstkind of getting along badly ensued. That’s the exact nature of M-D. You tearat your mate with unfounded suspicions, accusations, insane bitterness –enough to make you hate each other. It makes no sense. That’s why it’s crazybehavior. If you’re lucky, like my wife, your mate understands and gets youhome right away to have a smoke. It used to be that you could take trips,but the police have cracked down so hard that you don’t dare smoke a jointin the car.

I can bear witness to the probability of a near normal life situation for amanic-depressive if they’ve got good marihuana, a lifestyle that allows oneto be home nearly always, and an understanding partner.

Here is the account of another woman with bipolar disorder who findscannabis more useful than conventional medications:

I am a 35-year-old woman with severe manic depression. When I was growing upI was hypersensitive, cried all the time, and fought with my brothers andsister. My parents always said they had to handle me with kid gloves. I hadmore energy than most and used it to the hilt. I was an agile gymnast andone of the fastest swimmers in my school. I was also at the top of my classin algebra and good at art and creative writing. I used to stay awake atnight and dream up stories.

Around age 14 my mood swings began to get more intense. I was agitated,restless, and constantly fighting at home. I lay awake at night and lost alot of weight. Eventually I snapped and was sent to a mental hospital, whereI was diagnosed as having manic-depressive disorder. They put me on lithiumand told me I would have to take it the rest of my life. But lithium made melethargic. I had trouble communicating and lost all my animation andcreativity. Eventually I quit taking it. Recently I have also tried Tegretol[carbamazepine] and Depakote [valproic acid], neither of which helped.

Tegretol started a manic episode, and Depakote had some very bad sideeffects. I’d like to find something else, but I don’t have health insuranceor the money to spend trying out new medications.

Since the age of 14 I have had manic episodes regularly about once every sixmonths. It would always start with not being able to sleep or eat. After twoweeks I would just break down and seem to trip out into another world.

Usually I ended up in a mental hospital.

I smoked marihuana for the first time in high school and couldn’t believehow good it made me feel. My normally chaotic emotions subsided and I had asudden sense of calm, peace, and well-being. My perceptions of others andlife changed dramatically. The world no longer seemed hostile but morewithin my control. I could sleep easily and actually had cravings for food.There were practically no side effects. When I had enough marihuana I wouldjust naturally stop, because once you’ve gotten a certain effect you reallydon’t want any more.

Only another manic-depressive using marihuana could possibly know how muchthis has changed the quality of my life. Although they don’t know it, myfamily actually likes me better when I’m stoned than when I’m taking lithiumor not taking anything. When I’m stoned they can predict my moods andactually get close to me. But I can’t tell my family or the doctors becauseit’s illegal. I have to live a double life to get along.

I’ve often tried to quit marihuana, but I have a manic episode every time.Last year I decided I could control my emotional ups and downs withoutmarihuana, but it led to one of the worst episodes I’ve ever experienced. Ihad been having trouble sleeping as usual. I began to get super clear visionthat a disastrous earthquake was going to hit Los Angeles. I was feeling sogood I was sure I was right. Soon I had my roommate convinced that we didn’thave much time and would have to buy as many supplies as possible and thenleave. We thought that after the quake the New World Order would beimplemented and everyone would have to take the number that Revelationstalks about in the Bible. We planned to go to El Salvador, where her familylives, and hide out for the next three and a half years. Crazy! But I reallybelieved it. I maxed out all my credit cards, quit my job, and packed up allmy things, including disguises I thought we were going to need. Eventually Ihad to return home with no job and major bills.

I knew then and there that I would have to go back on marihuana. It’s beenseven months now since I resumed smoking marihuana, and I don’t know whatelse to do. I have to choose between obeying the law and staying sick orbreaking the law and being well.

J.P. is a 45-year-old health professional and the mother of a 20-year-oldson:

In late 1994 and early 1995 my son Michael, age 18, began to go out ofcontrol. He was unable to sleep, attend school, or function in a normalfashion. He was running around nonstop, acting on impulse without any senseof normal judgment. He was in serious danger of accidentally harming himselfor others. There was no way to reason with him, because he was unable tothink or listen long enough to understand what you were trying to say. Hehad become a human time-bomb.

Then, on February 14, 1995, he had a full-blown psychotic manic episode andrefused treatment. I had to petition a court to commit him to a psychiatrichospital in Portland, Maine, where he was given a diagnosis of manic-depressive disorder. Both Michael’s father and my grandmother sufferedfrom the same disorder, which is now called bipolar disorder.

During his nine days in the hospital (the time allotted by my insurancecompany) Michael was given lithium and Trilafon [perphenazine]. We were toldthat he would need lithium for the rest of his life. They explained that itworked very well in 60% of people with this disorder.

We returned home, and for the first month or two, the mania seemed to haveended. At the end of the second month the Trilafon was discontinued, butMichael was still taking a high dose of lithium. At that point he developeda rash on his neck and chest; he also had dark circles under his eyes, andhe was incoherent most of the time. The lithium level in his blood wasexactly where the doctor wanted it, but now he was acting like anAlzheimer’s patient. He couldn’t read or comprehend a paragraph, let alonefinish school. He was detached from his surroundings and himself. There wasno emotional content left in him. He was becoming unrecognizable. He hadalways been very much like [comedian] Robin Williams in personality andextremely athletic — a skier, football player, and weight lifter. It washeartbreaking to watch him lose himself in a medicated stupor. I becameconvinced that lithium did not eliminate the disease but instead wasdrowning his brain so the symptoms could not be activated. I could still seetiny mood swings and moments of complete restlessness, but in a body thatwas unable to become hypomanic.

Michael decided to cut his lithium in half. I knew this would be dangerousbut I agreed that something had to be done. Soon he was more himself,laughing and talking and almost back among the living. Then he started tobecome more hypomanic, and I knew we were headed for trouble. He was back tothe energy level of someone on high doses of speed, and this lasted formonths. He was running through life like a high-bred stallion, while I wasgathering everything ever written on manic-depressive disorder.

Then one day he came home and was perfectly normal in every respect. Ithought that maybe he was in remission because the disease is known to dothat, and I was thrilled at the possibility. Later that night he was back tofull speed ahead, and all hope sank within me. This continued as the weekspassed. There would be times when he was perfectly normal, but only forshort intervals. I could not figure it out. I started to chart his sleeppattern, his food intake, the kinds of foods, what chemicals he wassubjecting himself to, and so on. Finally one day I discovered that he wassmoking pot. Of course I freaked out. We talked about it at length and hetold me point blank, “I only feel normal when I smoke a joint.” By this timeI was ready to blame the disease on his pot smoking. I was totallyirrational about this. Michael and I fought constantly for a month about it.Finally he asked me to research cannabis and let him know what I found. Ifigured I would be able to find enough damaging information to put thesubject to rest. The next week was my week of discovery. Not only could Inot find what I was looking for, but I became convinced that there was nopermanent damage, and that cannabis was actually helpful for people withmood disorders.

I went on-line on the computer to talk to other people suffering frombipolar disorder, and I was overwhelmed by first-person stories of thebenefits that others had found.

The hardest part of this entire thing was rearranging my value system. I wasraised to be a law-abiding citizen. Although I grew up in the sixties andhad tried pot and inhaled, I was never a regular user because it wasillegal. I raised Mike right. He was taught to respect elders, do what youare supposed to do, and above all follow the law.

It is hard enough to live with an 18-year-old during a naturally rebellioustime, but to be forced to participate in an illegal activity is the absoluteworst scenario. But that is exactly what I’m doing. Mike has been smokingpot for two months now. He does not smoke daily, but when the mania beginshe smokes and within five minutes he is fine. He never appears to be “high,”just happy and relaxed. We don’t have to deal with mood swings anymore. Hecan work on his home-schooling program, and I don’t doubt that he willfinish by the end of summer. He has been repairing lobster traps with afriend and will be lobstering six days a week by the end of April.

At this point I expect to be arrested some day, because if Mike getsarrested, they will have to take me right along with him. I plan to grow aplant this summer for his use. I know I could end up in jail, but I alsoknow that without some kind of medication that works, my son could end up injail, institutionalized, or dead. What choice do I have?
Another account of cannabis use by a person with bipolar disorder emphasizesthe reduction of lithium side effects:

I am 29 years old, born and raised in North Carolina. My academic backgroundis in English literature, computer science, and law; I now work as atechnology consultant and writer, although I am contemplating returning tograduate school. I am divorced. I am reasonably active in my community,though work takes much of my time these days.

I was first diagnosed with bipolar disorder about five years ago, when I wasin law school (a psychiatrist also tentatively ventured this diagnosisduring my undergraduate years), but I suspect that I have had a mooddisorder for most of my life. I was certainly clinically depressed as earlyas age nine, and my first hypomanic episode occurred at 17. There is also afamily history of mood disorders, especially on my mother’s side. All threeof her brothers had “mercurial” personalities, and they all experiencedtremendous successes and notable failures in business. Their extravaganceand outgoing personalities resemble my behavior while manic or hypomanic.Although none of them was formally diagnosed with a mood disorder, both myparents have been treated for clinical depression.

Before I was diagnosed and found the right treatment, I had the typicalsymptoms of bipolar disorder. During depressive phases I became withdrawn,uncommunicative, and preoccupied with suicide. I found it nearly impossibleto function in school or at work. During hypomanic or manic phases I spentfreely, traveled all over the country (and world), made poor personal andbusiness decisions, engaged in risky sexual behavior, and so forth. Theillness has caused me a great deal of personal pain as well as financialwoes. I separated from my wife (who eventually divorced me) the summerbefore I was diagnosed. I’ve lost jobs, ruined friendships, and alienatedmembers of my family. Fortunately, much of this damage has been repairedwith time and understanding. I thank God that my ruined credit rating is theonly apparent lasting harm.

Thanks to lithium and sensible therapy, including the judicious use ofcannabis, I have been relatively stable and sane for the past three years,although my sleep is often disturbed and I still have (very much milder)hypomania and depression in much the same cyclic pattern as before.

I first used cannabis in my freshman year of college (1984). 1 preferred itto alcohol as an intoxicant, and used it a few times a week, almost alwaysby smoking (I still prefer to take it that way). In retrospect, it seemsclear to me that I was medicating myself for bipolar disorder even then.When depressed and anxious, I found that cannabis was soothing and enhancedmy ability to enjoy life. When I was in a manic phase, it relaxed me andhelped me get to sleep. I often felt as though I had so much energy insideme that I would jump out of my skin; the cannabis helped tremendously withthat. But there was a downside. Manics have a big problem with impulsecontrol, and cannabis seemed to exacerbate it. (“Drive to Canada? Greatidea. Let’s go!”) It also ratcheted up my already overactive libido a notchor two, which wasn’t the healthiest thing in the world.

When I was diagnosed and began treatment with lithium, I got almostimmediate relief, but I also suffered from nausea, pounding headaches, handtremors, and excess production of saliva. A friend suggested that I trygetting high, reasoning that if cannabis helped chemotherapy patients dealwith their nausea and discomfort, it might help me too. My doctor thoughtthe idea was absurd but admitted that it would be safe to take cannabistogether with lithium. So I tried it, and the results were remarkable. Thehand tremors subsided, the headaches vanished, and the saliva factoryresumed normal production levels. All I needed was one or two puffs on amarihuana cigarette. When lithium side effects get bad, the availability ofcannabis has been an absolute godsend. It is also nice to be able to usecannabis as an intoxicant, knowing that, unlike the combination of lithiumand alcohol, it cannot damage my kidneys.

Every one of the many thousands of Americans who use marihuana as a medicineruns a risk of being arrested. They have to worry about financial ruin, theloss of their careers, and forfeiture of their automobiles and homes. Somehave an additional burden because mandatory school drug programs and Parentsfor a Drug-Free America advertisements have given their children anexaggerated idea of the dangers of using marihuana. Many of these childrenbecome concerned about the health and well-being of their marihuana-usingparents. A few of those parents have been arrested because their worriedchildren informed on them to the police officers who serve as instructors inthe popular school drug program known as Drug Abuse Resistance Education(DARE).

The following accounts are by a 40-year-old software engineer and his37-year-old wife, who suffers from bipolar disorder. He speaks first:My wife and I and our two boys live in Tyngsboro, Massachusetts. My wife wasgiven a diagnosis of bipolar disorder in 1982 and has been taking lithiumsince 1992. She also uses marihuana for her symptoms. She has had sixpsychiatrists in the past 14 years and has been interviewed by many more. Ihave always told them that she uses marihuana regularly, and not one of themhas told her to stop. They do not even seem to care or pay attention.I posted a question about this to the alt.support.depression.manic newsgroupon the Internet. I asked whether doctors knew something about marihuana butcould not recommend it because of its illegality. The responses were varied,but most people who were manic-depressive said marihuana helped them, andone said that some doctors considered it effective in controlling mooddisorders.

My wife functions much better when she uses marihuana. When she ishypomanic, it relaxes her, helps her sleep, and slows her speech down. Whenshe is depressed and would otherwise lie in bed all day, the marihuana makesher more active. When she runs out of marihuana and can’t get more, shebecomes more irritable and hard to live with. Lithium is also effective, butit doesn’t always keep her in control.

Our dilemma is that our 13-year-old has been through the DARE program andhas learned about the evils of drugs and alcohol. He opposes all substanceuse, legal or illegal — and I want it that way. But he knows that my wifeuses marihuana and it “eats” at him, although he also knows about herillness and how marihuana helps. Understandably, all this confuses him.I believe that marihuana could help some people if it were made available asa prescription medicine. Certainly there are other health and social issuesinvolved, and I can’t decide what would be right for the country as a whole.All I know is that in this family it has relieved us all of much suffering.Now his wife:

I am 37, and I have been using marihuana for 20 years. I was diagnosedbipolar in 1982. 1 take lithium and Wellbutrin [bupropion), although Idislike these drugs. I've gained about 40 pounds since I started takinglithium, but otherwise there are no side effects.

My 13-year-old son knows about my illness. He has also known about mymarihuana smoking for about five years. He realized what I was doing afterhe participated in the DARE program in school. It bothers me when he comeshome and says they talked about drugs and he was thinking that his mother is"one of them," He doesn't want anyone to know his mother is a "druggie," anduntil now we've kept it as our secret. I don't think he would tell anyone,but I'm still afraid something might get out. Sometimes these programs usetricks to get kids to inform on their friends and relatives. They say, "Ifyou really care about this person, the only way you can help them is toreport them." My husband has talked to him about it. He has explained thatlithium and the other medications I'm taking are drugs. He also explainedthat many legal drugs are far more dangerous than marihuana and that no onehas ever died from using marihuana. But my son insists that if it isillegal, then it is wrong. This bothers me so much that I have consideredstopping.

The trouble is that at times when I feel tired and rundown, just a couplepuffs of marihuana bring me back to life. Sometimes I think it brings me toa level of normalcy that everyone else achieves naturally. At other times,when everything seems to be going like a whirlwind around me and I can'tkeep track of what I'm thinking about or saying or feeling, the marihuanajust seems to slow the world down a bit. When I have trouble sleeping, ithelps zonk me out, but if I have trouble waking up it brings me to life. Idon't like being thought of as a "drug-abusing mother," but I actually thinkI'm a better mom when I'm feeling in control because of marihuana.In some ways cannabis today is in a position analogous to that of lithium in1949, when J. F. J. Cade, after observing its sedative effect on guineapigs, administered it to patients suffering from "chronic and recurrentmania." His seminal paper, "Lithium Salts in the Treatment of PsychoticExcitement," presented ten one-paragraph case histories, and this compellinganecdotal evidence attracted the attention of psychiatrists around the worldbecause there was no adequate treatment for bipolar disorder. In his paperCade (1949) mentioned the need for "controlled observation[s] of asufficient number of treated and untreated patients.” In 1951, Noack andTrautner followed up by reporting on the treatment of another 30 patientswith “mania alone.” But they pointed out that not all patients improved,that many discontinued the treatment, and that “it does not appear to bejustified to accept the lithium treatment of mania as invariably safe.”(Noack & Trautner 1951).

In 1954, Schou and colleagues published a controlled study in which theyalternated lithium and a placebo at two-week intervals. Lithium was clearlybeneficial for 12 patients; 15 showed improvement that was “not asclearcut,” and three did not improve at all. Schou and his colleagues foundit “rather astonishing that [lithium's success] has failed to arouse greatergeneral interest among psychiatrists.” One explanation they offered was itslow therapeutic ratio. Another explanation was “the difficulties encounteredin attempts to convey to others in a quantitative manner … the effect of anew psychiatric therapy,” i.e. to move beyond anecdotal data to controlledstudies (Schou et al. 1954). But there was an even more compelling reasonfor the delay in lithium’s acceptance in the United States. In this country,drugs are introduced by pharmaceutical companies which invest in the studiesnecessary for official acceptance. They do this because they receive apatent (in the 1950s, for 17 years) on the new drug which allows them torecoup their investment. Lithium salts, of course, could not be patented.Similar obstacles face the medical use of cannabis today. Lithium had areputation for toxicity that grew out of its use as a salt substitute forcardiac patients in the 1940s. There were a number of deaths before itsdangers were fully appreciated, and today blood levels are carefullymonitored. Because of its nonmedical use, cannabis also has a reputation fortoxicity, in this case undeserved. Lithium was unpatentable, and so iscannabis. Finally, like the evidence for lithium in 1949, the evidence forthe therapeutic value of cannabis in bipolar disorder today is anecdotal.Although it has been repeatedly considered as a treatment for affectivedisorders in the Western medical literature since 1845, when Jacques-JosephMoreau de Tours (1857) recommended it for melancholia, there is little inthe medical literature on the use of cannabis as a mood stabilizer (seeParker & Wrigley 1950; Pond 1948; Stockings 1947).

Today drugs must undergo rigorous, expensive, and time-consuming tests towin approval by the Food and Drug Administration (FDA) for marketing asmedicines. The purpose of the testing is to protect the consumer byestablishing both safety and efficacy. First the drug’s safety (or ratherlimited toxicity) is established through animal and then human experiments.Next, double-blind controlled studies are conducted to determine whether thedrug has more than a placebo effect and is at least as useful as anavailable drug. As the difference between drug and placebo may be small,large numbers of patients are often needed in these studies for astatistically significant effect. Because no drug is completely safe(nontoxic) or always efficacious, a drug approved by the FDA has presumablysatisfied a risk-benefit analysis. When physicians prescribe for individualpatients they conduct an informal analysis of a similar kind, taking intoaccount not just the drug’s overall safety and efficacy but its risks andbenefits for a given patient and a given condition. The formal drug approvalprocedures help to provide physicians with the information they need to makethis analysis.

But devotion to formal procedures may have caused us to undervalue anecdotalevidence. Regulators today are willing to accept the experience ofphysicians and patients as evidence of adverse effects but not as evidenceof therapeutic effects (Lasagna 1985). Yet case histories and clinicalexperience are the source of much of our knowledge of synthetic medicines aswell as plant derivatives. Controlled experiments were not needed torecognize the therapeutic potential of chloral hydrate, barbiturates,aspirin, curare, insulin, or penicillin. More recently, the uses ofpropranolol for angina and hypertension, diazepam for status epilepticus,and imipramine for childhood enuresis were discovered in the same way,although these drugs were originally approved by regulators for otherpurposes.

A related source of evidence is the experimental method known as the “N of1″ clinical trial or single-patient randomized trial. This is the kind ofexperiment used by Schou and his colleagues (1954), in which active andplacebo treatments are administered in alternation or succession to apatient. The method is often used when large-scale controlled studies areimpossible or inappropriate because the disorder is rare, the patient isatypical, or the response to treatment is idiosyncratic. Several patientsthe authors have encountered carried out somewhat similar experiments onthemselves. They alternated periods of cannabis use with periods of no useand discovered that cannabis was effective.

The familiar deficiency of anecdotal evidence is the risk of countingsuccesses and ignoring failures. If many people suffering from clinicaldepression take, say, St. John’s Wort after unsuccessful treatment withconventional antidepressants and a few recover, those few stand out and cometo attention. Bipolar disorder is a cyclical condition, so it is essentialto avoid confusing natural remission with drug-induced improvement. Atpresent we do not know how many patients with bipolar disorder would benefitfrom cannabis. The promising anecdotal evidence points to the need for moresystematic clinical investigation, just as it did 50 years ago in the caseof lithium.

Thousands of years of widespread use as well as recent research designed todiscover toxic effects have made it clear that cannabis is an unusually safedrug. In fact, its long-term safety is better established than that of St.John’s Wort. Yet unlike St. John’s Wort, cannabis would be subject togovernment regulations that demand further time-consuming and unnecessarysafety tests. The classification of cannabis as a Schedule I drug createsfurther obstacles to clinical research. But given the disinterest ofpharmaceutical companies, there is no immediate prospect of such studiesbeing funded even if the political obstacles are removed. We are left withthe tantalizing possibility that cannabis (or one or more of its constituentcannabinoids) is useful in the treatment of bipolar disorder and the sadknowledge that in the present circumstances little can be done to explorethat potential.
REFERENCES
Cade, J.F.J. 1949. Lithium salts in the treatment of psychotic excitement.
Medical Journal of Australia, September 3: 349-52.

Grinspoon, L. & Bakalar, J.B. 1997. Marihuana, the Forbidden Medicine.Revised and Expanded Edition.
New Haven: Yale University Press.

Lasagna, L. 1985. Clinical trials in the natural environment.
In: C.Stiechele; W. Abshagen & J. Koch-Weser (Eds.) Drugs BetweenResearch and Regulations. New York: Springer-Verlag.

Moreau de Tours, J.-J. 1857. Lypemanie avec stupeur; Tendance =E0 lademence-tra=EEtment par 1′extrait (principe resineux) de cannabisindica-Gudrison.
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Noack, C.H. & Trautner, E.M. 1951. The lithium treatment of maniacal psychosis.
Medical Journal of Australia, August 18:219-22.

Parker, C.S. & Wrigley, F.W. 1950. Synthetic cannabis preparations inpsychiatry: I. Synhexyl.
Journal of Mental Science 96:276-79.

Pond, D.A, 1948. Psychological effects in depressive patients of themarihuana homologue syndexyl.
Journal of Neurology, Neurosurgery and Psychiatry 1 1:279.

Schou, M.; Juel-Nielsen, J.; Str=F6mgren, E. & Voldby, H. 1954. The treatment of manic psychoses by the administration of lithium salts.
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Stockings, G.T. 1947. A new euphoriant for depressive mental states.
British Medical Journal 1:918-22.

Opposite relationships between cannabis use and neurocognitive functioning in bipolar disorder and schizophrenia.

Cannabis use is associated with altered neurocognitive functioning in severe mental disorders, but data are still inconclusive and there are no studies of bipolar disorder. The aim of this study was to investigate the association between cannabis use and neurocognition in bipolar disorder compared with schizophrenia in a naturalistic setting.MethodA total of 133 patients with bipolar disorder and 140 patients with schizophrenia underwent neuropsychological assessments and clinical characterization including measures of substance use. Relationships between cannabis users and neurocognitive function were explored in the two diagnostic groups. Possible interactions between diagnosis and cannabis use were investigated, and findings were controlled for possible confounders.
RESULTS: In bipolar disorder subjects, cannabis use was associated with better neurocognitive function, but the opposite was the case for the schizophrenia subjects. There was a statistically significant interaction effect of diagnosis and cannabis use on focused attention (p=0.019), executive functioning (verbal fluency – set shifting) (p=0.009), logical memory-learning (p=0.007) and on logical memory-recall (p=0.004). These differences in neurocognitive function could not be explained by putative confounders.
CONCLUSIONS: The findings suggest that cannabis use may be related to improved neurocognition in bipolar disorder and compromised neurocognition in schizophrenia. The results need to be replicated in independent samples, and may suggest different underlying disease mechanisms in the two disorders.

Asthma and Marijuana

Abstract After experimental induction of acute bronchospasm in 8 subjects with clinically stable bronchial asthma, effects of 500 mg of smoked marijuana (2.0 per cent delta9-tetrahydrocannabinol) on specific airway conductance and thoracic gas volume were compared with those of 500 mg of smoked placebo marijuana (0.0 per cent delta9- tetrahydrocannabinol), 0.25 ml of aerosolized saline, and 0.25 ml of aerosolized isoproterenol (1,250 mug). Bronchospasm was induced on 4 separate occasions, by inhalation of methacholine and, on four other occasions, by exercise on a bicycle ergometer or treadmill. Methacholine and exercise caused average decreases in specific airway conductance of 40 to 55 per cent and 30 to 39 per cent, respectively, and average increases in thoracic gas volume of 35 to 43 per cent and 25 to 35 per cent, respectively. After methacholine-induced bronchospasm, placebo marijuana and saline inhalation produced minimal changes in specific airway conductance and thoracic gas volume, whereas 2.0 per cent marijuana and isoproterenol each caused a prompt correction of the bronchospasm and associated hyperinflation. After exercise-induced bronchospasm, placebo marijuana and saline were followed by gradual recovery during 30 to 60 min, whereas 2.0 per cent marijuana and isoproterenol caused an immediate reversal of exercise-induced asthma and hyperinflation.