or all of the hallucinogenic drug experiences after a period of normal
consciousness in a person who used the drug previously. The flashbacks may last
from minutes to days or months (usually a few hours). The estimated prevalence of
flashbacks varies widely in studies, and the etiology is still unclear.
occur spontaneously or be triggered by exercise, stress, or another drug (e.g.,
64 Treatment remains anecdotal; no randomized, controlled trials have
evaluated the efficacy of pharmacotherapy for HPPD.
LSD and other classic hallucinogens have low potential for chronic use disorder.
There does not appear to be a clinically important withdrawal syndrome associated
with their use. The rapid development of tolerance that occurs with these drugs may
explain the intermittent use patterns commonly seen.
to “dance all night without getting tired.” Are these effects common with MDMA?
Merck Pharmaceuticals patented MDMA in 1914, but it was not until the 1950s
that its use was examined in animal studies, when the US Army Intelligence
investigated it as a “brainwashing” agent. By the late 1970s, a few therapists and
psychiatrists began using the drug with reported success in patients with a wide range
66 MDMA produces a very manageable and comfortable entactogenic
effect, during which the person has a clear sensorium. The experience can be
recalled in detail, and the insights gained during the session can be incorporated into
normal life. The public gave several names to this drug, such as ecstasy, XTC, Adam,
and M&Ms. The media became aware of the anecdotal reports from both
psychiatrists and people self-experimenting with MDMA. In 1985, the DEA made
MDMA a schedule I drug. Subsequently, supplies of the drug proliferated in the
public illicit marketplace, and its popularity soared. In 2001, after successful
lobbying by researchers interested in reinstituting MDMA in clinical practice, the
FDA granted approval for a pilot study investigating the therapeutic use of MDMA in
67 The effects of MDMA are mainly exerted by three neurochemical
mechanisms: blockade of serotonin reuptake, stimulation of serotonin release, and
stimulation of dopamine release.
68 The common psychological effects of MDMA
intoxication include an overall heightened sense of empathy, interpersonal closeness,
increased acceptance of others, and a powerful sense of well-being.
is influenced by set and setting. The amphetamine-like side effects include mydriasis,
tachycardia, sweating, increased energy and alertness, bruxism, nausea, and
70 Users generally ingest MDMA in tablet form, and the onset of action is
usually after 30 to 60 minutes. Some users take a “booster” dose after 2 hours. The
usual duration of action of MDMA is 4 to 6 hours, and the half-life is approximately
8 hours. MDMA users in the rave scene often “stack” multiple doses, and polydrug
use is common. The combined use of ecstasy and LSD is referred to as “candy
R.X.’s feelings of love for everyone are consistent with the empathogenic effects
of MDMA, whereas P.B. is enjoying the amphetamine-like effects of increased
The rave scene, with its crowded conditions and often-high ambient temperatures,
has contributed to many adverse effects associated with MDMA ingestion. Because
of their increased physical activity, the ravers may become dehydrated. Additionally,
supplies of MDMA have been notoriously unreliable. Many other drugs have been
misrepresented as MDMA, including other phenethylamines such as 3,4-
methylenedioxy-amphetamine (MDA) and paramethoxyamphetamine (PMA);
amphetamine; cocaine; opiates; ketamine; and dextromethorphan. The common
polydrug use practiced at raves compounds the problem. Dextromethorphan taken at
high doses for its dissociative properties competes with MDMA for hepatic
metabolism, and its anticholinergic effects block perspiration, potentially leading to
The most dangerous adverse physical effect of MDMA is hyperthermia. MDMA
has a slight affinity for the 5-HT2
receptor, and the increased body temperature may
be the result of this activation.
68 The hyperthermia has led to rhabdomyolysis, and
acute renal and hepatic failure, disseminated intravascular coagulation (DIC), and
71 DIC has been the most common cause of death. Treatment of hyperthermia
involves cooling measures and IV fluids. Benzodiazepines (e.g., lorazepam 2 mg IM
or IV) and dantrolene (1 mg/kg IV) may be helpful. Other adverse physical effects
can include hypertension, cardiac arrhythmias, convulsions, cerebrovascular
accident, hepatitis, and hyponatremia (from over ingestion of water as a harm
reduction measure to avoid hyperthermia).
In 2011, there were 22,498, emergency
department visits associated with MDMA use.
72 Adverse psychological effects are
also possible, including anxiety, depression, panic attacks, agitation, paranoia, and
rarely psychosis. The treatment of these psychological adverse effects is the same as
for those associated with the classic hallucinogens, including talk-down therapy and
benzodiazepine administration. P.B. may be suffering from MDMA-induced
hyperthermia and needs urgent medical evaluation.
CASE 90-8, QUESTION 3: R.X. has read in the newspaper that MDMA is associated with “brain damage”
Animal studies have consistently demonstrated long-term MDMA-induced
serotonin depletion. This has been evidenced by lower levels of serotonin, decreased
metabolite levels, lowered levels of tryptophan hydroxylase, and loss of serotonin
66 This may explain the induction of panic attacks for chronic
users. MDMA damages serotonin axonal projections; axonal resprouting and
regeneration do occur, but it is unclear whether these new projections are
66,73 Both hepatotoxicity and neuronal toxicity occur with MDMA use and is
suspected to be due to oxidative stress, mitochondrial dysfunction, and
Several retrospective studies in humans have claimed lowered cognitive
performance in MDMA users compared with nonusers. These studies have
confounding variables, such as other drug use and adulterant exposure and lifestyle
Use of MDMA does not appear to produce physical dependence, but some users
may become psychologically dependent. Tolerance to the empathogenic effects
develops rapidly and may last 24 to 36 hours. This may explain in part the more
common practice of sporadic dosing of the drug.
57,69 No distinctive withdrawal
syndrome has been described that would require pharmacologic treatment.
Marijuana is the most widely used illicit substance in the United States. In 2014, 35.1
million Americans reported using marijuana in the past year.
ingredient in the Cannabis sativa plant is Δ-9-tetrahydrocannabinol (THC), although
the plant is known to contain more than 70 cannabinoids.
dried, chopped leaves and flowers of the Cannabis plant (grass, pot, weed, green
bud, chronic, mary jane) are rolled into a cigarette paper (marijuana cigarette, known
as a joint or blunt; a “roach” is the butt of the marijuana cigarette) or smoked in a
pipe or water pipe (“bong”). Each joint usually weighs 0.5 to 1 g, for a THC content
of about 5 mg (very weak), 30 mg (average), or 150 mg (highest-quality sinsemilla).
The sinsemilla (Spanish for “without seeds”) growing technique involves separating
the female plants from the males before pollination occurs. This results in female
plants with higher amounts of THC, up to 14%.
The raw resin of the Cannabis plant can be pressed into cakes, balls, or sticks,
called hashish (“hash,” “temple balls”), which is smoked or eaten. Hashish can
contain up to 8% THC. The oils can be extracted from the plant with organic solvents
to produce “hash oil,” perhaps the most potent Cannabis derivative, with THC
Researchers in cannabinoid neurobiology have discovered two cannabinoid
receptors in the CNS: CB1 and CB2
; however, additional receptors have been
proposed. Research has demonstrated that the main pharmacologic and addictive
effects are almost completely mediated by the CB1
endogenous cannabinoids (endocannabinoids) that act at the cannabinoid receptors
76 The best known are arachidonic acid ethanolamide
(anandamide) and 2-arachidonoylglycerol (2-AG).
76 Considerable evidence exists
supporting the role of THC–opioid interactions with enhanced antinociception.
Cannabinoids have been shown to release endogenous opioids, and cannabinoid
receptors colocalize with substance P (the neurotransmitter responsible for
transmitting pain information) receptors in the striatum. Subsequently, investigation
of THC as an adjunct to opioid treatment of pain, prevention of opioid tolerance, and
Marijuana’s therapeutic potential has been the center of much public controversy.
Research on the effects of cannabinoids has led to several potential therapeutic uses,
including relief of nausea and vomiting, appetite stimulation, and treatment of pain,
epilepsy, glaucoma, and movement disorders (Parkinson disease, Huntington disease,
Tourette syndrome, multiple sclerosis).
In 1999, the State of California passed the
law SB847, which commissioned the University of California to establish the Center
for Medicinal Cannabis Research (CMCR) to expand scientific knowledge on
purported therapeutic usages of marijuana. The center’s 2010 report to the California
legislature and governor presented clinical trial findings demonstrating that cannabis
has analgesic effects in pain conditions secondary to injury or disease and that
cannabis reduces MS spasticity.
78 A synthetic form of THC, dronabinol, is available
as prescription tablets, and a synthetic cannabinoid, nabilone (Cesamet), is available
as capsules, but advocates of medicinal marijuana use argue that inhalation allows
for faster onset and easier titration of the dose. In addition, nauseated patients want to
avoid the oral route of administration. Future research focuses on developing a safer
delivery system that will be reliable, rapid, and safe. An oromucosal spray, Sativex,
derived from botanical material, is under investigation in the United States. The
principal active components are THC and cannabidiol. This cannabis extract spray
has been approved in Canada, and is also being used in the United Kingdom. A
capsule formulation containing a mixed ratio of THC and cannabidiol produced by
Cannador in Germany is also available.
75 Other alternative delivery methods may
include vaporization, patches, and suppositories.
P.H.’s symptoms are consistent with marijuana use?
The pharmacologic effects sought by most users of cannabis products are sedation,
mental relaxation, euphoria, and mild hallucinogenic effects, and these effects depend
on set and setting. Other common effects that are usually perceived as pleasurable
include silliness, subjective slowing of time, gregariousness, hunger, and mild
perceptual changes of all the senses that engender an absorbing fascination with
music, eating, and other sensual and sensory activities. The state of mind generated is
referred to as “stoned,” “high,” “loaded,” “wasted,” and many other colloquial
terms. Smoking marijuana typically causes numbness and tingling of the extremities,
light-headedness, loss of concentration, and a floating sensation in the first 3 or 4
minutes. Some of these effects are probably caused by the hyperventilation
associated with deep inhalation of the smoke (referred to as a “hit” or “toke”) and
breath holding to allow maximal absorption from the lungs. During the first 10 to 30
minutes, the user may experience tachycardia (possibly palpitations), mild
diaphoresis, conjunctival injection (“red eye”), drying of the mouth, weakness,
postural hypotension, periods of tremulousness, incoordination, and ataxia along with
euphoria and the mental effects described above. These effects usually resolve by 1
to 3 hours and are followed by a 30- to 60-minute period of sleepiness before
complete clearing and return to normal consciousness. Oral ingestion of cannabis
products may delay the onset of effects by 45 to 60 minutes and prolong the
75 P.H. is experiencing euphoria, giddiness, and increased appetite,
consistent with marijuana intoxication.
is beating rapidly. He starts to panic. Is P.H.’s reaction caused by the marijuana?
Consistent with its widespread use, marijuana was the second most frequently
mentioned illicit substance in emergency department episodes in the United States in
2007. A total of 308,547 marijuana-related emergency department (ED) visits were
58 These visits include marijuana in combination with other drugs.
As the percentage of THC has increased in marijuana, so have the ED visits. The
majority of ED visits are from unexpected reactions, such as anxiety, paranoia, and
attacks. Despite these numbers, there are no documented cases of fatality in
humans from marijuana overdose, and adverse effects tend to be self-limiting and
often do not require medical treatment.
A syndrome consisting of anxiety, paranoia, depersonalization, disorientation, and
confusion that can lead to panic states and incapacitating fear is perhaps the most
frequently reported adverse effect of marijuana. Comforting reassurance (talk-down)
and reducing stressful stimuli can alleviate this condition. The dysphoria and anxiety
usually resolve in a few hours or less with such an approach. More severe incidents
that evolve into panic reactions that are not resolved by sympathetic counseling may
be relieved with oral benzodiazepine therapy in a dose equivalent to 5 to 10 mg of
57 These adverse psychological reactions to cannabis products commonly
occur with inexperienced users, high doses, concomitant use of other psychoactive
drugs, and overtly stressful situations. Severe reactions requiring pharmacologic
therapy are rare. A review of the literature found that cannabis use increases the risk
of developing psychotic disorders among vulnerable or predisposed individuals and
negatively affects the course of preexisting chronic psychosis.
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