DEBUNKING "AMOTIVATIONAL SYNDROME"
"There is no such thing as laziness. Laziness is only lack of incentive."
Norman Reider, MD
A graduate student in the psychology department at the University of Southern California, Sara Smucker Barnwell, has conducted a survey to assess whether or not cannabis use undermines motivation. She emailed a questionnaire to 200 undergraduates who had taken a course on drugs and human behavior, and to 100 acquaintances of a co-author, Mitch Earleywine, PhD, who in turn were asked to forward it to others. She got responses from some 1,300 people. She then analyzed the responses of everyday users ( 244 ) and those who had never used ( 243 ).
Barnwell's questionnaire comprised an "Apathy Evaluation Scale" and a "Satisfaction with Life Scale." Apathy was measured by 12 statements such as "I don't follow through on my plans" to which respondents gave their level of agreement ( "Not At All, Slightly, Somewhat, Very Much" ). Satisfaction was measured by agreement with five statements, including "If I could live my life over, I would change almost nothing." The mean age of the participants was 33. They were mostly Caucasian ( 79% ), with a preponderance of them students. One in three frequent cannabis users described their use as medical.
Much of Barnwell et al's paper consists of statistical methodology involving "T-distribution," "heteroscedasticity," "controlling for unequal variances," "outliers ( e.g. data points above/below three standard deviations )," "standard transformations ( e.g. square roots )," "trimmed means," "alternative measures of effect size ( the estimated measure of the degree of separations between two distributions )," "Cohen's delta calculations," "Pearson's correlations," "Welch's heteroscedastic means comparison," "Yuen's comparison of 20% trimmed means," etc. etc ...
The jargon is almost impenetrable, but it appears that statisticians allow themselves to discount "outlier" responses that don't jibe with the "central tendency" of the data. Barnwell et al's "robust statistical analysis" certainly makes their somewhat fuzzy survey seem supremely precise and worthy of publication in a peer-reviewed scientific journal.
But why quibble when they're "good on our issue?" Barnwell et al conclude: "Participants who used cannabis seven days a week demonstrated no difference from non-cannabis users on indices of motivation. These findings refute hypothesized associations between heavy cannabis use and low motivation ... Daily users reported slightly lower median subjective well-being scores ( 2 points less on a 28-point scale ) ... Post-hoc tests find that some portion of the differences in subjective wellbeing arose from medical users, whose illnesses may contribute to low subjective wellbeing more than their cannabis use."
The authors acknowledge that their results may have been skewed by not taking into account respondents' use of alcohol and other drugs. They list some other realistic caveats and counter-caveats: "Participant reactivity to questions of motivation may pose an additional confound. Despite a lack of empirical evidence supporting amotivational syndrome, the popular concept is well known among cannabis users. Perhaps cannabis users demonstrate sensitivity to questions regarding motivation, exaggerating their own motivation in an effort to defy stereotypes. In contrast, users tend to attribute low energy and motivation to cannabis even when they use alcohol problematically, so there may also be a bias for cannabis users to report lower motivation. Further, collecting data via the internet may prevent some low education or low income individuals from participating. Others may feel uncomfortable reporting drug use online. Simultaneously, individuals experiencing low motivation may be more likely to participate in internet-based research rather than traveling to a laboratory."
Common sense tells us that the main motivator in this society is the prospect of remuneration. Millions of Americans, young and old, are destined to do unfulfilling work for wages that won't enable them to support a family let alone own a home and retire with a sense of security. To define our condition in terms of amotivational syndrome or apathy is to conflate symptom and cause, to individualize a social phenomenon, to medicalize the political. Anti-prohibitionists should turn the meaning of amotivational syndrome around and peg it for what it obviously is: a manifestation of socioeconomic hopelessness.
Source
Cannabis as a First-line Treatment for Childhood Mental Disorders
By Tod H. Mikuriya, M.D.
Originally published in O'Shaughnessy's, Spring 2006
Alex P. was prescribed pharmaceutical stimulants, depressants, analgesics, and antipsychotics that exacerbated his problems. Cannabis has provided a benign, effective alternative.
In 1996, California legalized cannabis as a treatment for “any... condition for which it brings relief.” Although the law does not constrain physicians from approving the use of cannabis by children and adolescents, the state medical board has investigated physicians for doing so, exerting a profoundly inhibiting effect.
Even doctors associated with the Society of Cannabis Clinicians have been reluctant to approve cannabis use by patients under 16 years of age, and have done so only in cases in which prescribable pharmaceuticals had been tried unsuccessfully. The case of Alex P. suggests that the practice of employing pharmaceutical drugs as first-line treatment exposes children gratuitously to harmful side effects.
Alex P., accompanied by his mother, first visited my office in February 2005 at age 15 years, 6 months. At that time he had been prescribed and was taking Fioricet with codeine (30 mg, 3x/day); Klonopin (1 mg, 2x/day); Ativan (1 mg, 2x/day); and Dilaudid “as needed” to treat migraine headaches (346.1), insomnia (307.42), and outbursts of aggression to which various diagnoses —including bipolar with schizophrenic tendencies- had been attached by doctors in the Kaiser Healthcare system.
Alex had previously been prescribed Ritalin, Prozac, Paxil, Maxalt, Immitrex, Depacote, Phenergan, Inderal, Thorazine, Amitriptaline, Buspar, Vicodin, Seroquel, Risperdal, Zyprexa, Clozaril, Norco, and Oxycodone.
A history taken from Alex and a separate interview with his mother, Barbara P., were in full accordance. The mother described Alex as a healthy baby who was “never a good sleeper.” She had “a rocky relationship” with Alex’s father, who had three children from a previous marriage. Alex, their second son, “always saw himself as the peacemaker when there was arguing... I think that’s why, when it was time for him to go to school, he never wanted to go. He just didn’t like to leave the house.”
Although Alex showed facility communicating verbally, his reading and writing skills disappointed his teachers and prior to going to middle school he was evaluated for an Individual Educational Plan.
According to his mother, “They didn’t say he was dyslexic, they said he ‘had trouble processing things.’ He wasn’t acting wild in school. He was always well behaved. But they said he had ADD because he couldn’t concentrate and process things.” At age 11, Alex was prescribed Ritalin for attention deficit disorder.
In middle school Alex befriended some 13- and 14-year-olds, with whom he was caught stealing a car (and with whom he had shared his stimulant medication, and who introduced him to marijuana). Thus began a four-year sojourn through institutions of the Central Valley juvenile justice system and Kaiser-affiliated hospitals and clinics.
In this period, according to Barbara P., “They put him on all these medications and not only couldn’t he sleep at night, but he started having rampages, hitting —mainly me. He fought with his brother and his dad, too. He beat up the truck. He couldn’t remember afterwards what he actually did. He seemed like a completely different person. I don’t think that’s because of who he is. I think it was because of the medications he was taking.”
Barbara P. expresses remorse that she obeyed court orders to force Alex to take his prescribed medications.
At age 13 Alex made a serious attempt at suicide by hanging himself from a tree outside his house. He was rescued by his brother returning home unexpectedly. He reports making other attempts to overdose on pills.
Alex had known since age 11, when he first smoked cannabis with his older friends, that it had a calming effect. Many of his encounters with the juvenile justice system were for marijuana possession. His mother says, “He was aware that it helped him not feel stressed out and not have headaches. It helped him concentrate. It helped him sleep. All the things he needed. But I wasn’t for smoking it.” She reports feeling social pressure from her Central Valley community and pressure from her husband to oppose Alex’s attempts to obtain and use marijuana.
“ Alex went through three rehabs —two inpatient and one outpatient, all court-ordered, all for marijuana. He could not do inpatient and I told them that. It’s not that Alex wanted to be out there doing drugs, he wanted to be home! He had a thing where he didn’t want to be put in an institution where he didn’t know anybody. That would drive him more crazy. He ended up running from one rehab house and getting kicked out of another.”
Perceiving that Alex’s mental state was worsening, and in response to his repeated requests to be allowed to smoke marijuana, Barbara did research on the internet that alerted her to similarities between cannabis and Marinol (dronabinol), a legally prescribable drug. Her request that a Kaiser physician prescribe Marinol for Alex was rejected.
Through the internet she identified the author as a specialist in cannabinoid therapeutics and arranged an appointment for Alex.
A prescription was written in February 2005 for Marinol (10 mg), along with a recommendation to use cannabis by means of a vaporizer. Alex has consistently maintained he prefers smoking cannabis to ingestion by other means, due to rapidity of onset and ability to titrate dosage. (“It works great and you can use just as much as you need,” he says.)
When a drug test ordered by the Probation department turned up positive for cannabinoids, Alex had a hearing at which a Superior Court judge declared that because Marinol use could mask marijuana use, he would not allow it. He explicitly refused to recognize the validity of a specialist in the field of cannabis therapeutics and ordered Alex to take only drugs prescribed by Kaiser.
Barbara P. says: “I guess judges have authority over anything. He thought Alex had a drug problem with marijuana because he had smoked it before.” At a subsequent hearing another judge rescinded the order. When Alex’s Probation ended in May, 2005, he began medicating exclusively with smoked cannabis.
Dramatic Improvement
Alex and Barbara P. were seen by the author at a follow-up visit in February 2006. Alex reported dramatically improved mood and functionality with only one migraine attack in the past year, not severe enough to require a trip to the hospital for a Dilaudid injection. He is in an independent study program at a small public school and getting straight As and Bs. “They love me at school,” Alex asserts. His teacher is aware that he medicates with cannabis with a physician’s approval. He smokes approximately one ounce per week and would use 50% more if it were cheaper to obtain. He does not vaporize because a vaporizer is “too expensive” (although he has taken up the guitar and purchased several models). He summarizes his status thus: “I use(d) to use a lot of medication like Klonopin and other pain medication but I haven’t had to since the use of cannabis.”
His mother reports: “We knew after about three months on Marinol that he was going to be okay. He started doing a lot better. He sleeps well, he’s not on any of the other medications, I haven’t had to take him to the emergency room for migraine since he first went on Marinol. He’s been totally fine. He walks the dog, cleans up his room, does chores for the family. And I know that he’s going to be okay. Before, I never knew what was going to happen. I couldn’t picture him getting a job.” Alex’s father has relented in his disapproval of Alex’s cannabis use, having seen its effects on the household.
The case of Alex P. is one of iatrogenic illness in which drug-oriented school counselors and administrators played a harmful role. In a previous era, psychologists would have put more emphasis on examining the family constellation. An adequate work-up would have identified Alex’s insomnia as the likely cause of his poor scholastic performance. Failing an adequate work-up, the quasi-diagnosis “inability to process” led to a prescription of methylphenidate, a stimulant, for an 11-year-old with persistent insomnia. The resulting disinhibition led in turn to trouble with law enforcement, a cycle of extreme anxiety and distress, and the prescription of more drugs, irrationally chosen to counteract drug-induced symptoms.
As a result of the federal prohibition, there exist no official guidelines governing when and how cannabis should be used by patients suffering from a given condition. The Institute of Medicine Report of 2000 acknowledges the feasibility of cannabis being used to treat certain conditions when all pharmaceutical options have failed. The case of Alex P. suggests that employing pharmaceutical stimulants, antidepressants and anti-psychotics exposes children gratuitously to harmful side effects in violation of Hippocratic principles.
The first-line treatment for any condition, efficacy being equal, would be the drug or procedure least likely to cause harm. Given the benign side-effect profile of cannabis, it should be the first-line of treatment in a wide range of childhood mental disorders, including persistent insomnia.
Physicians and parents both face stigma and take risks in authorizing cannabis use by children, but the risks are legal and social rather than medical. The case of Alex P. exemplifies this reality.
Does medical marijuana produce lasting schizophrenia,
psychosis, or other mental disorders?
Mitchell Earleywine, Ph.D. and Thomas Denson state in their study "Decreased Depression in Marijuana Users," in press as of 3/3/06 in the journal Addictive Behaviors:
"[T]hose who used [marijuana] once per week or less had less depressed mood, more positive affect, and fewer somatic complaints than non-users. Daily users reported less depressed mood and more positive affect than non-users....
Separate analyses for medical vs. recreational users demonstrated that medical users reported more depressed mood and more somatic complaints than recreational users, suggesting that medical conditions clearly contribute to depression scores and should be considered in studies of marijuana and depression.
These data suggest that adults apparently do not increase their risk for depression by using marijuana."
(12/05) Mitch Earleywine Thomas Denson
Psychiatric Research reported in a March 30, 2005 article (Vol. 134, Issue 1, pages 37-42):
"Findings suggest that regular cannabis users are significantly more prone to cognitive and perceptual distortions as well as disorganization, but not interpersonal deficits, than non-regular users and those who have never used.
Additionally, the onset of schizotypal symptoms generally precedes the onset of cannabis use. The findings do not support a causal link between cannabis use and schizotypal traits."
(3/30/05) Psychiatric Research
The 1999 U.S. sponsored IOM Report stated on Page 84:
"Although euphoria is the more common reaction to smoking marijuana, adverse mood reactions can occur. Such reactions occur most frequently in inexperienced users after large doses of smoked or oral marijuana. They usually disappear within hours and respond well to reassurance and a supportive environment.
Anxiety and paranoia are the most common acute adverse reactions; others include panic, depression, dysphoria, depersonalization, delusions, illusions, and hallucinations. Of regular marijuana smokers, 17% report that they have experienced at least one of the symptoms, usually early in their use of marijuana. Those observations are particularly relevant for the use of medical marijuana in people who have not previously used marijuana."
(March 1999) IOM
The British Journal of Psychiatry published an August 1993 article "Psychiatric Symptoms in Cannabis Users" by H. Thomas that stated:
"Cannabis use can lead to a range of short-lived symptoms such as de-personalisation, de-realisation, a feeling of loss of control, fear of dying, irrational panic and paranoid ideas...
The evidence that cannabis has a causative role in chronic psychotic or affective disorders is not convincing, although the drug may modify the course of an already established illness."
(August 1993) British Journal of Psychiatry
Oakley Ray, Ph.D. and Charles Ksir, Ph.D., wrote in their textbook Drugs, Society and Human Behavior (NY: McGraw-Hill, 10th Edition, 2004):
"There have been reports of psychotic 'breakdowns' occuring with rare frequency after marijuana has been smoked, but the causal relationship is in question.
The psychotic episodes are generally self-limiting and seem to occur in individuals with a history of psychiatric problems."
2004 Oakley Ray Charles Ksir
Colin Blakemore, Ph.D., Chair of the Dept. of Physiology at the University of Oxford in Great Britain, wrote to ProCon.org on 12/27/02:
"It is conceivable that excessive use of cannabis sometimes contributes to acute schizophrenic episodes. But it is difficult to believe that cannabis is a strong risk factor for this disorder, because there is no evidence that the incidence of schizophrenia has risen dramatically over the past 50 years, in parallel with the huge increase in cannabis use.
Young schizophrenic patients are often heavy cigarette smokers too, but no-one would suggest that tobacco causes schizophrenia."
(12/27/02) Colin Blakemore
Bill Zimmerman, Ph.D. wrote in her 1998 book Is Marijuana The Right Medicine For You? (CT: Keats Publishing), pages 166-167:
"Some opponents [of medical marijuana] .... claim that marijuana can cause serious mental disorders, like schizophrenia.
There is no evidence to support this claim."
(1998) Bill Zimmerman
Lynn Zimmer, Ph.D., noted in her 1997 book Marijuana Myths, Marijuana Facts , page 83:
"Given that the incidence of schizophrenia declined substantially in Western societies in the 1970s, at the same time cannabis use was rising, it seems highly unlikely that marijuana causes schizophrenia in otherwise healthy people....
Cannabis psychosis is self-limiting, disappearing in a few days with or without medical treatment. Toxic psychosis probably occurs more commonly in individuals with preexisting psychiatric disorders....
Marijuana temporarily alters mood, thought, emotions, and perception, sometimes quite dramatically. None of marijuana's effects cause people to behave in any particular manner.
In the midst of a toxic psychosis, people may become agitated and frightened. In response to acute panic, people may become withdrawn and inactive.
Neither of these states eliminates the social and moral restraints that guide human behavior."
(1997) Lynn Zimmer
Is medical marijuana an effective treatment for depression, bipolar disorders, anxiety, and similar mood disorders?
Frank Lucido, M.D. states in his article "Implementation of the Compassionate Use Act in a Family Medical Practice: Seven Years Clinical Experience," available on his website as of 6/2/06:
"With appropriate use of medical cannabis, many of these patients have been able to reduce or eliminate the use of opiates and other pain pills, ritalin, tranquilizers, sleeping pills, anti-depressants and other psychiatric medicines..."
(6/2/06) Frank Lucido
Lester Grinspoon, M.D. states in his 1997 book Marihuana: The Forbidden Medicine:
"Thirty to 40 percent of patients with bipolar disorder are not consistently helped by conventional treatment. For some of them cannabis may be useful in ameliorating the symptoms, reducing side effects of lithium, or both."
(1997) Lester Grinspoon
George McMahon, a patient receiving marijuana from the U.S. government as part of the U.S. Food and Drug Administration's Investigational New Drug (IND) Program, states in his 2003 book Prescription Pot:
"People who have never struggled with a life threatening or disabling illness often do not comprehend how debilitating the resulting depression can be. Long days spent struggling with sickness can wear patients down, suppress their appetites and slowly destroy their wills to live. This psychological damage can result in physiological effects that may be the difference between living and dying.
The elevated mood associated with cannabis definitely affected my health in a positive manner. I was more engaged with life. I took walks and rode my bike, things I never considered doing before in my depressed state, even if I had been physically capable. I ate regular meals and I slept better at night. All of these individual factors contributed to a better overall sense of well-being."
2003 George McMahon
Tod Mikuriya, M.D. writes in the 1997 book Marijuana Medical Handbook (Oakland: Quick American Archives):
"The power of cannabis to fight depression is perhaps its most important property."
(1997) Tod Mikuriya
The Journal of Clinical Investigation states in the 10/13/05 article "Cannabinoids Promote Embryonic and Adult Hippocampus Neurogenesis and Produce Anxiolytic- and Antidepressant-like Effects" (Article in PDF format) by Xia Zhang et al.:
"We show that 1 month after chronic HU210 [high-potency cannabinoid] treatment, rats display increased newborn neurons [brain cell growth] in the hippocampal dentate gyrus [a portion of the brain] and significantly reduced measures of anxiety- and depression-like behavior.
Thus, cannabinoids appear to be the only illicit drug whose capacity to produce increased hippocampal newborn neurons is positively correlated with its anxiolytic- and antidepressant-like effects."
10/05 Journal of Clinical Investigation
The Journal of Acquired Immune Deficiency Syndrome (JAIDS), states in a January 2004 article on a study designed by Prentiss, Power, Balmas, Tzuang and Israelski "to examine the prevalence and patterns of smoked marijuana and perceived benefit" among 252 HIV patients, found:
"Overall prevalence of smoked marijuana in the previous month was 23%. Reported benefits included relief of anxiety and/or depression (57%), improved appetite (53%), increased pleasure (33%), and relief of pain (28%).
(01/04) Journal AIDS
Jay Cavanaugh Ph.D. writes in his 2003 article "Cannabis and Depression," which was published on the website of the American Alliance For Medical Cannabis:
"Numerous patients report significant improvement and stabilization with their bipolar disorder when they utilize adjunctive therapy with medical cannabis. While some mental health professionals worry about the impact of cannabis on aggravating manic states, most bipolar patients trying cannabis find they 'cycle' less often and find significant improvement in overall mood. Bipolar disorders vary tremendously in the time spent in the depressive versus manic states. Those who experience extended depressive episodes are more likely to be helped with cannabis.
Patients who use cannabis to 'relax' may be treating the anxiousness sometimes associated with depression. Cannabis aids the insomnia sometimes present in depression and can improve appetite. Better pain control with cannabis can reduce chronic pain related depression. While cannabis cannot yet be considered a primary treatment of major depression it may improve mood when used under physicians supervision and in combination with therapy and/or SSRI’s."
(2003) Jay Cavanaugh
Bill Zimmerman Ph.D. states in his 1998 book Is Marijuana the Right Medicine For You?:
"Some patients have found the mood altering effects of marijuana to be helpful for treating mood disorders such as anxiety, depression and bipolar (manic-depressive) illness. Using marijuana to treat mood disorders was described in medical writings in the 19th and early 20th centuries...
However, using marijuana to treat mood disorders can be very tricky... If you intend to use marijuana for this purpose, it is very important that you thoroughly discuss it with your doctor. Patients who respond well report that marijuana not only diminishes their undesirable moods, it also motivates them to productivity. For some of these patients, depression was a by-product of a debilitating disease or illness for which marijuana provided a welcome remedy. For others, the marijuana seems to have acted directly on the depression.
The mental component of the pre-menstrual syndrome (PMS) often causes psychological problems and is now technically classified as an atypical (not typical) depression. Many women report benefit from using marijuana to improve the symptoms of PMS."
(1998) Bill Zimmerman
Does marijuana cause depression or other mood disorders?
Mitch Earleywine, Ph.D., noted in an 11/17/05 press release :
"Not only does marijuana not cause depression, it looks like it may actually alleviate it...
Those who use marijuana to battle the symptoms of illness may be depressed because of their illness, not because of marijuana. Studies that do not identify medical use might falsely implicate marijuana, rather than sickness, as the cause of depressed feelings...
Thirty percent to 40% of patients with bipolar disorder are not consistently helped by or cannot tolerate standard medications. In the course of the authors' studies of the medical uses of cannabis (Grinspoon & Bakalar 1997), a number of sufferers were discovered who believed marihuana to be more effective than conventional anti-manic drugs, or who used it to relieve the side effects of lithium."
(11/17/05) Mitch Earleywine
Journal of Psychoactive Drugs noted in an April 1998 article by Psychiatrist Lester Grinspoon, M.D. (Volume 30 (2), pp. 171-177):
"Thirty percent to 40% of patients with bipolar disorder are not consistently helped by or cannot tolerate standard medications. In the course of the authors' studies of the medical uses of cannabis (Grinspoon & Bakalar 1997), a number of sufferers were discovered who believed marihuana to be more effective than conventional anti-manic drugs, or who used it to relieve the side effects of lithium."
(4/98) Journal of Psychoactive Drugs
Ethan Russo, M.D., wrote in the December 2002 issue of Cannabis Health (Vol. 1, No. 1, Page 12):
"A surprising number of people so afflicted [with bi-polar disorder] have independently made the discovery that cannabis has improved their conditions, whether the mania or depression. It may also reduce side effects of other drugs used in its treatment, such as Lithium, Carbamazepine (Tegretol) or Valproate (Depakote).
No doubt, cannabis is affecting the balance of neurotransmitters that are at the basis for this disorder.
Endocannabinoids seem to be intimately involved in emotional regulation mechanisms in the limbic system. Because THC and other chemicals in cannabis mimic our own internal biochemistry, they may help replace what is missing."
(12/02) Ethan Russo
Bill Zimmerman, Ph.D., wrote in his 1998 book Is Marijuana The Right Medicine For You? A Factual Guide to Medical Uses of Marijuana on page 139:
"Using marijuana to treat mood disorders can be very tricky. Since active mood disorders often warp one's observational skills, reports by patients about marijuana lifting them out of depression are inherently unreliable.
If you intend to use marijuana for this purpose, it is very important that you thoroughly discuss it with your doctor. Patients who respond well report that marijuana not only diminishes their undesirable moods, it also motivates them to productivity.
For some of these patients, depression was a by-product of a debilitating disease or illness for which marijuana provided a welcome remedy. For others, the marijuana seems to have acted directly on the depression."
(1998) Bill Zimmerman
Source
Cannabidiol, A Cannabis Sativa Constituent, As An Antipsychotic Drug
A.W. Zuardi2, J.A.S. Crippa2, J.E.C. Hallak2, F.A. Moreira1 and F.S. Guimarães1
1Departamento de Farmacologia, 2Departamento de Neurologia, Psiquiatria e Psicologia Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
For tables and images,
go here
Abstract
A high dose of D9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of D9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.
Key words: Cannabidiol, D9-Tetrahydrocannabinol, Cannabinoid, Anxiety, Antipsychotic, Schizophrenia
Introduction
The use Cannabis sativa (cannabis) extracts as medicine was described in China and India (1) before the birth of Christ. The therapeutic use of cannabis was introduced in Western medicine in the first half of the 19th century and reached its climax in the last two decades of the same century. At the turn of the century, several pharmaceutical companies were marketing cannabis extracts and tinctures which were prescribed by doctors for many different complaints including pain, whooping cough and asthma, and as a sedative/hypnotic agent (2). However, the use of cannabis as a medicine almost completely disappeared at about the middle of the 20th century. The main reasons for this disappearance were the variable potency of cannabis extracts, the erratic and unpredictable individual responses, the introduction of synthetic and more stable pharmaceutical substitutes such as aspirin, chloral hydrate and barbiturates, the recognition of important adverse effects such as anxiety and cognitive impairment, and the legal restrictions to the use of cannabis-derived medicines (2).
Today this situation has changed considerably. The main active psychotropic constituent of cannabis, D9-tetrahydrocannabinol (D9-THC), was isolated, identified and synthesized in the 1960's. Almost three decades later, cannabinoid receptors in the brain were described and cloned and the endogenous cannabinoids were isolated and identified (3). As a result of these discoveries the interest in cannabis research has remarkably increased. For instance, the number of publications using the key word "brain", compiled by the ISI Web of Knowledge, increased 26 times from 1960-1964 to 2000-2004, while the number of publications about `cannabis' increased 78.5 times during the same period. As a consequence, the research on the use of cannabis as medicine has been renewed.
Although D9-THC is commonly accepted as the main factor responsible for the effects of cannabis, several reports have demonstrated that other components of the plant influence its pharmacological activity (4). One of these components is cannabidiol (CBD), which may constitute up to 40% of cannabis extracts (5) and is devoid of the typical psychological effects of cannabis in humans (6). Studies on the interaction between D9-THC and CBD have produced apparently contradictory results (7). Although potentiation of the effects of D9-THC has been observed (8,9), this phenomenon probably involves pharmacokinetic interactions since CBD is a potent inhibitor of hepatic drug metabolism (10) and increases D9-THC concentrations in the brain (11). Several studies, however, have reported antagonism of the effects of D9-THC when both compounds are administered simultaneously to animals (12,13) or humans (6,14).
CBD (1 mg/kg) co-administered with D9-THC (0.5 mg/kg) significantly reduced the anxiety and the psychotomimetic symptoms induced by the latter drug in healthy volunteers (6). Since the dose of CBD used in that study did not change D9-THC levels in blood (15), it was suggested that CBD blocked the effects of D9-THC by some intrinsic pharmacological properties. Actually, when administered alone CBD produced its own effects, including hypnotic (16), anticonvulsive (17), neuroprotective (18), and hormonal (increased corticosterone and cortisol levels) effects (19,20). These effects led to the hypothesis that CBD could have anxiolytic and/or antipsychotic effects.
Anxiolytic effect of cannabidiol
The anxiolytic properties of CBD has been demonstrated by several pre-clinical studies that employed different paradigms such as the conditioned emotional response (21), the Vogel conflict test (22) and the elevated plus-maze (23,24). In the later study (24), the effective doses of CBD ranged from 2.5 to 10 mg/kg, and the drug produced an inverted U-shaped dose-response curve, the higher doses being no longer effective in rats. This could explain the negative results obtained with high doses of CBD (above 100 mg/kg) in a previous study employing the Geller-Seifter conflict test (25).
To evaluate a possible anxiolytic effect of CBD in humans, a double-blind study was conducted on healthy volunteers submitted to a simulation of the public speaking test. CBD (300 mg, po) was compared to ipsapirone (5 mg), diazepam (10 mg) or placebo. The results showed that both CBD and the two other anxiolytic compounds attenuated the anxiety induced by the test (26). The anxiolytic-like effect of CBD in healthy volunteers was also observed in a more recent double-blind study that investigated its effects on regional cerebral blood flow by single-photon emission computed tomography. Because the procedure, by itself, can be interpreted as an anxiogenic situation, it permits the evaluation of anxiolytic drugs. CBD induced a clear anxiolytic effect and a pattern of cerebral activity compatible with an anxiolytic activity (27). Therefore, similar to the data obtained in animal models, results from studies on healthy volunteers have strongly suggested an anxiolytic-like effect of CBD.
Antipsychotic effect
Studies employing animal models
Animal models used for screening antipsychotic drugs are based on the neurochemical hypothesis of schizophrenia, involving mainly the neurotransmitters dopamine and glutamate (28).
Antagonism of dopamine D2 receptors may be a common feature of most clinically effective antipsychotic drugs, especially those active against hallucinations and delusions (29). The dopamine-based models usually employ apomorphine, a direct agonist, or amphetamine, a drug that increases the release of this neurotransmitter and blocks its re-uptake. Another common effect of antipsychotic drugs is hyperprolactinemia that results from the antagonism of D2 receptors on anterior-pituitary mammotrophic cells. These cells are tonically inhibited by dopamine produced in the hypothalamic arcuate nucleus (30). Conventional or typical antipsychotic drugs, especially those with high affinity for D2 receptors (haloperidol being the standard compound), induce motor side effects characterized by a Parkinson-like syndrome. On the contrary, atypical antipsychotic drugs, of which clozapine is the prototype, are therapeutically effective at doses that induce fewer or no Parkinson-like effects (29). The probability of an antipsychotic agent to induce Parkinson-like symptoms may be evaluated in the catalepsy test (31). Atypical antipsychotics inhibit the stereotypies and hyperlocomotion induced by dopamine agonists at lower doses than those that produce catalepsy.
As a first step in the investigation of possible antipsychotic-like properties of CBD, the drug was compared to haloperidol in rats submitted to dopamine-based models (32). However, blocking D2 receptors is not necessarily the only mechanism for the antipsychotic activity. Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the mechanism of action of clozapine (33). The glutamate-based models of schizophrenia employ sub-anesthetic doses of ketamine, a glutamate NMDA receptor antagonist, or its related compound phencyclidine, to induce psychotic symptoms. A more recent study investigated the effects of CBD in both dopamine and glutamate-based models predictive of antipsychotic activity. The study compared the ability of CBD, haloperidol and clozapine to prevent the hyperlocomotion induced by amphetamine or ketamine in mice (34). The results of these two studies are summarized in Table 1.
Table 1. Summary of two studies employing animal models for the screening of antipsychotic drugs, which compared cannabidiol, haloperidol and clozapine in rats (32) and mice (34).
[View larger version of this table (87 K JPG file)]
CBD (15-60 mg/kg), like haloperidol (0.25-0.5 mg/kg), reduced the apomorphine-induced stereotyped behavior in rats in a dose-related manner. These drugs also increased the plasma levels of prolactin. However, higher doses of CBD were needed (120 and 240 mg/kg) to obtain such effects. Moreover, in contrast to haloperidol, CBD did not induce catalepsy, even at doses as high as 480 mg/kg. In agreement with the results obtained in rats, CBD (15-60 mg/kg) inhibited the hyperlocomotion induced by amphetamine in mice in a dose-related manner. In addition, the drug also attenuated the hyperlocomotion induced by ketamine, expanding its antipsychotic-like effects to a glutamate-based model. As expected, while both haloperidol (0.15-0.6 mg/kg) and clozapine (1.25-5.0 mg/kg) inhibited hyperlocomotion, only haloperidol induced catalepsy in this dose range. Therefore, similar to clozapine, CBD did not induce catalepsy at doses that inhibited hyperlocomotion in mice. These results support the view that CBD exhibits a profile similar to that of atypical antipsychotic drugs.
In addition to being tested on behavioral models, typical and atypical antipsychotics may also be distinguished according to their pattern of neural activation. This may be detected by the expression of the proto-oncogene c-Fos. For example, haloperidol induces Fos immunoreactivity in the dorsal striatum, probably reflecting its motor side effects, while clozapine induces Fos immunoreactivity in the prefrontal cortex but not in the dorsal striatum (35). The Fos immunoreactivity pattern induced by CBD (120 mg/kg) was compared to that of haloperidol (1 mg/kg) and clozapine (20 mg/kg) in rats. Only haloperidol increased Fos immunoreactivity in the dorsal striatum, while both CBD and clozapine, but not haloperidol, induced Fos immunoreactivity in the prefrontal cortex (36,37). These results are consistent with the behavioral data obtained when comparing CBD with these prototype antipsychotics.
In conclusion, animal models employing behavioral as well as neurochemical techniques suggest that CBD has a pharmacological profile similar to that of an atypical antipsychotic drug.
Safety studies
Safety studies of CBD were required before human tests. CBD was extensively investigated in laboratory animals to detect possible side or toxic effects (17). Acute CBD administration by the oral, inhalatory or intravenous route did not induce any significant toxic effect in humans (38). In addition, chronic administration of CBD for 30 days to healthy volunteers, at daily doses ranging from 10 to 400 mg, failed to induce any significant alteration in neurological, psychiatric or clinical exams (17). Finally, in patients suffering from Huntington's disease, daily doses of CBD (700 mg) for 6 weeks did not induce any toxicity (39). Therefore, confirming results from animal studies, the available clinical data suggest that CBD can be safely administered over a wide dose range.
Clinical use
In 1848 the French psychiatrist Jacques-Joseph Moreau de Tour began to investigate the effects of cannabis. He proposed for the first time the use of the plant as an experimental psychotomimetic (40). Results from a recent study, obtained with more appropriate measurements and scales, agreed with Moreau's observation that D9-THC administration induces subjective, cognitive and behavioral changes that resemble endogenous psychosis, suggesting that D9-THC can, indeed, be used as an experimental psychotomimetic drug (41).
In 1982, a study investigating a possible interaction between D9-THC and CBD in healthy volunteers demonstrated that the latter drug could inhibit D9-THC-induced subjective changes that resembled symptoms of psychotic diseases (6) (Figure 1). In the same year, it was observed that patients admitted to a psychiatric hospital in South Africa, after the use of a variety of cannabis virtually devoid of CBD, showed much higher frequency of acute psychotic episodes than in other countries (42). These lines of evidence led to several investigations of a possible antipsychotic effect of CBD.
Figure 1. Percentage of healthy volunteers who exhibited psychotic-like effects after the ingestion of 0.5 mg/kg D9-tetrahydrocannabinol (D9-THC; lozenges) and a combination of 0.5 mg/kg D9-THC + 1 mg/kg cannabidiol (circles).
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In order to evaluate the antipsychotic effects of new drugs in healthy volunteers, a useful model is the perception of binocular depth inversion. When a picture is presented separately to each eye, with a slight difference in the angle, it induces a three-dimensional perception. The inversion of this picture from one eye to the other normally induces a change in convexity. This change may not be perceived if familiar objects (faces, for example) are presented, with the expected image predominating, which is illusory. Schizophrenic patients have difficulty in perceiving this illusory image, reporting a more veridical judgment. During antipsychotic treatment, the inverted faces were seen as more illusionary (43). This veridical judgment may also be obtained by the administration of psychotomimetic drugs such as nabilone, a D9-THC analogue. In this model, impairment of the perception of the illusory image induced by nabilone was attenuated by CBD, suggesting an antipsychotic-like effect of this compound (44).
Another important model used to evaluate antipsychotic-like activity in healthy volunteers is the administration of sub-anesthetic doses of ketamine. This glutamate-based model induces a psychotic reaction that mimics both positive and negative symptoms of schizophrenia (45). A double-blind crossover procedure was performed to study the effect of CBD in this model (46). Nine healthy volunteers were assigned randomly to the placebo or CBD (600 mg) groups in two experimental sessions separated by a 1-week interval. After being submitted to psychiatric assessment scales, the volunteers received placebo orally or the drug and rested for 65 min. An infusion pump was then installed and an intravenous bolus of S-ketamine (0.26 mg/kg) was administered during 1 min followed by a maintenance dose of 0.25 mg/kg for 30 min. A Clinician-Administered Dissociative States Scale (CADSS) was applied at the beginning of the sessions and 90 min after the bolus injection. The volunteers were asked to respond the scale according to the period during which they felt most symptomatic. CBD attenuated the effects of ketamine on the total score of the CADSS and also on each of its factors separately. This effect was significant for the depersonalization factor, further reinforcing the antipsychotic-like properties of CBD (Figure 2).
Figure 2. Depersonalization factor scores of the Clinician-Administered Dissociative States Scale for each healthy volunteer (lines) during intravenous ketamine infusion, after oral placebo or cannabidiol (CBD) (600 mg) administration. Bars indicate the mean ± SEM. *P < 0.05 compared to placebo (paired t-test) for 9 volunteers.
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In view of the safe profile of CBD administration in humans and in laboratory animals, we decided to perform open-label clinical trials in a reduced number of patients. In 1995, CBD was tested in a case study with a 19-year-old schizophrenic female patient who presented serious side effects after treatment with conventional antipsychotics (47). Following a wash-out period of 4 days this patient received increasing oral doses of CBD dissolved in oil, reaching 1500 mg/day, for 4 weeks. After this period, CBD administration was interrupted and placebo was administered for 4 days. Finally, the treatment was shifted to increasing doses of haloperidol that reached 12.5 mg/day. The psychiatric interviews were video-recorded and the symptoms were assessed by a blinded-psychiatrist using the Brief Psychiatric Rating Scale (BPRS). A significant improvement was observed during CBD treatment, while a worsening was observed when the administration was interrupted. The improvement obtained with CBD was not increased by haloperidol (Figure 3, patient A). Further supporting the safe profile of CBD, no side effects were observed, as assessed by the Ugvalg for Kliniske Undersgelser (UKU) scale (47).
Figure 3. Brief Psychiatric Rating Scale (BPRS) scores for 4 schizophrenic patients treated with cannabidiol (CBD). Patient A received up to 1500 mg/day CBD and patients B, C, and D received up to 1280 mg/day. Bars indicate BPRS scores for each schizophrenic patient at the end point after the oral administration of placebo, CBD and a control antipsychotic drug (haloperidol for patient A and olanzapine for patients B, C and D). Placebo was administered before and after CBD treatment. Patient A is a woman who presented serious side effects with typical antipsychotics. Patients B, C, and D are men previously treated with typical antipsychotics with no response.
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More recently, CBD was administered to three 22- or 23-year-old male patients with a diagnosis of schizophrenia who had not responded to typical antipsychotic drugs (48). They received placebo for 5 days in the hospital followed by CBD from the 6th to the 35th day. After this period, they received placebo for an additional 5 days, followed by olanzapine for at least 15 days. The dose of CBD was increased from 40 up to 1280 mg/day. The patients were assessed by two psychiatrists, who were blind to the doses administered, using the BPRS and UKU scales. No side effects were observed during CBD treatment, even at the higher dose of 1280 mg/day. A partial improvement was observed in one patient (Figure 3, patient B) while slight or no improvement was observed in the other two (Figure 3, patients C and D). However, the patients (C and D) were considered to be refractory, since they did not even respond to clozapine, a fact that may explain the lack of CBD effectiveness (48). Figure 3 shows the results obtained with the 4 schizophrenic patients treated so far with CBD. These studies suggest, therefore, that CBD has an antipsychotic-like profile in healthy volunteers and may possess antipsychotic properties in schizophrenic patients, but not in the resistant ones.
Confirming this suggestion, a preliminary report from a 4-week, double-blind controlled clinical trial, using an adequate number of patients and comparing the effects of CBD with amisulpride in acute schizophrenic and schizophreniform psychosis, showed that CBD significantly reduced acute psychotic symptoms after 2 and 4 weeks of treatment when compared to baseline. In this trial CBD did not differ from amisulpride except for a lower incidence of side effects (49).
In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed.
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Correspondence and Footnotes
Address for correspondence: A.W. Zuardi, Departamento de Neurologia, Psiquiatria e Psicologia Médica, FMRP, USP, Av. Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brasil. E-mail:
awzuardi@fmrp.usp.br
Several studies reviewed here were supported by FAPESP and CNPq. Received August 9, 2005. Accepted December 14, 2005.
[PDF] Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug
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Also, to say that MARIJUANA gives you those symptoms isnt nessicairly true. What TYPE of marijuana do you smoke. Indica? Sativa? Also, what grade? THose two strains differ greatly, especially depending on quality. I cant smoke schwaggy Sativa, it will knock me out. A good indica will prevent any memory loss or head trips, and give me a smooth body high. You might want to consider picking a different strain, or reducig your intake to only weekends or leisure time. 
